Alternative titles; symbols
Other entities represented in this entry:
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q37.3 | {Multiple sclerosis, disease progression, modifier of} | 126200 | Multifactorial | 3 | PDCD1 | 600244 |
| 6p21.32 | {Multiple sclerosis, susceptibility to, 1} | 126200 | Multifactorial | 3 | HLA-DRB1 | 142857 |
| 6p21.32 | {Multiple sclerosis, susceptibility to, 1} | 126200 | Multifactorial | 3 | HLA-DQB1 | 604305 |
A number sign (#) is used with this entry because of evidence that susceptibility to multiple sclerosis-1 (MS1) is associated with variation in certain HLA genes on chromosome 6p21, including HLA-A (142800), HLA-DRB1 (142857), HLA-DQB1 (604305), HLA-DRA (142860), on chromosome 6p21.3.
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system (CNS) with various degrees of axonal damage. MS affects mainly young adults with predominance for females. The disorder often leads to substantial disability (summary by Bomprezzi et al., 2003).
Genetic Heterogeneity of Susceptibility to Multiple Sclerosis
Additional MS susceptibility loci include MS2 (612594) on chromosome 10p15, MS3 (612595) on chromosome 5p13, MS4 (612596) on chromosome 1p36, and MS5 (614810), conferred by variation in the TNFRSF1A gene (191190) on chromosome 12p13.
Familial aggregation in this disease is not strong; however, in a series of 91 cases, Bas (1964) found 3 instances of affected mother and daughter. From an extensive review, McAlpine (1965) concluded that the risk to a first-degree relative of a patient with multiple sclerosis is at least 15 times that for a member of the general population but that no definite genetic pattern is discernible. MacKay and Myrianthopoulos (1966) found that concordance is slightly higher in monozygotic than in dizygotic twins and that multiple sclerosis is about 20 times more frequent among relatives of probands than in the general population. The frequency declined as the relationship to the proband became more remote. They concluded that the family data were consistent with autosomal recessive inheritance with reduced penetrance but that exogenous factors must be very strong.
Ebers et al. (1986) surveyed 10 multiple sclerosis clinics across Canada and found 27 monozygotic and 43 dizygotic twin pairs with multiple sclerosis in at least 1 of each pair. Seven (25.9%) of the monozygotic pairs and 1 (2.3%) of the dizygotic pairs were concordant for multiple sclerosis. The concordance rate for nontwin sibs was 1.9%. Kinnunen et al. (1987) also reported a nationwide series of twins. The higher concordance rate in monozygotic twins despite the low recurrence risk in families is consistent with a polygenic model (Ebers, 1988). The situation may be the same as that for Hodgkin disease; see 236000.
Ebers et al. (1995) concluded that familial aggregation in MS is genetically determined. They could detect no effect of shared environment in a study of adopted index cases and MS cases with adopted relatives. Waksman (1995), in a commentary, reviewed evidence suggesting that environmental factors are not completely excluded.
Sadovnick et al. (1996) studied familial aggregation of multiple sclerosis in a sample of 16,000 multiple sclerosis cases in Canada. The age-adjusted multiple sclerosis rate in half sibs of index cases was 1.32%, compared with 3.46% in full sibs. There were similar risks in half sibs raised together and those raised apart. The risk for maternal and paternal half sibs was similar. They quoted previous studies which indicated a 300-fold increase of risk for monozygotic twins of index cases (Ebers et al., 1986) and 20- to 40-fold increase for biologic first-degree relatives (Mumford et al., 1994). Together, these studies suggested that familial aggregation in multiple sclerosis is genetic. However, since most monozygotic twins remain discordant, nongenetic risk factors are clearly important.
Steinman (1996) stated that the concordance rate among monozygotic twins is 30%, a 10-fold increase over that in dizygotic twins or first-degree relatives. The higher incidence rate among monozygotic twins emphasizes the importance of genetic factors, but the discordance rate of 70% among identical twins illuminates the role of nongenetic factors on disease penetrance.
From a review of genomic screens, Dyment et al. (1997) concluded that a number of genes with interacting effects are likely and that no single region has a major influence on familial risk. An HLA haplotype associated with the disease has been identified, but HLA contributes only modestly to overall susceptibility.
The Multiple Sclerosis Genetics Group (1998) reported demographic and clinical characteristics of 89 multiplex families. The mean difference in age of onset between probands and affected sibs was 8.87 years. There was a higher concordance rate among sister pairs than among brother pairs, but there was no difference in affection rate between sons and daughters of either affected mothers or affected fathers.
Chataway et al. (1998) reported a follow-up on the studies in progress in the United Kingdom for a systematic genome screen to determine the genetic basis of MS. They stated that a gene of major effect had been excluded from 95% of the genome and one with a moderate role from 65%. The results to date suggested that multiple sclerosis depends on independent or epistatic effects of several genes, each with small individual effects, rather than a very few genes of major biologic importance.
Sadovnick et al. (1999) provided familial risk data in a practical format for use during genetic counseling for MS.
Noseworthy et al. (2000) included genetic factors in an extensive review of multiple sclerosis.
Marrosu et al. (2002) examined the recurrence risk in sibs of 901 Sardinian MS patients and factors influencing risk, such as patient and sib sex, patient age at onset, sib birth cohort, and presence of affected relatives other than sibs. To evaluate the presence of distant familial relationships among patients, extended pedigrees were traced for all patients who were born in 1 Sardinian village. The authors found that 23 brothers and 36 sisters of the 2,971 sibs were affected with MS. Recurrence risk was greater in sibs of index patients with onset age less than 30 years (increased risk 2.33 times) and with a relative with MS other than a sib or parent (increased risk 2.90 times). Pedigree analysis of patients from the 1 village showed that all 11 patients descended from 3 pairs of ancestors, whereas no cases occurred in the remaining 2,346 inhabitants. In descendants from the 3 couples, MS prevalence was dramatically greater than the regional average and 1.5 times greater than that observed in sibs of affected cases.
In a longitudinal population-based study of twins with MS in Canada, Willer et al. (2003) analyzed 370 index cases from 354 pairs and obtained a probandwise concordance rate of 25.3% in monozygotic twin pairs, 5.4% in dizygotic pairs, and 2.9% for their nontwin sibs. The excess concordance in monozygotes was derived primarily from female pairs with a probandwise concordance rate of 34% for female monozygotic pairs compared to 3.8% for female dizygotic pairs. Willer et al. (2003) did not demonstrate a monozygotic/dizygotic difference in males, but they noted that the sample size was small.
Ristori et al. (2006) analyzed data from 216 Italian twin pairs in which at least 1 twin had MS, including 198 pairs from continental Italy and 18 pairs from Sardinia. These regions have estimated disease prevalences of 61.1 and 147.1 per 100,000 individuals, respectively. They found a twinning rate of 0.62% among MS patients, which was significantly less than the twinning rate of the general population. In continental Italy, concordance for MS was 14.5% and 4.0% for mono- and dizygotic twins, respectively. In Sardinia, concordance for MS was 22.2% for monozygotic twins and zero for dizygotic twins. Results from a questionnaire on nonheritable risk factors given to a subset of patients suggested a link to infection. Ristori et al. (2006) concluded that nonheritable variables play a role in the development of MS in Mediterranean regions, and they suggested a role for protective factors in particular.
In a study of 79 MS-discordant monozygotic twin pairs, Islam et al. (2007) found that childhood sun exposure offered protection against disease development. Depending on sun exposure, the odds ratio ranged from 0.25 to 0.57. The authors concluded that early sun exposure is protective against MS, independent of genetic susceptibility. The effect was significant only for female twins; however, there were only 13 male twin pairs. Islam et al. (2007) hypothesized that exposure to ultraviolet radiation may induce immunosuppression via several mechanisms.
In a cohort of 807 avuncular MS families with 938 affected aunt/uncle-niece/nephew pairs ascertained from a longitudinal, population-based Canadian database, Herrera et al. (2008) observed an increased number of avuncular pairs connected through unaffected mothers compared to unaffected fathers (p = 0.008). To restrict confounders introduced by families with multiple pairs, the overall number of maternal and paternal families were compared, and the comparison revealed a significantly higher number of maternal families (p = 0.038). The findings indicated a maternal parent-of-origin effect in susceptibility to MS.
Baranzini et al. (2010) reported the genome sequences of one MS-discordant monozygotic twin pair, and mRNA transcriptome and epigenome sequences of CD4+ lymphocytes from 3 MS-discordant, monozygotic twin pairs. No reproducible differences were detected between cotwins among approximately 3.6 million SNPs or approximately 0.2 million insertion-deletion polymorphisms. Nor were any reproducible differences observed between sibs of the 3 twin pairs in HLA haplotypes, confirmed MS susceptibility SNPs, copy number variations, mRNA and genomic SNP and insertion-deletion genotypes, or the expression of approximately 19,000 genes in CD4+ T cells. Only 2 to 176 differences in the methylation of approximately 2 million CpG dinucleotides were detected between sibs of the 3 twin pairs, in contrast to approximately 800 methylation differences between T cells of unrelated individuals and several thousand differences between tissues or between normal and cancerous tissues. In the first systematic effort to estimate sequence variation among monozygotic cotwins, Baranzini et al. (2010) did not find evidence for genetic, epigenetic, or transcriptome differences that explained disease discordance. Baranzini et al. (2010) noted that these were the first female, twin, and autoimmune disease individual genome sequences reported.
In patients with multiple sclerosis, treatment with interferon-beta reduces clinical exacerbations and disease burden via multiple immunomodulatory actions, including augmentation of apoptosis. In 10 of 18 patients with MS who responded to interferon-beta therapy, Sharief and Semra (2002) found a significant decline in cellular survivin expression after 6 and 12 months. Specifically, T-cell susceptibility to etoposide-induced apoptosis was increased in these patients, findings that were confirmed by in vitro experiments. These results suggested at least 1 mechanism by which interferon-beta treatment is effective in some patients with MS.
Miller et al. (2003) and Ghosh et al. (2003) reported clinical trials of natalizumab, a recombinant anticlonal antibody against alpha-4-integrins (192975), for the treatment of multiple sclerosis and Crohn disease (see 266600), respectively. Miller et al. (2003) reported that a group of patients with multiple sclerosis who received monthly injections of natalizumab had significantly fewer new inflammatory central nervous system lesions than the placebo group (a reduction of approximately 90%) and had approximately half as many clinical relapses. Ghosh et al. (2003) reported that patients with Crohn disease also had a favorable response to natalizumab, with remission rates that were approximately twice as high in patients who received 2 injections of the antibody as in patients from the placebo group. The rate of adverse events did not differ significantly between the natalizumab and placebo groups in either trial. Von Andrian and Engelhardt (2003) stated that natalizumab probably has therapeutic effects because it blocks the ability of alpha-4/beta-1 and alpha-4/beta-7 to bind to their respective endothelial counter-receptors, VCAM1 (192225) and MADCAM1 (102670). In both disorders, lesions result from autoimmune responses involving activated lymphocytes and monocytes. Alpha-4-integrin is expressed on the surface of these cells and plays an integral part in their adhesion to the vascular endothelium and migration into the parenchyma.
Williams and Johnson (2004) reported that 3 (8.6%) of 35 consecutive patients with neuroretinitis had previously been diagnosed with MS, suggesting that neuroretinitis is a late finding in MS rather than an initial presenting event. All 3 patients had been treated with interferon-beta before or concurrently with the development of neuroretinitis, which raised the question of whether interferon-beta might have been a causative agent of neuroretinitis in the patients.
Hoffmann et al. (2008) used high-resolution HLA class I and II typing to identify 2 HLA class II alleles associated with the development of antibodies to interferon-B in the treatment of multiple sclerosis. In 2 independent continuous and binary-trait association studies, HLA-DRB1*0401 and HLA-DRB1*0408 (odds ratio: 5.15), but not other HLA alleles, were strongly associated with the development of binding and neutralizing antibodies to interferon-B. The associated HLA-DRB1*04 alleles differ from nonassociated HLA-DRB1*04 alleles by a glycine-to-valine substitution in position 86 of the epitope-binding alpha-helix of the HLA class II molecule. The peptide-binding motif of HLA-DRB1*0401 and *0408 might promote binding and presentation of an immunogenic peptide, which may eventually break T cell tolerance and facilitate antibody development to interferon-beta. In summary, Hoffmann et al. (2008) identified genetic factors determining the immunogenicity of interferon-beta, a protein-based disease-modifying agent for the treatment of MS.
Kumpfel et al. (2008) identified 20 patients with MS who carried a heterozygous variant (R92Q) in the TNFRSF1A gene (191190) and had clinical features consistent with late-onset of the tumor necrosis factor receptor 1-associated periodic syndrome (TRAPS; 142680), including myalgias, arthralgias, headache, fatigue, and skin rashes. Most of these patients experienced severe side effects during immunomodulatory therapy for MS. Kumpfel et al. (2008) concluded that patients with coexistence of MS and features of TRAPS should be carefully observed during treatment.
Comabella et al. (2009) performed a genomewide association study in 53 MS patients who responded to beta-interferon treatment and 53 nonresponders in an attempt to identify a genetic basis influencing the variable response observed in patients. The discovery study and a replication study in 49 additional responders and 45 additional nonresponders pointed to 18 SNPs in various genes that showed a possible association (uncorrected p values of less than 0.05). The findings indicated that response to beta-interferon is a complex and polygenic trait.
Hla and Brinkmann (2011) and Soliven et al. (2011) provided reviews of the neurobiology of sphingosine 1-phosphate (S1P) signaling in the CNS via the S1P receptors (S1PRs), of which there are 5 subtypes (see, e.g., S1PR1; 601974), and discussed the benefit of the S1PR modulator, fingolimod (FTY720), in the treatment of MS. FTY720 was approved in 2010 as the first oral treatment for relapsing MS in the U.S. One effect of FTY720 is to downmodulate S1PR1 to retain circulating naive and central memory T and B lymphocytes in lymph nodes, while sparing effector memory T cells. The result is to reduce the infiltration of autoreactive lymphocytes into the CNS, causing a slowing of the disease process (Hla and Brinkmann, 2011). In addition, S1PR1 is expressed in oligodendrocytes, astrocytes, neurons, and microglia, where it may modulate cell survival, process dynamics, migration, differentiation, activation, and crosstalk. The presence of S1PRs on multiple cell lines in the CNS may represent a mechanism by which FTY720 may contribute to observed neurologic benefit in patients with MS via neuroprotective and regenerative effects (Soliven et al., 2011).
Steinman (1996) stated that multiple sclerosis is the most common autoimmune disease involving the nervous system and that approximately 250,000 individuals in the United States have MS.
Pugliatti et al. (2002) demonstrated a hotspot of MS in the southwestern part of Sassari province in Sardinia, bordering with the commune of Macomer, where MS was once hypothesized as having occurred as an epidemic. These areas of MS clustering comprised the Common Logudorese linguistic domain. The Catalan area, which is linguistically and genetically distant from the remaining Sardinian domains, did not show such high estimates.
Bell and Lathrop (1996) reviewed the work on linkage analysis in multiple sclerosis.
MS1 Locus Associated with HLA on Chromosome 6p21.3
Terasaki et al. (1976) described a high frequency of a B-lymphocyte antigen (group 4) in multiple sclerosis. Associations with HLA-A3, HLA-B7, and HLA-Dw2 have been demonstrated also. The association with Dw2 seems to be especially strong and probably indicates an immune-response mechanism.
Zipp et al. (1995) compared the production of lymphotoxin (tumor necrosis factor-beta (TNFB; 153440) and tumor necrosis factor-alpha (TNFA; 191160)) by T-cell lines isolated from multiple sclerosis patients in normal controls. There was greater production in those lines derived from HLA-DR2-positive donors than from those that were HLA-DR2-negative. Although both lymphotoxin and tumor necrosis factor-alpha are encoded within the HLA region, there was no significant association of cytokine production with individual lymphotoxin or TNF alleles. The authors suggested that the association of multiple sclerosis with HLA-DR2 results from a propensity of T cells to produce increased amounts of lymphotoxic TNF, controlled by a polymorphic gene in this region.
In a linkage analysis of 72 pedigrees, Tiwari et al. (1980) found evidence of linkage between HLA and a hypothesized multiple sclerosis susceptibility gene (MSSG) for both dominant and recessive models of inheritance and for a wide range of penetrance values. They suggested that the MSSG is located 15-20 recombination units from HLA, probably on the B-D side. The analysis showed no evidence of linkage heterogeneity, and the lod scores appeared not to be inflated artificially by the association of multiple sclerosis with HLA-B7. In linkage studies with HLA, Haile et al. (1980) assumed a dominant model of inheritance. With a penetrance value of 0.05, a maximal lod score of 2.411 was obtained for recombination fraction of 0.10. With high penetrance values, lod scores did not support linkage. Francis et al. (1987) did a study of familial MS: 10 affected sib pairs and 4 instances of affected parent and offspring, together with 1 family with 3 affected sibs and another with 2 affected sibs and an affected parent. They concluded that an MS susceptibility gene exists in the HLA complex in linkage disequilibrium with HLA-D.
In a 2-stage genome screen, Sawcer et al. (1996) found 2 principal regions of linkage with multiple sclerosis: 17q22 and the HLA region on 6p21. The results were considered compatible with genetic models involving epistatic interaction between these and several additional genes. A similar complete genomic screen by the Multiple Sclerosis Genetics Group (1996) yielded results suggesting a multifactorial etiology, including both environmental and multiple genetic factors of moderate effect. The results supported a role for the MHC region on 6p.
Ebers et al. (1996) found maximum lod scores (MLS) greater than 1 for MS at 5 loci on chromosomes 2, 3, 5, 11, and X. Two additional datasets containing 44 and 78 sib pairs respectively, were used to further evaluate the HLA region on 6p21 and a locus on chromosome 5 with an MLS of 4.24. Markers within 6p21 gave an MLS of 0.65. However, D6S461, just outside the HLA region, showed significant evidence for linkage disequilibrium by the transmission disequilibrium test (TDT), in all 3 datasets, suggesting to the investigators a modest susceptibility locus in this region. The chromosome 5p results from 3 datasets (222 sib pairs) yielded a multipoint MLS of 1.6. Ebers et al. (1996) concluded that the results support the genetic epidemiologic evidence that several genes interact epistatically to determine heritable susceptibility.
In a collaborative study, Haines et al. (1998) studied a data set of 98 multiplex MS families to test for an association to the HLA-DR2 allele in familial MS and to determine if genetic linkage to the major histocompatibility complex (MHC) was due solely to such an association. Three highly polymorphic markers (HLA-DR, D6S273, and TNF-beta) in the MHC demonstrated strong genetic linkage (parametric lod scores of 4.60, 2.20, and 1.24, respectively) and a specific association with the HLA-DR2 allele was confirmed; the transmission/disequilibrium test (TDT) yielded a P value of less than 0.001. Stratifying the results by HLA-DR2 status showed that the linkage results were limited to families segregating HLA-DR2 alleles. These results demonstrated that genetic linkage to the MHC can be explained by the HLA-DR2 allelic association. They also indicated that sporadic and familial MS share a common genetic susceptibility. In addition, preliminary calculations suggested that the MHC explains between 17% and 62% of the genetic etiology of MS. This heterogeneity is also supported by the minority of families showing no linkage or association with loci within the MHC. In a study of the Sardinian population, Marrosu et al. (1998) tested the role of other class II HLA loci in MS predisposition.
Fernandez-Arquero et al. (1999) found a significant correlation between a TNFA-376 promoter polymorphism with susceptibility to multiple sclerosis in a study of 238 patients and 324 controls. This association was independent of HLA class II association and synergistically increased risk in the presence of HLA-DRB1*1501. In a follow-up case-control study of 241 Spanish patients with MS, Martinez et al. (2004) confirmed an association between MS and the TNFA-376 polymorphism. Noting that another study (Weinshenker et al., 2001) had failed to replicate the findings in a mostly northern European population, Martinez et al. (2004) concluded that the positive association is specific to the Spanish white population or that only studies in this population have sufficient power because of the higher frequency of the TNFA-376 allele.
Ligers et al. (2001) assessed the importance of the HLA-DR locus to multiple sclerosis susceptibility in 542 sib pairs with MS and in their families. By genotyping 1,978 individuals for HLA-DRB1 (142857) alleles, they confirmed the well-established association of MS with HLA-DRB1*15 (HLA-DRB1*1501 and HLA-DRB5*0101, 604776), by the transmission/disequilibrium test. They obtained significant evidence of linkage throughout the whole dataset (mlod = 4.09; 59.9% sharing). Surprisingly, similar sharing was also observed in 58 families in which both parents lacked the DRB1*15 allele (mlod = 1.56; 62.7% sharing; p = 0.0081). The findings suggested that the notion that HLA-DRB1*15 is the sole MHC determinant of susceptibility in northern European populations with MS may be incorrect. The possibility remained that the association of MS with HLA-DRB1*15 is due to linkage disequilibrium with a nearby locus and/or to the presence of disease-influencing allele(s) in DRB1*15-negative haplotypes.
Lang et al. (2002) examined the association of MS with HLA-DRB1*1501 and -DRB5*0101 polymorphisms by determining the antigen-recognition profile of an MS patient with a relapsing-remitting disease course. A T-cell receptor (TCR) from the patient recognized both DRB1*1501-restricted myelin basic protein (MBP; 159430) (residues 85 to 99) and DRB5*0101-restricted Epstein-Barr virus DNA polymerase peptide. The crystal structure of both DRB-antigen complexes revealed a marked degree of structural equivalence at the surface presented for TCR recognition, with 4 identical TCR-peptide contacts. Lang et al. (2002) concluded that these similarities support the concept of molecular mimicry (in structural terms, a similarity of charge distribution) involving HLA molecules and suggested that these structural details may explain the preponderance of MHC class II associations in HLA-associated diseases. They noted the findings of Madsen et al. (1999) with transgenic mice, which also showed that MBP(85 to 99) associated with HLA-DRB1*1501 was involved in the development of an MS-like disease.
Models of disease susceptibility in MS often assume a dominant action for the HLA-DRB1*1501 (see 142857) allele and its associated haplotype, DRB1*1501-DQB1*0602, also known as DR2. Barcellos et al. (2003) found a dosage effect of HLA-DR2 haplotypes on MS susceptibility. Two copies of a susceptibility haplotype further increased disease risk. They also reported that DR2 haplotypes modify disease expression. There was a paucity of benign MS and an increase of severe MS in individuals homozygous for DR2.
Mattila et al. (2001) genotyped 97 patients with MS and 100 healthy controls and found an association between the pp polymorphism in the ESR1 (133430) gene on chromosome 6q25 in combination with the previously described association of HLA-DR2 in women with MS (odds ratio for MS in women with both ESR1pp and HLA-DR2 was 19.4 vs 5.1 with DR2 alone).
Marrosu et al. (2001) scanned an 11.4-Mb region encompassing the whole HLA complex on chromosome 6p21.3 for MS association in the founder population of Sardinia. Using 19 microsatellite markers, single-nucleotide polymorphisms (SNPs) within 12 candidate genes, and the extended transmission disequilibrium test (ETDT), a peak of association represented by the 3 adjacent DRB1, -DQA1, and -DQB1 loci was detected in the class II region. Two additional less significant areas of association were detected, respectively, in the centromeric side of the class II region at the DPB1 locus and, telomeric of the classically defined class I loci, at the D6S1683 microsatellite. Conditional ETDT analysis indicated that these regions of association could be independent of each other. Within the main peak of association, DRB1 and DQB1 contributed to the disease association independently of each other, whereas DQA1 had no detectable primary genetic effects. Five DQB1-DRB1 haplotypes positively associated with MS in Sardinia, which consistently included all the haplotypes previously found associated with MS in the various human populations. The authors concluded that their results are consistent with a multilocus model of the MHC-encoded susceptibility to MS.
In 30 patients with relapsing-remitting MS, which the authors termed 'benign,' and 25 patients with secondary-progressive MS, which the authors termed 'malignant,' from a region in northeast Italy, Perini et al. (2001) found a positive association between the HLA-DR13 haplotype (particularly the DRB1*1302 allele) and 'benign' MS. The DR13 haplotype was detected in 40% of patients with 'benign' MS, in 4% with 'malignant' MS, and in 16% of normal controls.
Association of MS with the HLA-DRB1*1501-DQB1*0602 haplotype has repeatedly been demonstrated in high-risk (northern European) populations. African populations are characterized by greater haplotypic diversity and distinct patterns of linkage disequilibrium compared with northern Europeans. To better localize the HLA gene responsible for MS susceptibility, Oksenberg et al. (2004) performed case-control and family-based association studies for the DRB1 and DQB1 loci in a large and well-characterized African American dataset. A selective association with HLA-DRB1*15 was revealed, indicating a primary role for the DRB1 locus in MS independent of DQB1*0602. This finding was unlikely to be solely explained by admixture, since a substantial proportion of the susceptibility chromosomes from African American patients with MS displayed haplotypes consistent with an African origin.
Genetic susceptibility to multiple sclerosis is associated with genes of the major histocompatibility complex (MHC), particularly HLA-DRB1 and HLA-DQB1. To clarify whether HLA-DRB1 itself, nearby genes in the region encoding the MHC, or combinations of these loci underlie susceptibility to multiple sclerosis, Lincoln et al. (2005) genotyped 1,185 Canadian and Finnish families with multiple sclerosis with a high-density SNP panel spanning the genes encoding the MHC and flanking genomic regions. Strong associations in Canadian and Finnish samples were observed with blocks in the HLA-II genomic region, but the strongest association was with HLA-DRB1. Conditioning on either HLA-DRB1 or the most significant HLA class II haplotype block found no additional block or SNP association independent of the HLA class II genomic region. This study therefore indicated that MHC-associated susceptibility to multiple sclerosis is determined by HLA class II alleles, their interactions, and closely neighboring variants.
Dyment et al. (2004) reported a multistage genome scan of 552 sib pairs from 442 MS families. Only markers at chromosome 6p showed significant evidence for linkage (MLOD = 4.40), while other regions were only suggestive. The replication analysis involving all 552 affected sib pairs confirmed suggestive evidence for 5 locations, namely, 2q27, 5p15, 18p11, 9q21, and 1p31. The overall excess allele sharing observed for the entire sample was due to increased allele sharing within the DRB1*15 negative subgroup alone. The authors concluded that their observations supported a model of genetic heterogeneity between HLA and other genetic loci.
Gregersen et al. (2006) reported that the MHC HLA-DR2 haplotype composed of DRB1*1501 (DR2b) and DRB5*0101 (DR2a), which predisposes to multiple sclerosis, shows more extensive linkage disequilibrium than other common Caucasian HLA haplotypes in the DR region and thus seems likely to have been maintained through positive selection. Characterization of 2 multiple sclerosis-associated HLA-DR alleles at separate loci by a functional assay in humanized mice indicates that the linkage disequilibrium between the 2 alleles may be due to a functional epistatic interaction, whereby 1 allele modifies the T-cell response activated by the second allele through activation-induced cell death. This functional epistasis is associated with a milder form of multiple sclerosis-like disease. Gregersen et al. (2006) suggested that such epistatic interaction might prove to be an important general mechanism for modifying exuberant immune responses that are deleterious to the host and could also help to explain the strong linkage disequilibrium in this and perhaps other HLA haplotypes.
The International Multiple Sclerosis Genetics Consortium (2007) found evidence that variation in the HLA-C gene (142840) influences susceptibility to MS independent of the HLA-DRB1 gene. Using a combination of microsatellite, SNP, and HLA typing in a family-based and case-control cohort beginning with a sample of 1,201 MS patients, the authors analyzed 264 patients without the common DRB1*1501, DRB1*03, and DRB1*0103 alleles. Significant association was found with the HLA-C locus (p = 5.9 x 10(-5)). Specifically, the HLA-C*05 allele was underrepresented in patients compared to controls (p = 3.3 x 10(-5)), suggesting a protective effect.
In a multistage genomewide association study involving a total of 1,540 multiple sclerosis family trios, 2,322 case subjects, and 5,418 control subjects, the International Multiple Sclerosis Genetics Consortium (2007) used the HLA-DRA (142860) A/G SNP rs3135388 as a proxy for the DRB1*1501 allele (complete concordance between the rs3135388 A allele and DRB1*1501 was found in 2,730 of 2,757 subjects for whom data were available) and confirmed unequivocally that the HLA-DRA locus was associated with MS (p = 8.94 X 10(-81); OR, 1.99).
Baranzini et al. (2009) conducted a genomewide association study in 978 well-characterized individuals with MS and 883 group-matched controls. The authors compared allele frequencies and assessed genotypic influences on susceptibility, age of onset, disease severity, as well as brain lesion load and normalized brain volume from MRI exams. Top SNPs were located in the MHC class-II subregion likely reflecting linkage disequilibrium with the HLA-DRB1*1501 allele. Logistic regression analysis adjusting for gender, study site, and DRB1*1501 suggested an independent association in the HLA-class I region localized around TRIM26 (600830), TRIM15, and TRIM10 (605701).
In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, the International Multiple Sclerosis Genetics Consortium and Wellcome Trust Case Control Consortium 2 (2011) replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci for multiple sclerosis. Within the MHC the International Multiple Sclerosis Genetics Consortium and Wellcome Trust Case Control Consortium 2 (2011) refined the identity of the HLA-DRB1 risk alleles as DRB1*1501 (142857.0002) and DRB1*1303, and confirmed that variation in the HLA-A gene (142800) underlies the independent protective effect attributable to the class I region. Immunologically relevant genes were significantly overrepresented among those mapping close to the identified loci and particularly implicated T helper cell differentiation in the pathogenesis of multiple sclerosis.
Disanto et al. (2011) found that 64 (24%) of 266 children with an initial attack of demyelination (acquired demyelinating syndrome, ADS) met criteria for a diagnosis of MS during a mean follow-up of 3.2 years. ADS children with 1 or more DRB1*15 alleles were more likely to be diagnosed with MS (OR of 2.7) compared to children without this allele. The association was most apparent in those children of European descent (OR of 3.3). Presence of DRB1*15 did not convey an increased risk for MS in ADS children of non-European descent. The findings indicated that DRB1*15 alleles confer increased susceptibility to pediatric-onset MS, supporting a fundamental similarity in genetic contribution to risk of chronic MS in both pediatric- and adult-onset disease.
Associations Pending Confirmation
Mycko et al. (1998) found an increased frequency of the K469 allele of intercellular adhesion molecule-1 (ICAM1; 147840) in 79 Polish multiple sclerosis patients compared with 68 ethnically matched controls (68% vs 49%). Homozygosity for this variant was also increased (53% vs 34%).
Vandenbroeck et al. (1998) found evidence that the interferon-gamma gene (IFNG; 147570) on chromosome 12q14 is a susceptibility factor for multiple sclerosis in those Sardinians who are at low risk by virtue of their HLA status.
In a genomewide association study (GWAS) involving 1,618 MS patients and 3,413 controls, with replication in an independent set of 2,256 cases and 2,310 controls, the Australia and New Zealand Multiple Sclerosis Genetics Consortium ANZgene (2009) identified several risk-associated SNPs on chromosome 12q13-14, including rs703842 in the METTL1 gene (604466) (p = 5.4 x 10(-11)); rs10876994, p = 2.7 x 10(-10); and rs12368653, p = 1.0 x 10(-7). The region encompassed 17 putative genes. Gandhi et al. (2010) determined that the MS-associated SNP rs703842 identified by the Australia and New Zealand Multiple Sclerosis Genetics Consortium ANZgene (2009) was also associated with expression of the FAM119B gene (615258), the MS susceptibility allele being the low-expressor of FAM119B.
Schrijver et al. (1999) found that patients with multiple sclerosis who were carriers of the IL1RN*2 allele (see 147679) and noncarriers of the IL1B*2 allele (see 147720) had a higher rate of progression than those with other allele combinations.
In 3 of 4 independent case-control studies, Jacobsen et al. (2000) demonstrated an association of a SNP in the PTPRC gene (151460) with MS. Furthermore, they found that the PTPRC mutation was linked to and associated with the disease in 3 MS nuclear families. However, studies by Vorechovsky et al. (2001) Barcellos et al. (2001), Cocco et al. (2004), and Szvetko et al. (2009) found no association between the PTPRC SNP and multiple sclerosis.
Dyment et al. (2001) analyzed and performed genotyping in 219 sib pairs assembled in connection with 4 published genome screens that had identified a number of markers with increased sharing in MS families but which did not reach statistical significance.
Dyment et al. (2001) used 105 markers previously identified as showing increased sharing in genome screens of Canadian, British, Finnish, and American MS families, but which did not reach statistical significance for linkage, in a genotype analysis of a Canadian sample of 219 sibs pairs. None of the markers met the criteria for significant linkage. Markers located at 5p14 and 17q22 were analyzed in a total of 333 sib pairs and attained maximum lod scores of 2.27 and 1.14, respectively. The known HLA-DRB1 association with MS was confirmed (p less than 0.0001). A significant transmission disequilibrium was also observed for D17S789 at 17q22 (p = 0.0015). The authors noted that the study highlighted the difficulty of searching for genes with only mild to moderate effects on susceptibility, although large effects of specific loci may still be present in individual families. They suggested that progress in the genetics of this complex trait may be helped by (1) focusing on more ethnically homogeneous samples, (2) using an increased number of MS families, and (3) using transmission disequilibrium analysis in candidate regions rather than the affected relative pair linkage analysis.
Xu et al. (2001) investigated 27 microsatellite markers from 8 chromosomal regions syntenic to loci of importance for experimental autoimmune diseases in the rat in 74 Swedish MS families. Possible linkage was observed with markers in the 7q35 (highest NPL score of 1.16) and 12p13.3 (highest NPL score of 1.16) regions, which are syntenic to the rat Cia3 (collagen-induced arthritis) and Oia2 (oil-induced arthritis) loci, respectively. Both regions overlapped with areas showing evidence for linkage in previous MS genomic screens.
The prevalence of MS in Sardinia (approximately 140 per 100,000) is significantly higher than in surrounding Mediterranean countries, suggesting that the isolated growth of this population has concentrated genetic susceptibility factors for the disease. Coraddu et al. (2001) performed a genomewide screen for linkage in 49 Sardinian multiplex families (46 sib pairs and 3 sib trios) using 327 markers. Nonparametric multipoint linkage analysis revealed suggestive linkage (MLS greater than 1.8) to chromosome regions 1q31, 10q23, and 11p15. Coraddu et al. (2001) concluded that the individual effects of genes determining susceptibility to MS are modest.
Pericak-Vance et al. (2001) reviewed linkage studies in multiple sclerosis. Genomic screens had suggested over 50 regions that might harbor MS susceptibility genes, but there had been little agreement between studies. The one region suggested by all 4 screens resided within chromosome 19q13. They examined this region in detail in an expanded dataset of MS families from the United States. Genetic linkage and association were tested with multiple markers in this region using both parametric and nonparametric analyses. Additional support for an MS susceptibility locus was observed, primarily in families with the MS-associated HLA-DR2 allele. While consistent, this effect appeared to be modest, probably representing no more than 10% of the overall genetic effect in MS.
Haines et al. (2002) studied a population of 266 individuals with MS belonging to 98 multiplex families. Their analysis continued to support linkage to chromosomes 6p21, 6q27, and 19q13 with lod scores higher than 3.0, and suggested that regions on chromosomes 12q23-q24 and 16p13 may also harbor susceptibility loci for MS. Analysis taking into account the known HLA-DR2 association identified additional potential linkage regions on chromosomes 7q21-22 and 13q33-34.
Vitale et al. (2002) identified a pedigree of Pennsylvania Dutch extraction in which MS segregated with an autosomal dominant inheritance pattern. Eighteen individuals, of whom 7 were affected, were serotyped for HLA class I and II and also analyzed by a genomewide screen for linkage analysis. There was suggestive linkage to markers on 12p12 with a maximum multipoint lod score of 2.71, conditional on the presence of HLA-DR15*DQ6. Contingency table analysis showed that all MS affected individuals had both the DR15*DQ6 allele and the 12p12 haplotype, whereas the unaffected individuals had either 1 or neither of these markers (P = 0.00011). The authors concluded that both HLA-DR15*DQ6 and a novel locus on chromosome 12p12 may be necessary for development of MS in this family.
He et al. (2002) studied a genetically isolated population in the Overkalix community of northern Sweden, which demonstrates a high incidence of MS. This ethnically homogeneous population was probably founded in the 17th century by a few couples. A genealogic analysis established that 19 of the MS patients originated from a single common ancestral couple. Five affected individuals from 4 nuclear families were selected for genomewide genotyping with 390 microsatellite markers. Seven shared haplotypes in 6 different chromosomal regions were identified. Only 1 of the suggested haplotypes was confirmed to be identical-by-descent after analysis of additional markers in 15 MS patients, and the identified region at 17p11 consisted of 4 markers spanning 7 cM. A significant excess of transmission of alleles to affected individuals (p less than 0.05) was observed for 3 of the markers by TDT. No increased sharing of haplotypes was observed for the HLA-DR and -DQ loci. The results suggested the presence of a susceptibility gene for MS in chromosome 17p11.
Saarela et al. (2002) carried out linkage analyses in 22 Finnish multiplex MS families originating from a regional subisolate that showed an exceptionally high prevalence of MS. The authors identified a 4-cM region flanked by the markers D17S1792 and ATA43A10 in 17 of 22 families. Using the combined power of linkage, association, and shared haplotype analyses, the authors restricted the MS locus on chromosome 17q to a region corresponding to a physical interval of 2.5 Mb.
By genomewide analysis of 779 Finnish MS patients and 1,165 controls, including those from an isolate in Southern Ostrobothnia, Jakkula et al. (2010) found an association between multiple sclerosis and the A allele of rs744166 in the STAT3 gene (102582) on 17q21; the A allele was protective. The findings were replicated in a total of 3,859 cases and 9,110 controls from various populations, including Norway, Denmark, the Netherlands, Switzerland, and the United States, yielding an overall p value of 2.75 x 10(-10) and an odds ratio of 0.87 (CI, 0.83-0.91). To validate the findings of Jakkula et al. (2010), Lill et al. (2012) performed a genetic association study of 2 SNPs in the STAT3 gene in a German case-control sample of 2,932 MS patients and 2,972 controls. There was a nominally significant association between the G allele of rs744166 and MS (OR of 1.09, p = 0.012), and no association with rs2293152. Lill et al. (2012) noted that rs744166 occurs in an intron and is not likely to have functional significance.
Kenealy et al. (2004) used a panel of 390 microsatellite markers for a genome screen in 245 U.S. and French multiplex families (the largest genomic screen for MS to that time). Four regions were thought to warrant further study.
Admixture mapping is a method for scanning the genome for gene variants that affect the risk for common, complex disease. The method has high statistical power to detect factors that differ markedly in frequency across human populations. Multiple sclerosis was an excellent candidate for admixture mapping because it is more prevalent in European Americans than in African Americans (Kurtzke et al., 1979, Wallin et al. (2004)). Reich et al. (2005) performed a high-powered admixture scan, focusing on 605 African American cases of multiple sclerosis and 1,043 African American controls. The individuals in their study had, on average, 21% European and 79% African ancestry. The goal was to identify genetic regions where individuals with multiple sclerosis tended to have an unusually high proportion of ancestry from either Europeans or Africans, indicative of the presence of a multiple sclerosis risk variant that differs in frequency between the ancestral populations. Reich et al. (2005) hypothesized that if there are genetic risk factors for multiple sclerosis that explain the epidemiology, they should be identifiable as regions with a high proportion of European ancestry in African Americans with multiple sclerosis compared with the average. They reported a locus on chromosome 1 that is significantly associated with multiple sclerosis. The 95% credible interval on chromosome 1 was estimated to be between 114.9 Mb and 144.7 Mb from 1pter, a region containing 68 known genes.
Among 242 patients with multiple sclerosis and 207 controls from a central Ohio population, Zhou et al. (2003) found that homozygosity for an ala57-to-val (A57V) SNP in the CD24 gene (600074) on chromosome 6q21 was associated with a 2-fold increased risk of MS in the general population, and the V57 allele was preferentially transmitted to affected individuals among familial MS cases. Most V57 homozygotes reached an expanded disability status within 5 years, whereas heterozygotes and A57 homozygotes reached this milestone in 16 and 13 years, respectively. Flow cytometric analysis demonstrated that CD24 was more highly expressed on T cells of V57 homozygous patients than A57 homozygous patients. Zhou et al. (2003) concluded that the A57V CD24 polymorphism genetically modifies susceptibility and progression of MS, perhaps by affecting the efficiency of CD24 expression. However, Goris et al. (2006) were unable to confirm the association between the A57V SNP and multiple sclerosis in a combined cohort of 1,180 cases and 1,168 unrelated and family-based controls from Belgium and the United Kingdom. Among 135 Spanish Basque patients with MS and 285 controls, Otaegui et al. (2006) found evidence for trend of association between the V56 allele and MS, but the results did not reach significance for an association study.
By fine mapping of a candidate locus at chromosome 1p13 in 1,278 trio families with MS and replication in an additional 3,341 MS patients, De Jager et al. (2009) observed a significant association between protection against MS and the G allele of rs2300747 in the CD58 gene (153420) (combined p of 1.1 x 10(-6); OR of 0.82). The protective G allele was associated with a dose-dependent increase in CD58 mRNA expression in lymphoblastic cells lines from MS patients (p = 1.1 x 10(-10)), suggesting a functional effect. De Jager et al. (2009) found that CD58 mRNA expression was higher in MS patients during clinical remission.
In a metaanalysis of genomewide association studies including 2,624 patients with MS and 7,220 controls, followed by replication in an independent set of 2,215 patients with MS and 2,116 controls, De Jager et al. (2009) identified loci for MS susceptibility on chromosome 12p13 in the TNFRSF1A gene (191190) (rs1800693; see MS5, 614810), on chromosome 16 (rs17445836) near the IRF8 gene (601565) (p = 3.73 x 10(-9)), and on chromosome 11q13 (rs17824933) in the CD6 gene (186720) (p = 3.79 x 10(-9)). In addition, the authors replicated the findings of an association between MS and SNP rs2300747 in the CD58 gene (p = 3.10 x 10(-10)). D'Netto et al. (2009) found an association between the C allele of rs12044852 in the CD58 gene and MS in 211 patients and 521 unaffected relatives from 43 multiplex MS families (OR, 1.05; p = 0.014), and in a case-control with the 211 patients and 182 unrelated controls (OR, 2.63; p = 8.5 x 10(-5)).
In a multistage genomewide association study (GWAS) involving a total of 1,540 multiple sclerosis family trios, 2,322 case subjects, and 5,418 control subjects, the International Multiple Sclerosis Genetics Consortium (2007) found an association between the G allele of rs6498169 in the KIAA0350 gene (611303) on chromosome 16p13 and MS (OR, 1.14; p = 3.83 x 10(-6)). D'Netto et al. (2009) found an association between MS and rs6498169 in a study of 211 MS patients and 182 controls (OR, 1.47; p = 0.014). However, significant associations with this SNP were not found among the 211 patients and 521 unaffected relatives from 43 multiplex MS families.
In a GWAS involving 1,618 MS patients and 3,413 controls, with replication in an independent set of 2,256 cases and 2,310 controls, the Australia and New Zealand Multiple Sclerosis Genetics Consortium ANZgene (2009) identified risk-associated SNPs on chromosome 20q13 (rs6074022, p = 1.3 x 10(-7) and rs1569723, p = 2.9 x 10(-7)). Both SNPs are located upstream of the CD40 gene (109535). Gandhi et al. (2010) determined that, of the 30 SNPs genotyped from the chromosome 20 CD40 linkage block by the Australia and New Zealand Multiple Sclerosis Genetics Consortium ANZgene (2009), rs6074022 had the strongest association with CD40 expression. The CD40 haplotype associated with increased MS susceptibility has decreased gene expression in MS.
Baranzini et al. (2009) conducted a GWAS in 978 well-characterized individuals with MS and 883 group-matched controls. The authors compared allele frequencies and assessed genotypic influences on susceptibility, age of onset, disease severity, as well as brain lesion load and normalized brain volume from MRI exams. They identified an association with SNP rs9523762 in the GPC5 gene (602446) (adjusted log p value = 5.155), which was replicated in an independent group of 974 MS patients (adjusted log p value = 2.42).
The International Multiple Sclerosis Genetics Consortium (2010) genotyped approximately 30,000 single-nucleotide polymorphisms (SNPs) that demonstrated mild to moderate levels of significance (p less than or equal to 0.10) in an initial GWAS of an independent set of 1,343 multiple sclerosis (MS) cases and 1,379 controls. The consortium further replicated several of the most significant findings in another independent data set of 2,164 MS cases and 2,016 controls. There was considerable evidence for a number of novel susceptibility loci including KIF21B (608322) (rs12122721, combined p = 6.56 x 10(-10), odds ratio = 1.22) and TMEM39A (rs1132200, p = 3.09 x 10(-8), odds ratio = 1.24), both of which met genomewide significance.
The Wellcome Trust Case Control Consortium and The Australo-Anglo-American Spondylitis Consortium (2007) and Ban et al. (2009) reported a possible protective effect in MS of a rare functional variant within the TYK2 gene, rs34536443. Because of the low frequency (0.04) of the minor allele (C), genomewide-significant association was not established. Mero et al. (2010) genotyped 5,429 Nordic MS cases and 6,167 healthy controls for this TYK2 nonsynonymous SNP, which encodes a proline-to-alanine substitution in exon 21, and then combined the Nordic genotype data with raw genotypes from the studies of the Wellcome Trust Case Control Consortium and The Australo-Anglo-American Spondylitis Consortium (2007) and Ban et al. (2009). The combined Nordic analysis showed significant association with MS (p = 5 x 10(-4), odds ratio 0.78), and by mega-analysis of 10,642 MS patients, 10,620 controls, and 2,110 MS trios, the association at genomewide significance level (p = 5.08 x 10(-9), odds ratio 0.77) was shown.
Association with APOE
The contribution of the major histocompatibility complex (MHC) to the pathogenesis of MS has been established in numerous genetic linkage and association studies. In addition to MHC, the chromosome 19p13 region surrounding the apolipoprotein E gene (APOE; 107741) has shown consistent evidence of involvement in MS when family-based analyses were conducted. Some clinical studies have suggested an association between the APOE4 allele and more severe disease and faster progression of disability (Fazekas et al., 2001; Chapman et al., 2001). Noting that the APOE4 allele has been associated with earlier age of onset in AD, but not disease progression, and with faster disease progression in MS, but not age of onset, Chapman et al. (2001) suggested that these apparent effects are influenced by whether the diagnosis is made late in disease course (as in AD) or relatively early in disease course (as in MS). The authors hypothesized that the APOE4 genotype influences neuronal disease in general via alterations in the efficacy of neuronal maintenance and repair, and that the apparent effects of the genotype on these 2 parameters are related to the threshold at which the disease manifests itself clinically.
Lucotte and French MS Consortium (2002) conducted a genomewide linkage analysis in 18 families with multiple cases of MS. An MS locus was linked to markers located in the 19q13.3 region (multipoint lod score = 2.1). They suggested that APOE, which is located in this region, is an excellent candidate gene for MS.
To examine further the role of APOE in MS, Schmidt et al. (2002) genotyped its functional alleles, as well as 7 single nucleotide polymorphisms (SNPs) located primarily within 13 kb of APOE, in 398 families. Using family-based association analysis, they found statistically significant evidence that a SNP haplotype near APOE is associated with MS susceptibility (p = 0.005). An analysis of disease progression in 614 patients with MS from 379 families indicated that APOE4 carriers are more likely to be affected with severe disease (p = 0.03), whereas a higher proportion of APOE2 carriers exhibited a mild disease course (p = 0.02). Kantarci et al. (2004) presented evidence suggesting that the APOE2 allele is associated with lesser disease severity in women with MS, as indicated by a longer time to reach an expanded disability status scale (EDSS) score of 6. In contrast, Zwemmer et al. (2004) reported no favorable role for the E2 allele in a study of 250 women with MS. In fact, they found a trend in the opposite direction: time to an EDSS score of 6 was shorter (6.8 years) in E2 carriers than in noncarriers (10.0 years). In addition, E2 carriers had a higher lesion load on MRI compared to noncarriers. In a response, Weinshenker and Kantarci (2004) noted that the study by Zwemmer et al. (2004) had a higher number of more severe primary progressive cases (22% of subjects) than that reported by Kantarci et al. (2004) (6.4% of subjects), which may explain the discrepancy.
In MS, a reduction in concentration of N-acetylaspartate (NAA), which has been shown to be contained almost exclusively in mature neurons, reflects neuronal loss, axonal loss, and generalized neuronal dysfunction. Moreover, the degree of reduction of NAA has been correlated with disease severity and extent of tissue destruction. In 72 patients with relapsing-remitting MS, Enzinger et al. (2003) showed by proton magnetic resonance spectroscopy (MRS) that patients with the APOE4 allele had a higher degree of disability and a significantly lower NAA:creatine ratio than patients without the E4 allele. During follow-up in 44 patients, the drop in the NAA:creatine ratio of E4 carriers was significantly larger and was paralleled by a higher number of relapses and a faster disease progression. Enzinger et al. (2003) concluded that the findings indicated more extensive axonal damage associated with the APOE4 allele.
Among 125 Greek MS patients, Koutsis et al. (2007) found that carriers of the APOE E4 allele had a 6-fold increase in the relative risk of verbal learning deficits compared to noncarriers. The effect was specific and was not observed in other cognitive domains.
Among 1,006 Australian patients with relapsing-remitting MS or secondary progressive MS, van der Walt et al. (2009) found no association between APOE allele status or promoter region heterogeneity at positions -219G-T (107741.0030) or +113C-G and clinical disease severity, cognition, or cerebral atrophy.
Ghaffar et al. (2010) found no differences in 11 cognitive outcome variables, including attention, processing speed, verbal and visual memory, and executive functions in a comparison of 50 MS patients with the E4 allele and 50 MS patients without the E4 allele who were well-matched regarding education and disease course and duration. The presence of cognitive impairment overall was 41%.
An HLA-DRB1*1501-DQB1*0602 haplotype (HLA-DR15) has repeatedly been demonstrated in high-risk (northern European) populations (Dyment et al., 1997).
Among 163 patients with sporadic MS, DeLuca et al. (2007) observed an association between relatively benign outcome and HLA-DRB1*01. The allele was present in 19% of 112 patients with milder disease compared to 3.9% of 51 patients with severe disease, yielding an odds ratio of 4.85. Severity analysis of a cohort of affected sib pairs discordant for the DRB1*01 allele confirmed the protective effect, but only reached significance when combined in the DRB1*1501 allele. Another group of Sardinian MS patients showed that 19 with benign disease had the DRB1*01 allele, compared to none with malignant disease. DeLuca et al. (2007) suggested that the DRB1*01 allele acts as a modifier of disease progression in MS.
Svejgaard (2008) provided a detailed review of the immunogenetics of multiple sclerosis, with special emphasis on the association with HLA molecules.
Epidemiologic evidence implicating epigenetic factors in MS includes complex distortion of disease transmission seen in aunt/uncle-niece/nephew (AUNN) pairs. In AUNN families, Chao et al. (2009) found that allele frequencies for HLA-DRB1*1501 were different between the first and second generations affected. Affected aunts had significantly lower HLA-DRB1*15 frequency compared with their affected nieces (P = 0.0016), whereas HLA-DRB1*15 frequency in affected males remained unaltered across the 2 generations (P = 0.63). The authors compared transmissions for the HLA-DRB1*15 allele using a family-based transmission disequilibrium test approach in 1,690 individuals from 350 affected sib-pair (ASP) families and 960 individuals from 187 AUNN families. Transmissions differed between the ASP and the AUNN families (P = 0.0085). The risk carried by HLA-DRB1*15 was increased in families with affected second-degree relatives (AUNN: OR = 4.07) when compared with those consisting only first-degree relatives (ASP: OR = 2.17), establishing heterogeneity of risk among HLA-DRB1*15 haplotypes based on whether collateral parental relatives are affected. The authors proposed gene-environment interactions in susceptibility and more specifically, that epigenetic modifications may differentiate among human leukocyte antigen class II risk haplotypes and may be involved in the determination of the gender bias in MS. The authors suggested that the female-specific increasing risk of MS is mediated through these alleles or adjacent variation.
Modifier Genes
Among 939 German patients with multiple sclerosis, Kroner et al. (2005) reported an association between the A allele of a SNP in the PDCD1 gene (600244) and disease progression. Of 94 patients with primary progressive MS, 44% had the G/G genotype, and 53% had the A/G genotype. Of 5 MS patients who were homozygous for the A allele, 3 had primary progressive MS, and 1 had secondary progressive MS. In vitro studies showed that PDCD1-mediated inhibition of T-cell activation and cytokine secretion was impaired in cells from patients with the A allele compared to cells from patients with only the G allele. Presence of the A allele did not confer susceptibility to disease development.
Barcellos et al. (2000) found that patients with multiple sclerosis carrying the CCR5 (601373)-delta-32 deletion showed an age at onset approximately 3 years later than did patients without the deletion. Studying 256 Israeli patients with MS, Kantor et al. (2003) presented evidence suggesting that the CCR5-delta-32 deletion may contribute to a slower rate of disease progression in MS.
Associations Pending Confirmation
For discussion of a possible association between a demyelinating brain disease reminiscent of multiple sclerosis and variation in the TPP2 gene, see 190470.0005.
Genetically determined susceptibility to a viral infection in childhood or adolescence has long been suspected as a cause of MS based on the occurrence of several 'MS epidemics' (Kurtzke and Hyllested, 1979; Sheremata et al., 1985). One of the epidemiologic facts that is compatible with viral etiology is that there is a direct correlation between latitude and frequency, i.e., the disease is most frequent in northern climes. A notable exception is in Japan, which is at the same latitude as the eastern coast of the United States from southern Maine to South Carolina. The basis of the exception may be the relative lack of Dw2 in Japan (except as introduced by Caucasians). MS is also rare in Africans. MS in American blacks is accounted for, to a considerable extent, by Caucasian admixture with acquisition of Dw2, which is low or absent in Africa.
Steinman (1996) reviewed what was known about the molecular mechanisms in the pathogenesis of multiple sclerosis. It is hoped that as understanding of the pathophysiology of MS increases, rational therapies will be devised that will arrest the immunologic attack on myelin without causing widespread immune suppression. Once the immune response is silenced, it will be important to repair the damaged myelin sheath. Steinman (1996) stated that possible methods to accomplish this repair by use of oligodendroglial transplants and growth factors to reinitiate myelination were under intense investigation.
Vyse and Todd (1996) gave a general review of genetic analysis of autoimmune diseases, including MS.
Reasoning that there could be an antigen present in the white matter of MS brain that is not found in normal white matter and that specifically activates T cells, van Noort et al. (1995) separated the proteins of the myelin sheath using reversed-phase HPLC and discovered that a particular fraction in the myelin of MS brain, but not in the myelin taken from healthy brain, stimulated proliferation of T cells. They showed that alpha-crystallin B (CRYAB; 123590) is expressed in glial cells from MS lesions but not in white matter from healthy individuals or in unaffected white matter from MS brain. This small heat-shock protein was found in oligodendroglial cells as well as in astrocytes in plaques from patients with acute and chronic MS. In light of the findings of van Noort et al. (1995), Steinman (1995) discussed the significance of the immune reaction against alpha-crystallin B in the pathology of MS. He stated that the efforts to determine which antigens trigger the pathologic response in MS brain may yield results that make it possible to induce immunologic tolerance to these proteins using strategies such as alteration of peptide ligands that bind to the T-cell receptor and the blockade of costimulatory molecules on T cells.
Chabas et al. (2001) performed large-scale sequencing of cDNA libraries derived from plaques dissected from brains of patients with multiple sclerosis and detected an abundance of transcripts for osteopontin (166490) that were completely absent from control brains.
During mammalian CNS development, contact-mediated activation of NOTCH1 (190198) receptors on oligodendrocyte precursors by the ligand JAG1 (601920) induces HES5 (607348), which inhibits maturation of these cells. John et al. (2002) tested whether the NOTCH pathway is reexpressed in the adult CNS in multiple sclerosis and found that TGF-beta-1 (190180), a cytokine upregulated in MS, specifically reinduced JAG1 in primary cultures of human astrocytes. Within and around active MS plaques lacking remyelination, JAG1 was expressed at high levels by hypertrophic astrocytes, whereas NOTCH1 and HES5 localized to cells with an immature oligodendrocyte phenotype, and TGF-beta-1 was associated with perivascular extracellular matrix in the same areas. In contrast, there was negligible JAG1 expression in remyelinated lesions. In vitro experiments showed that JAG1 signaling inhibited process outgrowth from primary human oligodendrocytes.
Progressive oligodendrocyte loss is part of the pathogenesis of MS. Oligodendrocytes are vulnerable to a variety of mediators of cell death, including free radicals, proteases, inflammatory cytokines, and glutamate excitotoxicity. Proinflammatory cytokine release in MS is mediated in part by microglial activation. Takahashi et al. (2003) found that interleukin-1-beta (IL1B), a prominent microglia-derived cytokine, caused oligodendrocyte death in coculture with astrocytes and microglia, but not in pure culture of oligodendrocytes alone. Because IL1B had been shown to impair the activity of astrocytes in the uptake and metabolism of glutamate, Takahashi et al. (2003) hypothesized that the indirect toxic effect of microglia-derived IL1B on oligodendrocytes involved increased glutamate excitotoxicity via modulation of astrocyte activity. In support, antagonists at glutamate receptors blocked the toxicity. Similar studies of TNF-alpha, another microglia-derived cytokine, yielded the same results. The findings provided a mechanistic link between microglial activation in MS with glutamate-induced oligodendrocyte destruction.
Bomprezzi et al. (2003) distinguished gene expression profiles of peripheral blood monocytes from MS patients versus healthy controls using cDNA microarrays. The authors hypothesized that activation of autoreactive T cells may be of primary importance in MS.
Among 939 German patients with MS Kroner et al. (2005) reported an association between an intronic SNP in the PDCD1 gene (600244.0001) and disease progression. The SNP did not confer susceptibility to disease development.
Alpha-B-crystallin (CRYAB; 123590) is the most abundant gene transcript present in early active multiple sclerosis lesions, whereas such transcripts are absent in normal brain tissue. This crystallin has antiapoptotic and neuroprotective functions. CRYAB is the major target of CD4+ T cell immunity to the myelin sheath from multiple sclerosis brain. Ousman et al. (2007) demonstrated that CRYAB is a potent negative regulator acting as a brake on several inflammatory pathways in both the immune system and central nervous system. Cryab-null mice showed worse experimental autoimmune encephalomyelitis at the acute and progressive phases, with higher Th1 and Th17 cytokine secretion from T cells and macrophages, and more intense CNS inflammation, compared with their wildtype counterparts. Furthermore, Cryab-null astrocytes showed more cleaved caspase-3 (600636) and more TUNEL staining, indicating an antiapoptotic function of Cryab. Antibody to CRYAB was detected in cerebrospinal fluid from multiple sclerosis patients and in sera from mice with autoimmune encephalomyelitis. Administration of recombinant CRYAB ameliorated autoimmune encephalomyelitis. Thus, Ousman et al. (2007) concluded that the immune response against the negative regulator of inflammation, CRYAB, in multiple sclerosis, would exacerbate inflammation and demyelination. They suggested that this can be countered by giving CRYAB itself for therapy of ongoing disease.
Using a proteomics approach, Derfuss et al. (2009) identified CNTN2 (190197) as a candidate autoantigen in 3 of 5 serum samples from patients with multiple sclerosis. A larger sample of MS patients showed significantly increased T-cell and IgG immune responses to CNTN2 compared to controls. Increased levels of IFN-gamma (147570) and IL17 (603149) were also observed in MS patients. Adoptive transfer of Cntn2-specific T cells induced experimental autoimmune encephalitis in rats that was characterized by a preferential inflammation of gray matter of the spinal cord and cortex. Cotransfer of these T cells with a myelin oligodendrocyte glycoprotein-specific monoclonal antibody generated focal perivascular demyelinating lesions in the cortex and extensive demyelination in spinal cord gray and white matter. These findings indicated that CNTN2 is an autoantigen targeted by T cells and autoantibodies in MS and suggested that a CNTN2-specific T-cell response contributes to the development of gray matter pathology in MS.
Viral pathogens have been implicated in the etiology and pathogenesis of MS. Plasmacytoid dendritic cells (PDCs) sense viral DNA and produce increased levels of alpha-interferon (IFNA1; 147660) in response to functional processed TLR9 (605474), which is generated by cleaving the N terminus to generate a functional C-terminal TLR9. Balashov et al. (2010) found that PDCs from untreated patients with relapsing-remitting MS had increased levels of IFNA1 compared to PDCs from 14 patients treated with beta-interferon (IFNB1; 147640). PDCs from IFNB1-treated patients had significantly reduced levels of processed TLR9 protein but normal levels of full-length TLR9 and TLR9 gene expression compare to untreated patients. In vitro cellular studies showed that IFNB1 inhibited the processing of TLR9 in PDCs. Balashov et al. (2010) suggested that the findings represented a new immunomodulatory mechanism of beta-interferon.
Bittner et al. (2010) demonstrated that a T-cell potassium channel TASK2 (KCNK5; 603493) was significantly upregulated (2-fold) on peripheral CD4+ T cells derived from patients with relapsing-remitting MS compared to those from MS patients with stable disease and to controls. TASK2 expression on peripheral CD8+ T cells was more significantly increased in MS patients with acute relapse (7.6-fold) and in those with stable disease (3.3-fold). CSF-derived and CNS lesion-derived cytotoxic T cells from MS patients showed an even greater increase in TASK2 expression compared to peripheral cells. No increase in TASK2 expression was seen in patients with neuromyelitis optica, another neurologic inflammatory disease believed to be mediated by B cells. Pharmacologic or siRNA-mediated knockdown of TASK2 in T cells reduced proliferation and cytokine production, indicating that TASK2 is a key mediator of T-cell physiology.
Srivastava et al. (2012) screened serum IgG from persons with MS to identify antibodies that are capable of binding to brain tissue and observed specific binding of IgG to glial cells in a subgroup of patients. Using a proteomics approach focused on membrane proteins, Srivastava et al. (2012) identified the ATP-sensitive inwardly rectifying potassium channel KIR4.1 (602208) as the target of the IgG antibodies. Serum levels of antibodies to KIR4.1 were higher in persons with MS than in persons with other neurologic diseases and healthy donors (p less than 0.001 for both comparisons). This finding was replicated in 2 independent groups of persons with MS or other neurologic diseases (p less than 0.001 for both comparisons). Analysis of the combined data sets indicated the presence of serum antibodies to KIR4.1 in 186 of 397 persons with MS (46.9%), in 3 of 329 persons with other neurologic diseases (0.9%), and in none of the 59 healthy donors. These antibodies bound to the first extracellular loop of KIR4.1. Injection of KIR4.1 serum IgG into the cisternae magnae of mice led to a profound loss of KIR4.1 expression, altered expression of glial fibrillary acidic protein in astrocytes, and activation of the complement cascade at sites of KIR4.1 expression in the cerebellum. Srivastava et al. (2012) concluded that KIR4.1 is a target of the autoantibody response in a subgroup of individuals with multiple sclerosis.
Raj et al. (2014) performed an expression quantitative trait locus (eQTL) study of purified CD4 (186940)+ T cells and monocytes, representing adaptive and innate immunity, in a multiethnic cohort of 461 healthy individuals. Context-specific cis- and trans-eQTLs were identified, and cross-population mapping allowed, in some cases, putative functional assignment of candidate causal regulatory variants for disease-associated loci. Raj et al. (2014) noted an overrepresentation of T cell-specific eQTLs among susceptibility alleles for autoimmune diseases, including rheumatoid arthritis (180300) and multiple sclerosis, and of monocyte-specific eQTLs among Alzheimer disease (104300) and Parkinson disease (168600) variants. Raj et al. (2014) concluded that this polarization implicates specific immune cell types in these diseases and points to the need to identify the cell-autonomous effects of disease susceptibility variants.
Epstein-Barr virus (EBV) infection has been epidemiologically linked to MS. Lanz et al. (2022) demonstrated high-affinity molecular mimicry between the EBV transcription factor EBV nuclear antigen-1 (EBNA1) and the central nervous system protein glial cell adhesion molecule (GlialCAM; 611642) and provided structural and in vivo functional evidence for its relevance. A crossreactive CSF-derived antibody was initially identified by single-cell sequencing of the paired-chain B cell repertoire of MS blood and CSF, followed by protein microarray-based testing of recombinantly expressed CSF-derived antibodies against MS-associated viruses. Sequence analysis, affinity measurements, and the crystal structure of the EBNA1 peptide epitope in complex with the autoreactive antigen-binding fragment (Fab) enabled tracking of the development of the naive EBNA1-restricted antibody to a mature EBNA1-GlialCAM crossreactive antibody. Molecular mimicry was facilitated by phosphorylation of GlialCAM. EBNA1 immunization exacerbated disease in a mouse model of MS, and anti-EBNA1 and anti-GlialCAM antibodies were prevalent in patients with MS.
Association With Vitamin D
In a population-based study examining month of birth of 17,874 Canadian MS patients and 11,502 British MS patients, with the addition of data from 6,276 Danish and 6,393 Swedish patients, Willer et al. (2005) found that significantly more (9.1% more) people with MS were born in May and significantly fewer (8.5% fewer) were born in November. This represented a 19% decreased risk of MS for those born in November compared to those born in May. The effect was greatest in Scotland. Willer et al. (2005) discussed possible interpretations of the data, including interactions between genes and environment related to climate, such as variation in sun exposure and vitamin D levels.
Munger et al. (2006) observed an association between increased serum 25-hydroxyvitamin D levels and protection from multiple sclerosis among whites from a military registry. Among 148 cases and 296 controls, the risk of multiple sclerosis significantly decreased with increasing levels of 25-hydroxyvitamin D (odds ratio (OR) of 0.59). The inverse relation with multiple sclerosis risk was particularly strong for 25-hydroxyvitamin D levels measured before age 20 years. No significant associations were found between 109 black and Hispanic cases compared to 218 controls, although these groups had lower 25-hydroxyvitamin D levels compared to whites. The results suggested that high circulating levels of vitamin D are associated with a lower risk of multiple sclerosis.
Ramagopalan et al. (2009) identified a vitamin D response element (VDRE) in the promoter region of HLA-DRB1. Sequencing of this promoter in HLA-DRB1 homozygotes showed absolute conservation of this putative VDRE on HLA-DRB1*15 haplotypes in 322 MS-affected and unaffected individuals. In contrast, there was striking variation among 168 individuals with non-MS-associated haplotypes. Electrophoretic mobility shift assays showed specific recruitment of vitamin D receptor to the VDRE in the HLA-DRB1*15 promoter, confirmed by chromatin immunoprecipitation experiments using lymphoblastoid cells homozygous for HLA-DRB1*15. Transient transfection of the promoter in B cells showed increased expression on stimulation with 1,25-dihydroxyvitamin D3 that was lost both on deletion of the VDRE. This study further implicated vitamin D as a strong environmental candidate in MS by demonstrating direct functional interaction with the major locus determining genetic susceptibility. These findings support a connection between the main epidemiologic and genetic features of this disease.
Torkildsen et al. (2008) reported 3 Norwegian patients from 2 families with childhood-onset vitamin D hydroxylation-deficient rickets (VDDR1A; 264700) due to mutations in the CYP27B1 gene (609506) who all developed multiple sclerosis. Since this form of vitamin D-dependent rickets is very uncommon, the authors proposed a link between defects in vitamin D metabolism and increased risk of multiple sclerosis. Ramagopalan et al. (2010) found that all 3 Norwegian patients with VDDR1A and MS reported by Torkildsen et al. (2008) had the MS risk allele HLA-DRB1*15, with the vitamin D response element in the promoter. Two patients were homozygous for the HLA risk allele.
By whole-exome sequencing of 43 probands with multiple sclerosis, each from a family in which 4 or more individuals had MS, Ramagopalan et al. (2011) failed to find a common loss of function or predicted damaging variant. However, 1 patient had a heterozygous loss-of-function arg389-to-his (R389H; 609506.0012) substitution (rs118204009) in the CYP27B1 gene that was found to be present in all 4 (100%) affected family members and 33% of genotyped unaffected family members. This variant was also found to be overtransmitted in an analysis of 3,046 parent-affected child MS trios (p = 1 x 10(-5)) and in a further 422 parent-affected sib MS pairs (p = 0.046). None of the individuals had evidence of vitamin D hydroxylation-deficient rickets. Two additional pathogenic variants in the CYP27B1 gene, E189G (609506.0017) and L343F (609506.0016), were found to be overtransmitted in the larger trio cohort. None of the individuals with any of these mutations were of French Canadian origin. Serum from 1 individual with the R389H mutation showed low calcitriol levels compared to controls, and 3 of 96 additional MS patients with low calcitriol levels were found to carry putative pathogenic CYP27B1 variants, suggesting that heterozygosity for loss of function alleles results in lower calcitriol levels. Overall, the findings supported a causative role for variation in the CYP27B1 gene in MS risk, which correlated with the geographic latitude gradient that appeared to influence disease risk.
Ban et al. (2013) found no significant association between the R389H and L343F variants in the CYP27B1 gene and MS among 495 multiplex families, 2,092 single affected families, and 4,594 patients with the disorder compared to 3,583 controls. The populations were from the U.K., U.S., and Norway. Barizzone et al. (2013) also found no association between the R389H variant and MS among 2,608 patients and 1,987 controls from Italy and Belgium. Plasma measurement of 1 MS patient and 1 unaffected individual, both of whom had a heterozygous R389H variant, showed no decrease in 1,25-dihydroxyvitamin D levels. Screening of the CYP27B1 coding sequence in 134 Italian multiplex MS families revealed no mutations. Ban et al. (2013) and Barizzone et al. (2013) independently concluded that mutant CYP27B1 alleles do not influence the risk of developing MS.
Gandhi et al. (2010) measured the whole blood mRNA transcriptome for 99 untreated MS patients, comprising 43 with primary progressive MS, 20 with secondary progressive MS, and 36 with relapsing remitting MS, and 45 age-matched healthy controls. The authors genotyped more than 300,000 SNPs for 115 of these samples. Transcription from genes regulating translation, oxidative phosphorylation, immune synapse, and antigen presentation pathways was markedly increased in all forms of MS. Expression of genes predominantly expressed in T cells was also upregulated in MS. A T-cell gene signature predicted disease state with a concordance index of 0.79 with age and gender as covariables, but the signature was not associated with clinical course or disability. The authors concluded that dysregulation of T cells can be detected in the whole blood of untreated MS patients, and they supported targeting of activated T-cells in therapy for all forms of MS.
There appear to be rare forms of multiple sclerosis or multiple sclerosis-like diseases that are mendelian; see 169500. Also see spastic ataxia (108600) for a disorder that closely resembles disseminated sclerosis. Ekbom (1966) described a familial form of multiple sclerosis associated with narcolepsy (223300): in 1 family 2 brothers had MS, combined in 1 with narcolepsy; in another family 3 sisters had MS, and of the 3 one had narcolepsy. As noted in 161400, narcolepsy shows a strong association with HLA-DR2.
Natowicz and Bejjani (1994) provided a review of genetic disorders that masquerade as multiple sclerosis. They usefully divided these into biochemically defined disorders and clinically defined disorders. The former included Leber hereditary optic neuropathy with associated neurologic features; the latter included hereditary spastic paraparesis and hereditary adult-onset leukodystrophy (169500).
In CSF samples from 19 of 29 patients with MS, Irani et al. (2006) identified a 12.5-kD cleavage product of cystatin C (CST3; 604312) formed by the removal of the last 8 amino acids from the C terminus. The 12.5-kD peak was not identified in CSF samples from 27 patients with unrelated neurologic disorders or 27 additional patients with acute transverse myelitis, but lower levels than that of MS patients were found in some patients with HIV infection. Overall, the presence of the 12.5-kD peak provided 66% sensitivity and 100% specificity for the detection of MS. Irani et al. (2006) suggested that cleavage of cystatin C may be an adaptive host response.
Del Boccio et al. (2007) and Hansson et al. (2007) independently identified a 12.5-kD product of cystatin C that is formed by degradation of the first 8 N-terminal amino acids resulting from inappropriate storage at -20 degrees Celsius. Compared to controls, no significant differences in cystatin C fragments were observed in the CSF of 21 and 43 MS patients, respectively. Both groups concluded that CSF cystatin C is not a useful marker for the diagnosis of MS. In a response, Wheeler et al. (2007) stated that they had stored the CSF samples at -80 degrees Celsius (Irani et al., 2006), and that the cleavage site identified by them was at the C-terminal. A more accurate measurement indicated that the C-terminal fragment was 12,546.6 Da and the N-terminal fragment was 12,561.3 Da, suggesting that there are 2 similarly sized, yet distinct fragments of cystatin C.
Sawcer et al. (2010) discussed the utility of genetic screening for predicting risk of multiple sclerosis and refining diagnosis or predicting prognosis of multiple sclerosis. They noted that the epidemiologic and genetic evidence on MS supported a polygenic/biometric model with a multiplicative model of risk. The authors concluded that very few individuals would carry a level of genetically determined risk that would allow confident prediction. Sawcer et al. (2010) emphasized that the overall prevalence of MS in the general population is low, that familial clustering is modest, and that, with the exception of the MHC locus, most all MS risk alleles identified are anonymous variants, thereby reducing the utility of genetic screening efforts at this time.
Exclusion Studies
Salier et al. (1986) found a combined influence on MS of 2 genetic loci that are unlinked but related to immune response: Gm (IGHG1; 147100) and HLA. Gaiser et al. (1987) found a negative association with a RFLP related to a genomic Ig gamma-1 probe. Among patients with myasthenia gravis and others with Graves disease, the frequency of the marker was the same as in controls. In a study using 15 immunoglobulin heavy chain constant and variable region polymorphisms in 34 sib pairs concordant for MS and in 23 sporadic MS patients, Walter et al. (1991) found no significant association between MS and constant region genes but a significant correlation between MS and a polymorphism of the VH2-5 gene segment. This segment is located in the proximal part of the variable region within a distance of 180 to 360 kb from the constant region.
Hall (1983) raised a question of arthrogryposis (e.g., 208100) occurring causally in offspring of women with MS. McKusick (1983) saw clubfoot in 3 children and full-blown arthrogryposis multiplex congenita in the youngest of these, the fourth child of a woman with MS.
Beall et al. (1989) and Seboun et al. (1989) presented evidence that a MS susceptibility gene lies near or within the T-cell receptor beta-chain locus (TCRB; see 186930). Charmley et al. (1991) presented further evidence based on the patterns of linkage disequilibrium. Utz et al. (1993) analyzed the role of T-cell receptor (TCR) genes in multiple sclerosis by comparing TCR usage in monozygotic twins who were either concordant or discordant in response to self and foreign antigens. They found that after stimulation with myelin basic protein or tetanus toxoid, control twin sets as well as concordant twin sets selected similar V-alpha chains. Only the discordant twin sets selected different TCRs after stimulation with antigens. The study involved 6 monozygotic twin pairs. Two were concordant (both affected) and 2 discordant (1 twin affected) for MS. One control twin set was discordant for bipolar mental disorder and a second was clinically healthy. It is not clear whether the discordance was due to the effect of the disease or represented a preexisting condition. One possibility is that it was preexisting and contributed to the susceptibility of the affected twin; another possibility is the occurrence of somatic changes during development, especially alterations in the TCR genes.
By study of 49 MS sib pairs using restriction fragment length polymorphisms and of 82 sib pairs using a microsatellite repeat polymorphism, Eoli et al. (1994) found no evidence of linkage between the TCRA locus (see 186880) and the disease; in neither case did genotype or haplotype sharing differ significantly from expected rates. Stratification of patients according to DR15 status did not alter the distribution of haplotypes in affected sibs.
Adopting a candidate gene approach, Tienari et al. (1992) used polymorphism of the myelin basic protein (MBP; 159430) gene, which is located on chromosome 18, in genetic linkage and association studies in a Finnish population. They investigated 21 MS families, 51 additional unrelated patients with definite MS, and 85 controls. All subjects were from an area with an exceptional familial clustering of MS. Magnetic resonance imaging (MRI) was used to examine subclinical disease in symptom-free family members. In the association analysis, the allele frequencies between MS patients and controls differed significantly (p = 0.000049), the difference being attributable mainly to a higher frequency of a 1.27-kb allele among patients. In the linkage analysis, based on an autosomal dominant model and penetrance of 0.05, a maximum lod score of 3.42 at theta = 0.00 was obtained when patients with optic neuritis and their symptom-free sibs with abnormal MRI findings were classified as 'affected.' In the set of Finnish multiplex families in which they had previously found linkage between MS susceptibility and 2 independent loci, MBP and HLA, Tienari et al. (1994) performed linkage analysis conditional on 2 loci contributing to the disease. Responding to a comment by Colover (1993), Tienari et al. (1993) suggested that if demyelination in multiple sclerosis is secondary to reduced remyelination capacity and if MBP is a candidate gene, several genetically determined factors might be involved: low levels of MBP expression in multiple sclerosis patients; differences in MBP isoforms; and amino acid variation in MBP leading to a functionally defective protein. In Utah, Rose et al. (1993) likewise studied linkage between MS and the polymorphic tetranucleotide repeat region immediately 5-prime to exon 1 of MBP used in the Finnish study. In studies of 14 multiplex families with 36 affected individuals, linkage analysis, using either an autosomal dominant or an autosomal recessive model, showed negative cumulative lod scores. Thus, linkage between MS and MBP could not be demonstrated. Eoli et al. (1994) studied the multiallelic polymorphism adjacent to the gene for MBP in Italian patients. In a study of 54 sporadic patients, 55 control subjects, and 18 families with 2 or more affected individuals, they found no evidence for either association or linkage according to autosomal dominant or autosomal recessive modes of inheritance between MBP and MS in the Italian population. Wood et al. (1994) used 2 adjacent amplification fragment length polymorphisms to examine the relationship of myelin basic protein to multiple sclerosis in the United Kingdom. No allelic association was found in a comparison of 77 cases and 88 controls, nor was there evidence for linkage in 73 affected sib pairs, using the methods of identity by descent and identity by state.
The chronic variant of experimental allergic encephalomyelitis (EAE), a T cell-mediated autoimmune disease in rodents, represents a relevant animal model for MS given the chronic relapsing disease course and inflammatory changes observed in the CNS in these demyelinating disorders. Kuokkanen et al. (1996) tested human chromosomal regions homologous to murine loci predisposing to EAE as candidate regions for genetic susceptibility to MS. Three chromosomal regions (1p23-q22, 5p14-p12, and Xq13.2-q22) were screened in 21 Finnish multiplex MS families, most originating from a high-risk region in western Finland. Several markers yielded positive lod scores on 5p14-p12, syntenic to the murine locus Eae2. Thus, Kuokkanen et al. (1996) concluded that there may be a predisposing locus for MS in this chromosomal region.
In transgenic mice, Madsen et al. (1999) expressed 3 human components involved in T-cell recognition of an MS-related autoantigen presented by the HLA-DR2 molecule: DRA*0101/DRB1*1501 (HLA-DR2), an MHC class II candidate MS susceptibility gene found among individuals of European descent; a T-cell receptor (TCR) from an MS patient-derived T-cell clone specific for the HLA-DR2-bound immunodominant myelin basic protein (MBP; 159430) 84-101 peptide; and the human CD4 coreceptor (186940). The amino acid sequence of MBP 84-102 peptide was the same in both human and mouse MBP. Following administration of the MBP peptide, together with adjuvant and pertussis toxin, transgenic mice developed focal central nervous system inflammation and demyelination that led to clinical manifestations and disease courses resembling those seen in MS. Spontaneous disease was observed in 4% of mice. When DR2 and TCR double transgenic mice were backcrossed twice to RAG2 (179616)-deficient mice, the incidence of spontaneous disease increased, demonstrating that T cells specific for the HLA-DR2-bound MBP peptide are sufficient and necessary for the development of disease. Madsen et al. (1999) concluded that their study provided evidence that HLA-DR2 can mediate both induced and spontaneous disease resembling MS by presenting a MBP self-peptide to T cells.
The cytokine ciliary neurotrophic factor (CNTF; 118945), which was originally identified as a survival factor for isolated neurons, promotes differentiation, maturation, and survival of oligodendrocytes. To investigate the role of endogenous CNTF in inflammatory demyelinating disease, Linker et al. (2002) studied myelin oligodendrocyte glycoprotein (MOG)-induced EAE in CNTF-deficient and wildtype C57BL/6 mice. Disease was more severe in CNTF-deficient mice and recovery was poor, with a 60% decrease in the number of proliferating oligodendrocyte precursor cells and a more than 50% increase in the rate of oligodendrocyte apoptosis. In addition, vacuolar dystrophy of myelin and axonal damage were more severe in CNTF-deficient mice. These specific pathologic features could be prevented by treatment with an antiserum against tumor necrosis factor-alpha, suggesting that endogenous CNTF may counterbalance this effect of TNF-alpha. Thus, Linker et al. (2002) identified a factor that modulates, in an inflammatory environment, glial cell survival and is an outcome determinant of EAE.
Kalyvas and David (2004) found high expression of phospholipase A2 (PLA2; see 172411) in endothelial and immune cells within CNS lesions from EAE mice throughout the disease course. Inhibition of PLA2 resulted in a significant reduction in the onset and progression of the disease, and was correlated with decreased expression of multiple chemokine and chemokine receptor genes. Kalyvas and David (2004) suggested that cytosolic PLA2 plays a central role in inflammation in EAE.
Arnett et al. (2004) demonstrated that Olig1 (606385) has an essential role in oligodendrocyte differentiation and consequent remyelination in the context of white matter injury. Olig1 -/- mice exhibited failure of remyelination of induced lesions, contrasting dramatically with the extensive remyelination of normal controls. The authors demonstrated a genetic requirement for Olig1 in repairing the types of lesions that occur in patients with multiple sclerosis.
IL12 is composed of p35 (IL12A; 161560) and p40 (IL12B) subunits, while IL23 is composed of a p19 subunit (IL23A; 605580) and the IL12 p40 subunit. Cua et al. (2003) generated mice lacking only IL23 (p19 -/-), only IL12 (p35 -/-), or both IL23 and IL12 (p40 -/-) and immunized them with MOG in an EAE model of multiple sclerosis. The p19 -/- mice were generated by completely removing the p19 locus. Mice lacking p19 or p40 were resistant to development of EAE, whereas mice lacking only p35 were at least as susceptible as wildtype mice. Exogenous IL23 delivered into the CNS, but not intravenously, 2 days before expected onset of disease reconstituted EAE in both p19 -/- and p40 -/- mice, although onset in the latter was delayed and disease was less severe. Administration of recombinant IL12 for 7 days, followed by IL23 gene transfer on day 8, also induced intense EAE, suggesting that IL12 promotes the development of Th1 cells, while IL23 is required for subsequent inflammatory events. MOG immunization induced Th1 cells and proinflammatory cytokines in p19 -/- mice, whereas in p35 -/- and p40 -/- mice, a Th2 phenotype was observed. Flow cytometric and real-time PCR analyses demonstrated the entry of Th1 cells into the CNS in the absence of IL23, without the recruitment of additional T cells or macrophages or the activation of resident microglia. During EAE, IL23R (607562) and IL12RB1 (601604) were coexpressed by inflammatory macrophages, whereas resident microglia expressed only IL12RB1. Although resident microglia and inflammatory macrophages produced IL23, only inflammatory macrophages responded to IL23. In contrast, IL12 was produced primarily by inflammatory macrophages, and both macrophages and microglia had the potential to respond to IL12. Cua et al. (2003) concluded that IL12 promotes the development of naive T cells, while IL23 mediates late-stage inflammation and seems to be necessary for chronic inflammation.
Friese et al. (2008) noted that HLA-A3 and HLA-B7 had been found in increased frequencies in individuals with MS, but that these associations were later thought to be due to strong linkage disequilibrium with HLA-DR2, encoded by HLA-DRB1*1501, which showed an even stronger association with MS. However, HLA-A*310, which encodes HLA-A3, was found to double the risk of MS, independently of HLA-DR2. In contrast, risk conferred by HLA-A3 or HLA-DR2 is halved in individuals bearing HLA-A*0201, encoding HLA-A2. To study mechanisms of MS susceptibility, Friese et al. (2008) generated a humanized mouse model with mice expressing HLA-A3 or HLA-A2 and a myelin-specific autoreactive T-cell receptor, termed 2D1-TCR, derived from an MS patient. Only 4% of mice doubly transgenic for HLA-A3 and 2D1-TCR developed MS-like disease spontaneously, but they developed disease more frequently and severely after immunization with myelin proteolipid protein (PLP; 300401), which is presented by HLA-A3. CNS infiltration by Cd4- and Cd8-positive T cells showed that the latter were involved in disease induction and the former in disease progression. Mice expressing HLA-A2 had diminished T-cell responsiveness to PLP, and flow cytometry revealed modulated 2D1-TCR expression. Friese et al. (2008) concluded that MHC class I alleles and CD8-positive T cells are directly implicated in the pathogenesis of MS, and that a network of MHC interactions shapes the risk of MS in each individual.
Tan et al. (2009) found that Pacap (ADCYAP1; 102980)-deficient mice developed heightened clinical and pathologic manifestations in response to induced experimental autoimmune encephalitis compared to wildtype mice. The increased sensitivity of the mutant mice was accompanied by enhanced mRNA expression of proinflammatory cytokines, chemokines and chemotactic factor receptors, and downregulation of antiinflammatory cytokines in the spinal cord. There was also a decrease in regulatory T cells associated with increased lymphocyte proliferation and decreased TGFB1 secretion in lymph nodes. The results demonstrated that endogenous Pacap provides protection in a mouse model of autoimmune encephalitis, and also identified PACAP as an intrinsic regulator of regulatory T cell abundance after inflammation.
Using intravital 2-photon imaging and flow cytometric analysis in a Lewis rat model of EAE, Bartholomaus et al. (2009) demonstrated the interactive processes between effector T cells and cerebral structures from their first arrival to the manifestation of autoimmune disease. Initially, T cells were arrested at leptomeningeal vessels and crawled preferentially against the blood flow along the luminal surface. After diapedesis, the cells continued their scan on the abluminal vascular surface and the underlying pial membrane. There, T cells encountered phagocytes that presented antigens, both foreign as well as myelin proteins. Over time, there was an increase in the number and duration of T cell-antigen presenting cell contacts, with increased expression of Ifng and Il17 in the meninges and brain parenchyma and intensified invasion of non-specific T cells in the CNS mediating further inflammation. Bartholomaus et al. (2009) concluded that autoimmune lesions are initiated around pial veins, with incoming T cells systematically scanning first the inner, then the outer vascular surfaces on at least 3 distinct levels.
Therapeutic Strategies
Chabas et al. (2001) used microarray analysis of spinal cords from rats paralyzed by experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, and identified increased osteopontin (OPN) transcripts. Osteopontin-deficient mice were resistant to progressive EAE and had frequent remissions, and myelin-reactive T cells in Opn -/- mice produced more interleukin-10 (124092) and less interferon-gamma (147570) than in Opn +/+ mice. Chabas et al. (2001) concluded that osteopontin appears to regulate T helper cell-1 (TH1)-mediated demyelinating disease, and may offer a potential target in blocking development of progressive MS.
Butzkueven et al. (2002) showed that the neurotrophic cytokine leukemia inhibitory factor (LIF; 159540) directly prevents oligodendrocyte death in animal models of MS, oligodendrocytes being the cells responsible for myelination in the CNS. They also demonstrated that this therapeutic effect complements endogenous LIF receptor (LIFR; 151443) signaling, which already serves to limit oligodendrocyte loss during immune attack. The results provided a novel approach for the treatment of MS.
Youssef et al. (2002) tested atorvastatin (Lipitor) in chronic and relapsing EAE, a CD4+ Th1-mediated CNS demyelinating disease model of multiple sclerosis. Youssef et al. (2002) showed that oral atorvastatin prevented or reversed chronic and relapsing paralysis. Atorvastatin induced STAT6 (601512) phosphorylation and secretion of Th2 cytokines IL4 (147780), IL5 (147850), and IL10, and of TGF-beta (190180). Conversely, STAT4 (600558) phosphorylation was inhibited and secretion of Th1 cytokines, including IL2 (147680), IL12 (see IL12B; 161561), IFN-gamma, and TNF-alpha, was suppressed. Atorvastatin promoted differentiation of Th0 cells into Th2 cells. In adoptive transfer, these Th2 cells protected recipient mice from EAE induction. Atorvastatin reduced CNS infiltration and MHC class II (see 142857) expression. Treatment of microglia inhibited IFNG-inducible transcription at multiple MHC class II transactivator promoters and suppressed class II upregulation. Atorvastatin suppressed IFN-gamma-inducible expression of CD40 (109535), CD80 (112203), and CD86 (601020) costimulatory molecules. L-mevalonate, the product of HMG-CoA reductase, reversed atorvastatin's effects on antigen-presenting cells (APC) and T cells. Atorvastatin treatment of either APC or T cells suppressed antigen-specific T-cell activation. Youssef et al. (2002) concluded that atorvastatin has pleiotropic immunomodulatory effects involving both APC and T cell compartments.
Chen et al. (2006) found that treating mice with anti-Il23 p19, like anti-Il23 p40, effectively blocked both acute EAE and EAE relapse. Anti-Il23 treatment blocked invasion of the CNS by T cells and inflammatory macrophages, and it reduced serum Il17 (603149) levels and CNS expression of Ifng, Ip10 (CXCL10; 147310), Il17, Il6 (147620), and Tnf mRNA. Anti-Il23 prevented EAE relapse, at least in part, by inhibiting epitope spreading. Although anti-Il17 blocked EAE relapse, it did not significantly reduce the number of infiltration foci, suggesting no effect on inflammatory cell migration but a possible downregulation of inflammatory effector cell function.
Beraud et al. (2006) demonstrated that intracerebroventricular infusion of BgK-F6A, a selective blocker of the potassium channel Kcna1 (176260), greatly reduced neurologic deficits in EAE rats. BgK-F6A increased the frequency of miniature excitatory postsynaptic currents in cultured rat hippocampal cells without affecting T-cell activation. Treated rats showed decreased ventriculomegaly, decreased cerebral injury, and preservation of brain bioenergetics compared to control rats.
In mice with EAE, Yang et al. (2010) found that inhibition of Nogoa (see 604475) using small interfering RNA (siRNA) resulted in suppression of Nogoa expression and functional neurologic recovery. Myelin-specific T-cell proliferation and cytokine production were unchanged, and the response was determined to result from increased axonal repair, as demonstrated by enhanced GAP43 (162060)-positive axons in the lesions. Of note, mice given the treatment at the time of disease onset showed a better response than those given treatment at the time of disease induction, indicating that a compromised blood-brain barrier was necessary for the siRNA to gain access to the central nervous system. The findings indicated that inhibition of NogoA can promote neuronal repair and functional recovery in a mouse model of MS.
Using the relapsing-remitting mouse model of spontaneously developing experimental autoimmune encephalomyelitis, Berer et al. (2011) showed that the commensal gut flora, in the absence of pathogenic agents, is essential in triggering immune processes, leading to a relapsing-remitting autoimmune disease driven by myelin-specific CD4+ T cells. Berer et al. (2011) showed further that recruitment and activation of autoantibody-producing B cells from the endogenous immune repertoire depends on availability of the target autoantigen, myelin oligodendrocyte glycoprotein (MOG; 159465), and commensal microbiota. Berer et al. (2011) concluded that their observations identified a sequence of events triggering organ-specific autoimmune disease and that these processes may offer novel therapeutic targets.
Arnett, H. A., Fancy, S. P. J., Alberta, J. A., Zhao, C., Plant, S. R., Kaing, S., Raine, C. S., Rowitch, D. H., Franklin, R. J. M., Stiles, C. D. bHLH transcription factor Olig1 is required to repair demyelinated lesions in the CNS. Science 306: 2111-2115, 2004. [PubMed: 15604411] [Full Text: https://doi.org/10.1126/science.1103709]
Australia and New Zealand Multiple Sclerosis Genetics Consortium ANZgene. Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20. Nature Genet. 41: 824-828, 2009. [PubMed: 19525955] [Full Text: https://doi.org/10.1038/ng.396]
Balashov, K. E., Aung, L. L., Vaknin-Dembinsky, A., Dhib-Jalbut, S., Weiner, H. L. Interferon-beta inhibits toll-like receptor 9 processing in multiple sclerosis. Ann. Neurol. 68: 899-906, 2010. [PubMed: 21061396] [Full Text: https://doi.org/10.1002/ana.22136]
Ban, M., Caillier, S., Mero, I.-L., Myhr, K.-M., Celius, E. G., Aarseth, J., Torkildsen, O., Harbo, H. F., Oksenberg, J., Hauser, S. L., Sawcer, S., Compston, A. No evidence of association between mutant alleles of the CYP27B1 gene and multiple sclerosis. Ann. Neurol. 73: 430-432, 2013. [PubMed: 23444327] [Full Text: https://doi.org/10.1002/ana.23833]
Ban, M., Goris, A., Lorentzen, A. R., Baker, A., Mihalova, T., Ingram, G., Booth, D. R., Heard, R. N., Stewart, G. J., Bogaert, E., Dubois, B., Harbo, H. F., and 19 others. Replication analysis identifies TYK2 as a multiple sclerosis susceptibility factor. Europ. J. Hum. Genet. 17: 1309-1313, 2009. [PubMed: 19293837] [Full Text: https://doi.org/10.1038/ejhg.2009.41]
Baranzini, S. E., Mudge, J., van Velkinburgh, J. C., Khankhanian, P., Khrebtukova, I., Miller, N. A., Zhang, L., Farmer, A. D., Bell, C. J., Kim, R. W., May, G. D., Woodward, J. E., and 17 others. Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis. Nature 464: 1351-1356, 2010. [PubMed: 20428171] [Full Text: https://doi.org/10.1038/nature08990]
Baranzini, S. E., Wang, J., Gibson, R. A., Galwey, N., Naegelin, Y., Barkhof, F., Radue, E.-W., Lindberg, R. L. P., Uitdehaag, B. M. G., Johnson, M. R., Angelakopoulou, A., Hall, L., and 25 others. Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis. Hum. Molec. Genet. 18: 767-778, 2009. [PubMed: 19010793] [Full Text: https://doi.org/10.1093/hmg/ddn388]
Barcellos, L. F., Caillier, S., Dragone, L., Elder, M., Vittinghoff, E., Bucher, P., Lincoln, R. R., Pericak-Vance, M., Haines, J. L., Weiss, A., Hauser, S. L., Oksenberg, J. R. PTPRC (CD45) is not associated with the development of multiple sclerosis in U.S. patients. Nature Genet. 29: 23-24, 2001. [PubMed: 11528386] [Full Text: https://doi.org/10.1038/ng722]
Barcellos, L. F., Oksenberg, J. R., Begovich, A. B., Martin, E. R., Schmidt, S., Vittinghoff, E., Goodin, D. S., Pelletier, D., Lincoln, R. R., Bucher, P., Swerdlin, A., Pericak-Vance, M. A., Haines, J. L., Hauser, S. L. HLA-DR2 dose effect on susceptibility to multiple sclerosis and influence on disease course. Am. J. Hum. Genet. 72: 710-716, 2003. [PubMed: 12557126] [Full Text: https://doi.org/10.1086/367781]
Barcellos, L. F., Schito, A. M., Rimmler, J. B., Vittinghoff, E., Shih, A., Lincoln, R., Callier, S., Elkins, M. K., Goodkin, D. E., Haines, J. L., Pericak-Vance, M. A., Hauser, S. L., Oksenberg, J. R. CC-chemokine receptor 5 polymorphism and age of onset in familial multiple sclerosis. Immunogenetics 51: 281-288, 2000. [PubMed: 10803840] [Full Text: https://doi.org/10.1007/s002510050621]
Barizzone, N., Pauwels, I., Luciano, B., Franckaert, D., Guerini, F. R., Cosemans, L., Hilven, K., Salviati, A., Dooley, J., Danso-Abeam, D., di Sapio, A., Cavalla, P., Decallonne, B., Mathieu, C., Liston, A., Leone, M., Dubois, B., D'Alfonso, S., Goris, A. No evidence for a role of rare CYP27B1 functional variations in multiple sclerosis. Ann. Neurol. 73: 433-437, 2013. [PubMed: 23483640] [Full Text: https://doi.org/10.1002/ana.23834]
Bartholomaus, I., Kawakami, N., Odoardi, F., Schlager, C., Miljkovic, D., Ellwart, J. W., Klinkert, W. E. F., Flugel-Koch, C., Issekutz, T. B., Wekerle, H., Flugel, A. Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions. Nature 462: 94-98, 2009. [PubMed: 19829296] [Full Text: https://doi.org/10.1038/nature08478]
Bas, H. Sclerosis multiplex familiaris. Z. Arztl. Fortbild. (Jena) 58: 153-155, 1964. [PubMed: 14151717]
Beall, S. S., Concannon, P., Charmley, P., McFarland, H. F., Gatti, R. A., Hood, L. E., McFarlin, D. E., Biddison, W. E. The germline repertoire of T cell receptor beta-chain genes in patients with chronic progressive multiple sclerosis. J. Neuroimmun. 21: 59-66, 1989. [PubMed: 2562801] [Full Text: https://doi.org/10.1016/0165-5728(89)90159-8]
Bell, J. I., Lathrop, G. M. Multiple loci for multiple sclerosis. Nature Genet. 13: 377-378, 1996. [PubMed: 8696322] [Full Text: https://doi.org/10.1038/ng0896-377]
Beraud, E., Viola, A., Regaya, I., Confort-Gouny, S., Siaud, P., Ibarrola, D., Le Fur, Y., Barbaria, J., Pellissier, J.-F., Sabatier, J.-M., Medina, I., Cozzone, P. J. Block of neural Kv1.1 potassium channels for neuroinflammatory disease therapy. Ann. Neurol. 60: 586-596, 2006. [PubMed: 17044011] [Full Text: https://doi.org/10.1002/ana.21007]
Berer, K., Mues, M., Koutrolos, M., Al Rasbi, Z., Boziki, M., Johner, C., Wekerle, H., Krishnamoorthy, G. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 479: 538-541, 2011. [PubMed: 22031325] [Full Text: https://doi.org/10.1038/nature10554]
Bird, T. D. Apparent familial multiple sclerosis in three generations: report of a family with histocompatibility antigen typing. Arch. Neurol. 32: 414-416, 1975. [PubMed: 1131074] [Full Text: https://doi.org/10.1001/archneur.1975.00490480080009]
Bittner, S., Bobak, N., Herrmann, A. M., Gobel, K., Meuth, P., Hohn, K. G., Stenner, M.-P., Budde, T., Wiendl, H., Meuth, S. G. Upregulation of K(2P)5.1 potassium channels in multiple sclerosis. Ann. Neurol. 68: 58-69, 2010. [PubMed: 20582984] [Full Text: https://doi.org/10.1002/ana.22010]
Bomprezzi, R., Ringner, M., Kim, S., Bittner, M. L., Khan, J., Chen, Y. Elkahloun, A., Yu, A., Bielekova, B., Meltzer, P. S., Martin, R., McFarland, H. F., Trent, J. M. Gene expression profile in multiple sclerosis patients and healthy controls: identifying pathways relevant to disease. Hum. Molec. Genet. 12: 2191-2199, 2003. [PubMed: 12915464] [Full Text: https://doi.org/10.1093/hmg/ddg221]
Butzkueven, H., Zhang, J.-G., Soilu-Hanninen, M., Hochrein, H., Chionh, F., Shipham, K. A., Emery, B., Turnley, A. M., Petratos, S., Ernst, M., Bartlett, P. F., Kilpatrick, T. J. LIF receptor signaling limits immune-mediated demyelination by enhancing oligodendrocyte survival. Nature Med. 8: 613-619, 2002. [PubMed: 12042813] [Full Text: https://doi.org/10.1038/nm0602-613]
Chabas, D., Baranzini, S. E., Mitchell, D., Bernard, C. C. A., Rittling, S. R., Denhardt, D. T., Sobel, R. A., Lock, C., Karpuj, M., Pedotti, R., Heller, R., Oksenberg, J. R., Steinman, L. The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science 294: 1731-1735, 2001. [PubMed: 11721059] [Full Text: https://doi.org/10.1126/science.1062960]
Chao, M. J., Ramagopalan, S. V., Herrera, B. M., Lincoln, M. R., Dyment, D. A., Sadovnick, A. D., Ebers, G. C. Epigenetics in multiple sclerosis susceptibility: difference in transgenerational risk localizes to the major histocompatibility complex. Hum. Molec. Genet. 18: 261-266, 2009. [PubMed: 19098025] [Full Text: https://doi.org/10.1093/hmg/ddn353]
Chapman, J., Korczyn, A. D, Karussis, D. M., Michaelson, D. M. The effects of APOE genotype on age at onset and progression of neurodegenerative diseases. Neurology 57: 1482-1485, 2001. [PubMed: 11673593] [Full Text: https://doi.org/10.1212/wnl.57.8.1482]
Chapman, J., Vinokurov, S., Achiron, A., Karussis, D. M., Mitosek-Szewczyk, K., Birnbaum, M., Michaelson, D. M., Korczyn, A. D. APOE genotype is a major predictor of long-term progression of disability in MS. Neurology 56: 312-316, 2001. [PubMed: 11171894] [Full Text: https://doi.org/10.1212/wnl.56.3.312]
Charmley, P., Beall, S. S., Concannon, P., Hood, L., Gatti, R. A. Further localization of a multiple sclerosis susceptibility gene on chromosome 7q using a new T cell receptor beta-chain DNA polymorphism. J. Neuroimmun. 32: 231-240, 1991. [PubMed: 1674514] [Full Text: https://doi.org/10.1016/0165-5728(91)90193-b]
Chataway, J., Feakes, R., Coraddu, F., Gray, J., Deans, J., Fraser, M., Robertson, N., Broadley, S., Jones, H., Clayton, D., Goodfellow, P., Sawcer, S., Compston, A. The genetics of multiple sclerosis: principles, background and updated results of the United Kingdom systematic genome screen. Brain 121: 1869-1887, 1998. [PubMed: 9798743] [Full Text: https://doi.org/10.1093/brain/121.10.1869]
Chen, Y., Langrish, C. L., Mckenzie, B., Joyce-Shaikh, B., Stumhofer, J. S., McClanahan, T., Blumenschein, W., Churakovsa, T., Low, J., Presta, L., Hunter, C. A., Kastelein, R. A., Cua, D. J. Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis. J. Clin. Invest. 116: 1317-1326, 2006. [PubMed: 16670771] [Full Text: https://doi.org/10.1172/JCI25308]
Cocco, E., Murru, M. R., Melis, C., Schirru, L., Solla, E., Lai, M., Rolesu, M., Marrosu, M. G. PTPRC (CD45) C77G mutation does not contribute to multiple sclerosis susceptibility in Sardinian patients. J. Neurol. 251: 1085-1088, 2004. [PubMed: 15372250] [Full Text: https://doi.org/10.1007/s00415-004-0485-1]
Colover, J. Genetic susceptibility to multiple sclerosis linked to myelin basic protein gene. Lancet 341: 56, 1993. [PubMed: 7678049] [Full Text: https://doi.org/10.1016/0140-6736(93)92534-z]
Comabella, M., Craig, D. W., Morcillo-Suarez, C., Rio, J., Navarro, A., Fernandez, M., Martin, R., Montalban, X. Genome-wide scan of 500,000 single-nucleotide polymorphisms among responders and nonresponders to interferon beta therapy in multiple sclerosis. Arch. Neurol. 66: 972-978, 2009. [PubMed: 19667218] [Full Text: https://doi.org/10.1001/archneurol.2009.150]
Coraddu, F., Sawcer, S., D'Alfonso, S., Lai, M., Hensiek, A., Solla, E., Broadley, S., Mancosu, C., Pugliatti, M., Marrosu, M. G., Compston, A. A genome screen for multiple sclerosis in Sardinian multiplex families. Europ. J. Hum. Genet. 9: 621-626, 2001. [PubMed: 11528508] [Full Text: https://doi.org/10.1038/sj.ejhg.5200680]
Cua, D. J., Sherlock, J., Chen, Y., Murphy, C. A., Joyce, B., Seymour, B., Lucian, L., To, W., Kwan, S., Churakova, T., Zurawski, S., Wiekowski, M., Lira, S. A., Gorman, D., Kastelein, R. A., Sedgwick, J. D. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421: 744-748, 2003. [PubMed: 12610626] [Full Text: https://doi.org/10.1038/nature01355]
D'Netto, M. J., Ward, H., Morrison, K. M., Ramagopalan, S. V., Dyment, D. A., DeLuca, G. C., Handunnetthi, L., Sadovnick, A. D., Ebers, G. C. Risk alleles for multiple sclerosis in multiplex families. Neurology 72: 1984-1988, 2009. [PubMed: 19506219] [Full Text: https://doi.org/10.1212/WNL.0b013e3181a92c25]
De Jager, P. L., Baecher-Allan, C., Maier, L. M., Arthur, A. T., Ottoboni, L., Barcellos, L., McCauley, J. L., Sawcer, S., Goris, A., Saarela, J., Yelensky, R., Price, A., and 26 others. The role of the CD58 locus in multiple sclerosis. Proc. Nat. Acad. Sci. 106: 5264-5269, 2009. [PubMed: 19237575] [Full Text: https://doi.org/10.1073/pnas.0813310106]
De Jager, P. L., Jia, X., Wang, J., de Bakker, P. I. W., Ottoboni, L., Aggarwal, N. T., Picco, L., Raychaudhuri, S., Tran, D., Aubin, C., Briskin, R., Romano, S., and 22 others. Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nature Genet. 41: 776-782, 2009. [PubMed: 19525953] [Full Text: https://doi.org/10.1038/ng.401]
Del Boccio, P., Pieragostino, D., Lugaresi, A., Di Ioia, M., Pavone, B., Travaglini, D., D'Aguanno, S., Bernardini, S., Sacchetta, P., Federici, G., Di Ilio, C., Gambi, D., Urbani, A. Cleavage of cystatin C is not associated with multiple sclerosis. Ann. Neurol. 62: 201-204, 2007. [PubMed: 17006926] [Full Text: https://doi.org/10.1002/ana.20968]
DeLuca, G. C., Ramagopalan, S. V., Herrera, B. M., Dyment, D. A., Lincoln, M. R., Montpetit, A., Pugliatti, M., Barnardo, M. C. N., Risch, N. J., Sadovnick, A. D., Chao, M., Sotgiu, S., Hudson, T. J., Ebers, G. C. An extremes of outcome strategy provides evidence that multiple sclerosis severity is determined by alleles at the HLA-DRB1 locus. Proc. Nat. Acad. Sci. 104: 20896-20901, 2007. [PubMed: 18087043] [Full Text: https://doi.org/10.1073/pnas.0707731105]
Derfuss, T., Parikh, K., Velhin, S., Braun, M., Mathey, E., Krumbholz, M., Kumpfel, T., Moldenhauer, A., Rader, C., Sonderegger, P., Pollmann, W., Tiefenthaller, C., Bauer, J., Lassmann, H., Wekerle, H., Karagogeos, D., Hohlfeld, R., Linington, C., Meinl, E. Contactin-2/TAG-1-directed autoimmunity is identified in multiple sclerosis patients and mediates gray matter pathology in animals. Proc. Nat. Acad. Sci. 106: 8302-8307, 2009. [PubMed: 19416878] [Full Text: https://doi.org/10.1073/pnas.0901496106]
Disanto, G., Magalhaes, S., Handel, A. E., Morrison, K. M., Sadovnick, A. D., Ebers, G. C., Banwell, B., Bar-Or, A., Canadian Pediatric Demyelinating Disease Network. HLA-DRB1 confers increased risk of pediatric-onset MS in children with acquired demyelination. Neurology 76: 781-786, 2011. [PubMed: 21288988] [Full Text: https://doi.org/10.1212/WNL.0b013e31820ee1cd]
Dyment, D. A., Sadnovich, A. D., Ebers, G. C. Genetics of multiple sclerosis. Hum. Molec. Genet. 6: 1693-1698, 1997. Note: Erratum: Hum. Molec. Genet. 6: 2189 only, 1997. [PubMed: 9300661] [Full Text: https://doi.org/10.1093/hmg/6.10.1693]
Dyment, D. A., Sadovnick, A. D., Willer, C. J., Armstrong, H., Cader, Z. M., Wiltshire, S., Kalman, B., Risch, N., Ebers, G. C. An extended genome scan in 442 Canadian multiple sclerosis-affected sibships: a report from the Canadian Collaborative Study Group. Hum. Molec. Genet. 13: 1005-1015, 2004. [PubMed: 15069025] [Full Text: https://doi.org/10.1093/hmg/ddh123]
Dyment, D. A., Willer, C. J., Scott, B., Armstrong, H., Ligers, A., Hillert, J., Paty, D. W., Hashimoto, S., Devonshire, V., Hooge, J., Kastrukoff, L., Oger, J., and 24 others. Genetic susceptibility to MS: a second stage analysis in Canadian MS families. Neurogenetics 3: 145-151, 2001. [PubMed: 11523565] [Full Text: https://doi.org/10.1007/s100480100113]
Ebers, G. C., Bulman, D. E., Sadovnick, A. D., Paty, D. W., Warren, S., Hader, W., Murray, T. J., Seland, T. P., Duquette, P., Grey, T., Nelson, R., Nicolle, M., Brunet, D. A population-based study of multiple sclerosis in twins. New Eng. J. Med. 315: 1638-1642, 1986. [PubMed: 3785335] [Full Text: https://doi.org/10.1056/NEJM198612253152603]
Ebers, G. C., Cousin, H. K., Feasby, T. E., Paty, D. W. Optic neuritis in familial MS. Neurology 31: 1138-1142, 1981. [PubMed: 7196536] [Full Text: https://doi.org/10.1212/wnl.31.9.1138]
Ebers, G. C., Kukay, K., Bulman, D. E., Sadovnick, A. D., Rice, G., Anderson, C., Armstrong, H., Cousin, K., Bell, R. B., Hader, W., Paty, D. W., Hashimoto, S., Oger, J., Duquette, P., Warren, S., Gray, T., O'Connor, P., Nath, A., Auty, A., Metz, L., and 10 others. A full genome search in multiple sclerosis. Nature Genet. 13: 472-476, 1996. [PubMed: 8696345] [Full Text: https://doi.org/10.1038/ng0896-472]
Ebers, G. C., Sadovnick, A. D., Risch, N. J., Canadian Collaborative Study Group. A genetic basis for familial aggregation in multiple sclerosis. Nature 377: 150-151, 1995. [PubMed: 7675080] [Full Text: https://doi.org/10.1038/377150a0]
Ebers, G. C. Personal Communication. London, Ontario, Canada 8/29/1988.
Ekbom, K. A. Familial multiple sclerosis associated with narcolepsy. Arch. Neurol. 15: 337-344, 1966. [PubMed: 5912493] [Full Text: https://doi.org/10.1001/archneur.1966.00470160003001]
Enzinger, C., Ropele, S., Strasser-Fuchs, S., Kapeller, P., Schmidt, H., Poltrum, B., Schmidt, R., Hartung, H.-P., Fazekas, F. Lower levels of N-acetylaspartate in multiple sclerosis patients with the apolipoprotein E epsilon-4 allele. Arch. Neurol. 60: 65-70, 2003. [PubMed: 12533090] [Full Text: https://doi.org/10.1001/archneur.60.1.65]
Eoli, M., Pandolfo, M., Milanese, C., Gasparini, P., Salmaggi, A., Zeviani, M. The myelin basic protein gene is not a major susceptibility locus for multiple sclerosis in Italian patients. J. Neurol. 241: 615-619, 1994. [PubMed: 7530769] [Full Text: https://doi.org/10.1007/BF00920626]
Eoli, M., Wood, N. W., Kellar-Wood, H. F., Holmans, P., Clayton, D., Compston, D. A. S. No linkage between multiple sclerosis and the T cell receptor alpha chain locus. J. Neurol. Sci. 124: 32-37, 1994. [PubMed: 7931419] [Full Text: https://doi.org/10.1016/0022-510x(94)90007-8]
Fazekas, F., Strasser-Fuchs, S., Kollegger, H., Berger, T., Kristoferitsch, W., Schmidt, H., Enzinger, C., Schiefermeier, M., Schwarz, C., Kornek, B., Reindl, M., Huber, K., Grass, R., Wimmer, G., Vass, K., Pfeiffer, K. H., Hartung, H. P., Schmidt, R. Apolipoprotein E epsilon4 is associated with rapid progression of multiple sclerosis. Neurology 57: 853-857, 2001. [PubMed: 11552016] [Full Text: https://doi.org/10.1212/wnl.57.5.853]
Fernandez-Arquero, M., Arroyo, R., Rubio, A., Martin, C., Vigil, P., Conejero, L., Figueredo, M. A., de la Concha, E. G. Primary association of a TNF gene polymorphism with susceptibility to multiple sclerosis. Neurology 53: 1361-1363, 1999. [PubMed: 10522904] [Full Text: https://doi.org/10.1212/wnl.53.6.1361]
Francis, D. A., Batchelor, J. R., McDonald, W. I., Dodi, I. A., Hing, S. N., Hern, J. E. C., Downie, A. W. HLA genetic determinants in familial MS: a study from the Grampian region of Scotland. Tissue Antigens 29: 7-12, 1987. [PubMed: 3590146]
Friese, M. A., Jakobsen, K. B., Friis, L., Etzensperger, R., Craner, M. J., McMahon, R. M., Jensen, L. T., Huygelen, V., Jones, E. Y., Bell, J. I., Fugger, L. Opposing effects of HLA class I molecules in tuning autoreactive CD8+ T cells in multiple sclerosis. Nature Med. 14: 1227-1235, 2008. [PubMed: 18953350] [Full Text: https://doi.org/10.1038/nm.1881]
Gaiser, C. N., Johnson, M. J., de Lange, G., Rassenti, L., Cavalli-Sforza, L. L., Steinman, L. Susceptibility to multiple sclerosis associated with an immunoglobulin gamma 3 restriction fragment length polymorphism. J. Clin. Invest. 79: 309-313, 1987. [PubMed: 2878940] [Full Text: https://doi.org/10.1172/JCI112801]
Gandhi, K. S., McKay, F. C., Cox, M., Riveros, C., Armstrong, N., Heard, R. N., Vucic, S., Williams, D. W., Stankovich, J., Brown, M., Danoy, P., Stewart, G. J., Broadley, S., Moscato, P., Lechner-Scott, J., Scott, R. J., Booth, D. R., ANZgene Multiple Sclerosis Genetics Consortium. The multiple sclerosis whole blood mRNA transcriptome and genetic associations indicate dysregulation of specific T cell pathways in pathogenesis. Hum. Molec. Genet. 19: 2134-2143, 2010. [PubMed: 20190274] [Full Text: https://doi.org/10.1093/hmg/ddq090]
Ghaffar, O., Reis, M., Pennell, N., O'Connor, P., Feinstein, A. APOE epsilon-4 and the cognitive genetics of multiple sclerosis. Neurology 74: 1611-1618, 2010. [PubMed: 20479360] [Full Text: https://doi.org/10.1212/WNL.0b013e3181e074a7]
Ghosh, S., Goldin, E., Gordon, F. H., Malchow, H. A., Rask-Madsen, J., Rutgeerts, P., Vyhnalek, P., Zadorova, Z., Palmer, T., Donoghue, S. Natalizumab for active Crohn's disease. New Eng. J. Med. 348: 24-32, 2003. [PubMed: 12510039] [Full Text: https://doi.org/10.1056/NEJMoa020732]
Goris, A., Maranian, M., Walton, A., Yeo, T. W., Ban, M., Gray, J., Dubois, B., Compston, A., Sawcer, S. CD24 Ala/Val polymorphism and multiple sclerosis. J. Neuroimmun. 175: 200-202, 2006. [PubMed: 16631259] [Full Text: https://doi.org/10.1016/j.jneuroim.2006.03.009]
Gregersen, J. W., Kranc, K. R., Ke, X., Svendsen, P., Madsen, L. S., Thomsen, A. R., Cardon, L. R., Bell, J. I., Fugger, L. Functional epistasis on a common MHC haplotype associated with multiple sclerosis. Nature 443: 574-577, 2006. [PubMed: 17006452] [Full Text: https://doi.org/10.1038/nature05133]
Haile, R. W., Hodge, S. E., Visscher, B. R., Spence, M. A., Detels, R., McAuliffe, T. L., Park, M. S., Dudley, J. P. Genetic susceptibility to multiple sclerosis: a linkage analysis with age-of-onset corrections. Clin. Genet. 18: 160-167, 1980. [PubMed: 7438496] [Full Text: https://doi.org/10.1111/j.1399-0004.1980.tb00864.x]
Haines, J. L., Bradford, Y., Garcia, M. E., Reed, A. D., Neumeister, E., Pericak-Vance, M. A., Rimmler, J. B., Menold, M. M., Martin, E. R., Oksenberg, J. R., Barcellos, L. F., Lincoln, R., Hauser, S. L. Multiple susceptibility loci for multiple sclerosis. Hum. Molec. Genet. 11: 2251-2256, 2002. [PubMed: 12217953] [Full Text: https://doi.org/10.1093/hmg/11.19.2251]
Haines, J. L., Terwedow, H. A., Burgess, K., Pericak-Vance, M. A., Rimmler, J. B., Martin, E. R., Oksenberg, J. R., Lincoln, R., Zhang, D. Y., Banatao, D. R., Gatto, N., Goodkin, D. E., Hauser, S. L. Linkage of the MHC to familial multiple sclerosis suggests genetic heterogeneity. Hum. Molec. Genet. 7: 1229-1234, 1998. [PubMed: 9668163] [Full Text: https://doi.org/10.1093/hmg/7.8.1229]
Hall, J. G. Personal Communication. Seattle, Wash. 1983.
Hansson, S. F., Simonsen, A. H., Zetterberg, H., Andersen, O., Haghighi, S., Fagerberg, I., Andreasson, U., Westman-Brinkmalm, A., Wallin, A., Ruetschi, U., Blennow, K. Cystatin C in cerebrospinal fluid and multiple sclerosis. Ann. Neurol. 62: 193-196, 2007. [PubMed: 16900522] [Full Text: https://doi.org/10.1002/ana.20945]
He, B., Giedraitis, V., Ligers, A., Binzer, M., Andersen, P. M., Forsgren, L., Sandkuijl, L. A., Hillert, J. Sharing of a conserved haplotype suggests a susceptibility gene for multiple sclerosis at chromosome 17p11. Europ. J. Hum. Genet. 10: 271-275, 2002. [PubMed: 12032736] [Full Text: https://doi.org/10.1038/sj.ejhg.5200802]
Herrera, B. M., Ramagopalan, S. V., Lincoln, M. R., Orton, S. M., Chao, M. J., Sadovnick A. D., Ebers, G. C. Parent-of-origin effects in MS: observations from avuncular pairs. Neurology 71: 799-803, 2008. [PubMed: 18480463] [Full Text: https://doi.org/10.1212/01.wnl.0000312377.50395.00]
Hla, T., Brinkmann, V. Sphingosine 1-phosphate (S1P): physiology and the effects of S1P receptor modulation. Neurology 76 (suppl. 3): S3-S8, 2011. [PubMed: 21339489] [Full Text: https://doi.org/10.1212/WNL.0b013e31820d5ec1]
Hoffmann, S., Cepok, S., Grummel, V., Lehmann-Horn, K., Hackermuller, J., Stadler, P. F., Hartung, H.-P., Berthele, A., Deisenhammer, F., Wassmuth, R., Hemmer, B. HLA-DRB1*0401 and HLA-DRB1*0408 are strongly associated with the development of antibodies against interferon-beta therapy in multiple sclerosis. Am. J. Hum. Genet. 83: 219-227, 2008. Note: Erratum: Am. J. Hum. Genet. 83: 541 only, 2008. [PubMed: 18656179] [Full Text: https://doi.org/10.1016/j.ajhg.2008.07.006]
International Multiple Sclerosis Genetics Consortium, Wellcome Trust Case Control Consortium 2. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476: 214-219, 2011. [PubMed: 21833088] [Full Text: https://doi.org/10.1038/nature10251]
International Multiple Sclerosis Genetics Consortium. A second major histocompatibility complex susceptibility locus for multiple sclerosis. Ann. Neurol. 61: 228-236, 2007. [PubMed: 17252545] [Full Text: https://doi.org/10.1002/ana.21063]
International Multiple Sclerosis Genetics Consortium. Risk alleles for multiple sclerosis identified by a genomewide study. New Eng. J. Med. 357: 851-862, 2007. [PubMed: 17660530] [Full Text: https://doi.org/10.1056/NEJMoa073493]
International Multiple Sclerosis Genetics Consortium. Comprehensive follow-up of the first genome-wide association study of multiple sclerosis identifies KIF21B and TMEM39A as susceptibility loci. Hum. Molec. Genet. 19: 953-962, 2010. [PubMed: 20007504] [Full Text: https://doi.org/10.1093/hmg/ddp542]
Irani, D. N., Anderson, C., Gundry, R., Cotter, R., Moore, S., Kerr, D. A., McArthur, J. C., Sacktor, N., Pardo, C. A., Jones, M., Calabresi, P. A., Nath, A. Cleavage of cystatin C in the cerebrospinal fluid of patients with multiple sclerosis. Ann. Neurol. 59: 237-247, 2006. [PubMed: 16437581] [Full Text: https://doi.org/10.1002/ana.20786]
Islam, T., Gauderman, W. J., Cozen, W., Mack, T. M. Childhood sun exposure influences risk of multiple sclerosis in monozygotic twins. Neurology 69: 381-388, 2007. [PubMed: 17646631] [Full Text: https://doi.org/10.1212/01.wnl.0000268266.50850.48]
Jacobsen, M., Schweer, D., Ziegler, A., Gaber, R., Schock, S., Schwinzer, R., Wonigeit, K., Lindert, R.-B., Kantarci, O., Schaefer-Klein, J., Schipper, H. I., Oertel, W. H., Heidenreich, F., Weinshenker, B. G., Sommer, N., Hemmer, B. A point mutation in PTPRC is associated with the development of multiple sclerosis. Nature Genet. 26: 495-499, 2000. [PubMed: 11101853] [Full Text: https://doi.org/10.1038/82659]
Jakkula, E., Leppa, V., Sulonen, A.-M., Varilo, T., Kallio, S., Kemppinen, A., Purcell, S., Koivisto, K., Tienari, P., Sumelahti, M.-L., Elovaara, I., Pirttila, T., and 17 others. Genome-wide association study in a high-risk isolate for multiple sclerosis reveals associated variants in STAT3 gene. Am. J. Hum. Genet. 86: 285-291, 2010. [PubMed: 20159113] [Full Text: https://doi.org/10.1016/j.ajhg.2010.01.017]
John, G. R., Shankar, S. L., Shafit-Zagardo, B., Massimi, A., Lee, S. C., Raine, C. S., Brosnan, C. F. Multiple sclerosis: re-expression of a developmental pathway that restricts oligodendrocyte maturation. Nature Med. 8: 1115-1121, 2002. [PubMed: 12357247] [Full Text: https://doi.org/10.1038/nm781]
Kalyvas, A., David, S. Cytosolic phospholipase A2 plays a key role in the pathogenesis of multiple sclerosis-like disease. Neuron 41: 323-335, 2004. [PubMed: 14766173] [Full Text: https://doi.org/10.1016/s0896-6273(04)00003-0]
Kantarci, O. H., Hebrink, D. D., Achenbach, S. J., Pittock, S. J., Altintas, A., Schaefer-Klein, J. L., Atkinson, E. J., de Andrade, M., McMurray, C. T., Rodriguez, M., Weinshenker, B. G. Association of APOE polymorphisms with disease severity in MS is limited to women. Neurology 62: 811-814, 2004. [PubMed: 15007140] [Full Text: https://doi.org/10.1212/01.wnl.0000113721.83287.83]
Kantor, R., Bakhanashvili, M., Achiron, A. A mutated CCR5 gene may have favorable prognostic implications in MS. Neurology 61: 238-240, 2003. [PubMed: 12874407] [Full Text: https://doi.org/10.1212/01.wnl.0000069921.20347.9e]
Kenealy, S. J., Babron, M.-C., Bradford, Y., Schnetz-Boutaud, N., Haines, J. L., Rimmler, J. B., Schmidt, S., Pericak-Vance, M. A., Barcellos, L. F., Lincoln, R. R., Oksenberg, J. R., Hauser, S. L., Clanet, M., Brassat, D., Edan, G., Yaouanq, J., Semana, G., Cournu-Rebeix, I., Lyon-Caen, O., Fontaine, B., American-French Multiple Sclerosis Genetics Group. A second-generation genomic screen for multiple sclerosis. Am. J. Hum. Genet. 75: 1070-1078, 2004. [PubMed: 15494893] [Full Text: https://doi.org/10.1086/426459]
Kinnunen, E., Koskenvuo, M., Kaprio, J., Aho, K. Multiple sclerosis in a nationwide series of twins. Neurology 37: 1627-1629, 1987. [PubMed: 3658169] [Full Text: https://doi.org/10.1212/wnl.37.10.1627]
Koutsis, G., Panas, M., Giogkaraki, E., Potagas, C., Karadima, G., Sfagos, C., Vassilopoulos, D. APOE epsilon-4 is associated with impaired verbal learning in patients with MS. Neurology 68: 546-549, 2007. [PubMed: 17310023] [Full Text: https://doi.org/10.1212/01.wnl.0000254468.51973.44]
Kroner, A., Mehling, M., Hemmer, B., Rieckmann, P., Toyka, K. V., Maurer, M., Wiendl, H. A PD-1 polymorphism is associated with disease progression in multiple sclerosis. Ann. Neurol. 58: 50-57, 2005. [PubMed: 15912506] [Full Text: https://doi.org/10.1002/ana.20514]
Kumpfel, T., Hoffmann, L.-A., Pellkofer, H., Pollmann, W., Feneberg, W., Hohlfeld, R., Lohse, P. Multiple sclerosis and the TNFRSF1A R92Q mutation: clinical characteristics of 21 cases. Neurology 71: 1812-1820, 2008. [PubMed: 19029521] [Full Text: https://doi.org/10.1212/01.wnl.0000335930.18776.47]
Kuokkanen, S., Sundvall, M., Terwilliger, J. D., Tienari, P. J., Wikstrom, J., Holmdahl, R., Pettersson, U., Peltonen, L. A putative vulnerability locus to multiple sclerosis maps to 5p14-p12 in a region syntenic to the murine locus Eae2. Nature Genet. 13: 477-480, 1996. [PubMed: 8696346] [Full Text: https://doi.org/10.1038/ng0896-477]
Kurtzke, J. F., Beebe, G. W., Norman, J. E., Jr. Epidemiology of multiple sclerosis in U.S. veterans: 1. Race, sex, and geographic distribution. Neurology 29: 1228-1235, 1979. [PubMed: 573402] [Full Text: https://doi.org/10.1212/wnl.29.9_part_1.1228]
Kurtzke, J. F., Hyllested, K. Multiple sclerosis in the Faroe Islands: I. Clinical and epidemiological features. Ann. Neurol. 5: 6-21, 1979. [PubMed: 371519] [Full Text: https://doi.org/10.1002/ana.410050104]
Lang, H. L. E., Jacobsen, H., Ikemizu, S., Andersson, C., Harlos, K., Madsen, L., Hjorth, P., Sondergaard, L., Svejgaard, A., Wucherpfennig, K., Stuart, D. I., Bell, J. I., Jones, E. Y., Fugger, L. A functional and structural basis for TCR cross-reactivity in multiple sclerosis. Nature Immun. 3: 940-943, 2002. [PubMed: 12244309] [Full Text: https://doi.org/10.1038/ni835]
Lanz, T. V., Brewer, R. C., Ho, P. P., Moon, J.-S., Jude, K. M., Fernandez, D., Fernandes, R. A., Gomez, A. M., Nadj, G.-S., Bartley, C. M., Schubert, R. D., Hawes, I. A., and 18 others. Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Nature 603: 321-327, 2022. [PubMed: 35073561] [Full Text: https://doi.org/10.1038/s41586-022-04432-7]
Ligers, A., Dyment, D. A., Willer, C. J., Sadovnick, A. D., Ebers, G., Risch, N., Hillert, J., Canadian Collaborative Study Groups. Evidence of linkage with HLA-DR in DRB1*15-negative families with multiple sclerosis. Am. J. Hum. Genet. 69: 900-903, 2001. [PubMed: 11519010] [Full Text: https://doi.org/10.1086/323480]
Lill, C. M., Schjeide, B.-M. M., Akkad, D. A., Blaschke, P., Winkelmann, A., Gerdes, L.-A., Hoffjan, S., Luessi, F., Dorner, T., Li, S.-C., Steinhagen-Thiessen, E., Lindenberger, U., and 10 others. Independent replication of STAT3 association with multiple sclerosis in a large German case-control sample. Neurogenetics 13: 83-86, 2012. [PubMed: 22095036] [Full Text: https://doi.org/10.1007/s10048-011-0305-6]
Lincoln, M. R., Montpetit, A., Cader, M. Z., Saarela, J., Dyment, D. A., Tiislar, M., Ferretti, V., Tienari, P. J., Sadovnick, A. D., Peltonen, L., Ebers, G. C., Hudson, T. J. A predominant role for the HLA class II region in the association of the MHC region with multiple sclerosis. Nature Genet. 37: 1108-1112, 2005. [PubMed: 16186814] [Full Text: https://doi.org/10.1038/ng1647]
Linker, R. A., Maurer, M., Gaupp, S., Martini, R., Holtmann, B., Giess, R., Rieckmann, P., Lassmann, H., Toyka, K. V., Sendtner, M., Gold, R. CNTF is a major protective factor in demyelinating CNS disease: a neurotrophic cytokine as modulator in neuroinflammation. Nature Med. 8: 620-624, 2002. [PubMed: 12042814] [Full Text: https://doi.org/10.1038/nm0602-620]
Lucotte, G., French MS Consortium. Confirmation of a gene for multiple sclerosis (MS) to chromosome region 19q13.3. Genet. Counsel. 13: 133-138, 2002. [PubMed: 12150212]
MacKay, R. P., Myrianthopoulos, N. C. Multiple sclerosis in twins and their relatives: final report. Arch. Neurol. 15: 449-462, 1966. [PubMed: 5955946] [Full Text: https://doi.org/10.1001/archneur.1966.00470170003001]
Madsen, L. S., Andersson, E. C., Jansson, L., Krogsgaard, M., Andersen, C. B., Engberg, J., Strominger, J. L., Svejgaard, A., Hjorth, J. P., Holmdahl, R., Wucherpfennig, K. W., Fugger, L. A humanized model for multiple sclerosis using HLA-DR2 and a human T-cell receptor. Nature Genet. 23: 343-347, 1999. [PubMed: 10610182] [Full Text: https://doi.org/10.1038/15525]
Marrosu, M. G., Lai, M., Cocco, E., Loi, V., Spinicci, G., Pischedda, M. P., Massole, S., Marrosu, G., Contu, P. Genetic factors and the founder effect explain familial MS in Sardinia. Neurology 58: 283-288, 2002. [PubMed: 11805258] [Full Text: https://doi.org/10.1212/wnl.58.2.283]
Marrosu, M. G., Murru, M. R., Costa, G., Murru, R., Muntoni, F., Cucca, F. DRB1-DQA1-DQB1 loci and multiple sclerosis predisposition in the Sardinian population. Hum. Molec. Genet. 7: 1235-1237, 1998. [PubMed: 9668164] [Full Text: https://doi.org/10.1093/hmg/7.8.1235]
Marrosu, M. G., Murru, R., Murru, M. R., Costa, G., Zavattari, P., Whalen, M., Cocco, E., Mancosu, C., Schirru, L., Solla, E., Fadda, E., Melis, C., Porru, I., Rolesu, M., Cucca, F. Dissection of the HLA association with multiple sclerosis in the founder isolated population of Sardinia. Hum. Molec. Genet. 10: 2907-2916, 2001. [PubMed: 11741834] [Full Text: https://doi.org/10.1093/hmg/10.25.2907]
Martinez, A., Rubio, A., Urcelay, E., Fernandez-Arquero, M., de las Heras, V., Arroyo, R., Villoslada, P., Montalban, X., de la Concha, E. G. TNF-376A marks susceptibility to MS in the Spanish population: a replication study. Neurology 62: 809-810, 2004. [PubMed: 15007139] [Full Text: https://doi.org/10.1212/01.wnl.0000113722.93895.8b]
Mattila, K. M., Luomala, M., Lehtimaki, T., Laippala, P., Koivula, T., Elovaara, I. Interaction between ESR1 and HLA-DR2 may contribute to the development of MS in women. Neurology 56: 1246-1247, 2001. [PubMed: 11342704] [Full Text: https://doi.org/10.1212/wnl.56.9.1246]
McAlpine, D. Familial incidence and its significance. In: McAlpine, D.; Lumsden, C. E.; Acheson, E. D.: Multiple Sclerosis: A Reappraisal. Baltimore: Williams and Wilkins Co. (pub.) 1965. Pp. 61-74.
McKusick, V. A. Personal Communication. Baltimore, Md. 1983.
Mero, I.-L., Lorentzen, A. R., Ban, M., Smestad, C., Celius, E. G., Aarseth, J. H., Myhr, K.-M., Link, J., Hillert, J., Olsson, T., Kockum, I., Masterman, T., and 10 others. A rare variant of the TYK2 gene is confirmed to be associated with multiple sclerosis. Europ. J. Hum. Genet. 18: 502-504, 2010. [PubMed: 19888296] [Full Text: https://doi.org/10.1038/ejhg.2009.195]
Miller, D. H., Khan, O. A., Sheremata, W. A., Blumhardt, L. D., Rice, G. P. A., Libonati, M. A., Willmer-Hulme, A. J., Dalton, C. M., Miszkiel, K. A., O'Connor, P. W. A controlled trial of natalizumab for relapsing multiple sclerosis. New Eng. J. Med. 348: 15-23, 2003. [PubMed: 12510038] [Full Text: https://doi.org/10.1056/NEJMoa020696]
Multiple Sclerosis Genetics Group. A complete genomic screen for multiple sclerosis underscores a role for the major histocompatability (sic) complex. Nature Genet. 13: 469-471, 1996. [PubMed: 8696344] [Full Text: https://doi.org/10.1038/ng0896-469]
Multiple Sclerosis Genetics Group. Clinical demographics of multiplex families with multiple sclerosis. Ann. Neurol. 43: 530-534, 1998. [PubMed: 9546337] [Full Text: https://doi.org/10.1002/ana.410430419]
Mumford, C. J., Wood, N. W., Kellar-Wood, H., Thorpe, J. W., Miller, D. H., Compston, D. A. S. The British Isles survey of multiple sclerosis in twins. Neurology 44: 11-15, 1994. [PubMed: 8290043] [Full Text: https://doi.org/10.1212/wnl.44.1.11]
Munger, K. L., Levin, L. I., Hollis, B. W., Howard, N. S., Ascherio, A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 296: 2832-2838, 2006. [PubMed: 17179460] [Full Text: https://doi.org/10.1001/jama.296.23.2832]
Mycko, M. P., Kwinkowski, M., Tronczynska, E., Szymanska, B., Selmaj, K. W. Multiple sclerosis: the increased frequency of the ICAM-1 exon 6 gene point mutation genetic type K469. Ann. Neurol. 44: 70-75, 1998. [PubMed: 9667594] [Full Text: https://doi.org/10.1002/ana.410440113]
Natowicz, M. R., Bejjani, B. Genetic disorders that masquerade as multiple sclerosis. Am. J. Med. Genet. 49: 149-169, 1994. [PubMed: 8116663] [Full Text: https://doi.org/10.1002/ajmg.1320490202]
Noseworthy, J. H., Lucchinetti, C., Rodriguez, M., Weinshenker, B. G. Multiple sclerosis. New Eng. J. Med. 343: 938-952, 2000. [PubMed: 11006371] [Full Text: https://doi.org/10.1056/NEJM200009283431307]
Oksenberg, J. R., Barcellos, L. F., Cree, B. A. C., Baranzini, S. E., Bugawan, T. L., Khan, O., Lincoln, R. R., Swerdlin, A., Mignot, E., Lin, L., Goodin, D., Erlich, H. A., Schmidt, S., Thomson, G., Reich, D. E., Pericak-Vance, M. A., Haines, J. L., Hauser, S. L. Mapping multiple sclerosis susceptibility to the HLA-DR locus in African Americans. Am. J. Hum. Genet. 74: 160-167, 2004. [PubMed: 14669136] [Full Text: https://doi.org/10.1086/380997]
Otaegui, D., Saenz, A., Camano, P., Blazques, L., Goicoechea, M., Ruiz-Martinez, J., Olaskoaga, J., Emparanza, J. A., de Munain, A. L. CD24 V/V is an allele associated with the risk of developing multiple sclerosis in the Spanish population. Mult. Scler. 12: 511-514, 2006. [PubMed: 16900767] [Full Text: https://doi.org/10.1191/135248506ms1314sr]
Ousman, S. S., Tomooka, B. H., van Noort, J. M., Wawrousek, E. F., O'Connor, K. C., Hafler, D. A., Sobel, R. A., Robinson, W. H., Steinman, L. Protective and therapeutic role for alpha-beta-crystallin in autoimmune demyelination. Nature 448: 474-479, 2007. [PubMed: 17568699] [Full Text: https://doi.org/10.1038/nature05935]
Pericak-Vance, M. A., Rimmler, J. B., Martin, E. R., Haines, J. L., Garcia, M. E., Oksenberg, J. R., Barcellos, L. F., Lincoln, R., Goodkin, D. E., Hauser, S. L. Linkage and association analysis of chromosome 19q13 in multiple sclerosis. Neurogenetics 3: 195-201, 2001. [PubMed: 11714099] [Full Text: https://doi.org/10.1007/s100480100119]
Perini, P., Tagliaferri, C., Belloni, M., Biasi, G., Gallo, P. The HLA-DR13 haplotype is associated with 'benign' multiple sclerosis in northeast Italy. Neurology 57: 158-159, 2001. [PubMed: 11445652] [Full Text: https://doi.org/10.1212/wnl.57.1.158]
Pugliatti, M., Solinas, G., Sotgiu, S., Castiglia, P., Rosati, G. Multiple sclerosis distribution in northern Sardinia: spatial cluster analysis of prevalence. Neurology 58: 277-282, 2002. [PubMed: 11805257] [Full Text: https://doi.org/10.1212/wnl.58.2.277]
Raj, T., Rothamel, K., Mostafavi, S., Ye, C., Lee, M. N., Replogle, J. M., Feng, T., Lee, M., Asinovski, N., Frohlich, I., Imboywa, S., Von Korff, A., and 15 others. Polarization of the effects of autoimmune and neurodegenerative risk alleles in leukocytes. Science 344: 519-523, 2014. [PubMed: 24786080] [Full Text: https://doi.org/10.1126/science.1249547]
Ramagopalan, S. V., Dyment, D. A., Cader, M. Z., Morrison, K. M., Disanto, G., Morahan, J. M., Berlanga-Taylor, A. J., Handel, A., De Luca, G. C., Sadovnick, A. D., Lepage, P., Montpetit, A., Ebers, G. C. Rare variants in the CYP27B1 gene are associated with multiple sclerosis. Ann. Neurol. 70: 881-886, 2011. [PubMed: 22190362] [Full Text: https://doi.org/10.1002/ana.22678]
Ramagopalan, S. V., Hanwell, H. E. C., Giovannoni, G., Knappskog, P. M., Nyland, H. I., Myhr, K.-M., Ebers, G. C., Torkildsen, O. Vitamin D-dependent rickets, HLA-DRB1, and the risk of multiple sclerosis. Arch. Neurol. 67: 1034-1035, 2010. [PubMed: 20697062] [Full Text: https://doi.org/10.1001/archneurol.2010.182]
Ramagopalan, S. V., Maugeri, N. J., Handunnetthi, L., Lincoln, M. R., Orton, S.-M., Dyment, D. A., DeLuca, G. C., Herrera, B. M., Chao, M. J., Sadovnick, A. D., Ebers, G. C., Knight, J. C. Expression of the multiple sclerosis-associated MHC class II allele HLA-DRB1*1501 is regulated by vitamin D. PLoS Genet. 5: e1000369, 2009. Note: Electronic Article. [PubMed: 19197344] [Full Text: https://doi.org/10.1371/journal.pgen.1000369]
Reich, D., Patterson, N., De Jager, P. L., McDonald, G. J., Waliszewska, A., Tandon, A., Lincoln, R. R., DeLoa, C., Fruhan, S. A., Cabre, P., Bera, O., Semana, G., Kelly, M. A., Francis, D. A., Ardlie, K., Khan, O., Cree, B. A. C., Hauser, S. L., Oksenberg, J. R., Hafler, D. A. A whole-genome admixture scan finds a candidate locus for multiple sclerosis susceptibility. Nature Genet. 37: 1113-1118, 2005. [PubMed: 16186815] [Full Text: https://doi.org/10.1038/ng1646]
Rife, D. C. Populations of hybrid origin as source material for the detection of linkage. Am. J. Hum. Genet. 6: 26-33, 1954. [PubMed: 13138567]
Ristori, G., Cannoni, S., Stazi, M. A., Vanacore, N., Cotichini, R., Alfo, M., Pugliatti, M., Sotgiu, S., Solaro, C., Bomprezzi, R., Di Giovanni, S., Talamanca, L. F., and 10 others. Multiple sclerosis in twins from continental Italy and Sardinia: a nationwide study. Ann. Neurol. 59: 27-34, 2006. [PubMed: 16240370] [Full Text: https://doi.org/10.1002/ana.20683]
Rose, J., Gerken, S., Lynch, S., Pisani, P., Varvil, T., Otterud, B., Leppert, M. Genetic susceptibility in familial multiple sclerosis not linked to the myelin basic protein gene. Lancet 341: 1179-1181, 1993. [PubMed: 7683738] [Full Text: https://doi.org/10.1016/0140-6736(93)91003-5]
Saarela, J., Schoenberg Fejzo, M., Chen, D., Finnila, S., Parkkonen, M., Kuokkanen, S., Sobel, E., Tienari, P. J., Sumelahti, M.-L., Wikstrom, J., Elovaara, I., Koivisto, K., Pirttila, T., Reunanen, M., Palotie, A., Peltonen, L. Fine mapping of a multiple sclerosis locus to 2.5 Mb on chromosome 17q22-q24. Hum. Molec. Genet. 11: 2257-2267, 2002. [PubMed: 12217954] [Full Text: https://doi.org/10.1093/hmg/11.19.2257]
Sadovnick, A. D., Dircks, A., Ebers, G. C. Genetic counselling in multiple sclerosis: risks to sibs and children of affected individuals. Clin. Genet. 56: 118-122, 1999. [PubMed: 10517247] [Full Text: https://doi.org/10.1034/j.1399-0004.1999.560204.x]
Sadovnick, A. D., Ebers, G. C., Dyment, D. A., Risch, N. J., Canadian Collaborative Study Group. Evidence for genetic basis of multiple sclerosis. Lancet 347: 1728-1730, 1996. [PubMed: 8656905] [Full Text: https://doi.org/10.1016/s0140-6736(96)90807-7]
Sadovnick, A. D., Macleod, P. M. J. The familial nature of multiple sclerosis: empiric recurrence risks for first-, second-, and third-degree relatives of patients. Neurology 31: 1039-1041, 1981. [PubMed: 7196517] [Full Text: https://doi.org/10.1212/wnl.31.8.1039]
Sadovnick, A. D., Spence, M. A., Tideman, S. A goodness-of-fit test for the polygenic threshold model: application to multiple sclerosis. Am. J. Med. Genet. 8: 355-361, 1981. [PubMed: 7234906] [Full Text: https://doi.org/10.1002/ajmg.1320080315]
Salier, J.-P., Sesboue, R., Martin-Mondiere, C., Daveau, M., Cesaro, P., Cavelier, B., Coquerel, A., Legrand, L., Goust, J. M., Degos, J. D. Combined influences of Gm and HLA phenotypes upon multiple sclerosis susceptibility and severity. J. Clin. Invest. 78: 533-538, 1986. [PubMed: 3461005] [Full Text: https://doi.org/10.1172/JCI112605]
Sawcer, S., Ban, M., Wason, J., Dudbridge, F. What role for genetics in the prediction of multiple sclerosis? Ann. Neurol. 67: 3-10, 2010. [PubMed: 20186855] [Full Text: https://doi.org/10.1002/ana.21911]
Sawcer, S., Jones, H. B., Feakes, R., Gray, J., Smaldon, N., Chataway, J., Robertson, N., Clayton, D., Goodfellow, P. N., Compston, A. A genome screen in multiple sclerosis reveals susceptibility loci on chromosome 6p21 and 17q22. Nature Genet. 13: 464-468, 1996. [PubMed: 8696343] [Full Text: https://doi.org/10.1038/ng0896-464]
Schmidt, S., Barcellos, L. F., DeSombre, K., Rimmler, J. B., Lincoln, R. R., Bucher, P., Saunders, A. M., Lai, E., Martin, E. R., Vance, J. M., Oksenberg, J. R., Hauser, S. L., Pericak-Vance, M. A., Haines, J. L., Multiple Sclerosis Genetics Group. Association of polymorphisms in the apolipoprotein E region with susceptibility to and progression of multiple sclerosis. Am. J. Hum. Genet. 70: 708-717, 2002. [PubMed: 11836653] [Full Text: https://doi.org/10.1086/339269]
Schrijver, H. M., Crusius, J. B. A., Uitdehaag, B. M. J., Garcia Gonzalez, M. A., Kostense, P. J., Polman, C. H., Pena, A. S. Association of interleukin-1-beta and interleukin-1 receptor antagonist genes with disease severity in MS. Neurology 52: 595-599, 1999. [PubMed: 10025794] [Full Text: https://doi.org/10.1212/wnl.52.3.595]
Seboun, E., Robinson, M. A., Doolittle, T. H., Ciulla, T. A., Kindt, T. J., Hauser, S. L. A susceptibility locus for multiple sclerosis is linked to the T cell receptor beta chain complex. Cell 57: 1095-1100, 1989. [PubMed: 2567636] [Full Text: https://doi.org/10.1016/0092-8674(89)90046-9]
Sharief, M. K., Semra, Y. K. Down-regulation of survivin expression in T lymphocytes after interferon beta-1a treatment in patients with multiple sclerosis. Arch. Neurol. 59: 1115-1121, 2002. [PubMed: 12117359] [Full Text: https://doi.org/10.1001/archneur.59.7.1115]
Sheremata, W. A., Poskanzer, D. C., Withum, D. G., MacLeod, C. L., Whiteside, M. E. Unusual occurrence on a tropical island of multiple sclerosis. Lancet 325: 618 only, 1985. Note: Originally Volume II. [PubMed: 2863628] [Full Text: https://doi.org/10.1016/s0140-6736(85)90621-x]
Soliven, B., Miron, V., Chun, J. The neurobiology of sphingosine 1-phosphate signaling and sphingosine 1-phosphate receptor modulators. Neurology 76 (suppl. 3): S9-S14, 2011. [PubMed: 21339490] [Full Text: https://doi.org/10.1212/WNL.0b013e31820d9507]
Srivastava, R., Aslam, M., Kalluri, S. R., Schirmer, L., Buck, D., Tackenberg, B., Rothhammer, V., Chan, A., Gold, R., Berthele, A., Bennett, J. L., Korn, T., Hemmer, B. Potassium channel KIR4.1 as an immune target in multiple sclerosis. New Eng. J. Med. 367: 115-123, 2012. [PubMed: 22784115] [Full Text: https://doi.org/10.1056/NEJMoa1110740]
Steinman, L. Presenting an odd autoantigen. Nature 375: 739-740, 1995. [PubMed: 7541112] [Full Text: https://doi.org/10.1038/375739b0]
Steinman, L. Multiple sclerosis: a coordinated immunological attack against myelin in the central nervous system. Cell 85: 299-302, 1996. [PubMed: 8616884] [Full Text: https://doi.org/10.1016/s0092-8674(00)81107-1]
Svejgaard, A. The immunogenetics of multiple sclerosis. Immunogenetics 60: 275-286, 2008. [PubMed: 18461312] [Full Text: https://doi.org/10.1007/s00251-008-0295-1]
Szvetko, A. L., Jones, A., Mackenzie, J., Tajouri, L., Csurhes, P. A., Greer, J. M., Pender, M. P., Griffiths, L. R. An investigation of the C77G and C772T variations within the human protein tyrosine phosphatase receptor type C gene for association with multiple sclerosis in an Australian population. Brain Res. 1255: 148-152, 2009. [PubMed: 19111528] [Full Text: https://doi.org/10.1016/j.brainres.2008.12.017]
Takahashi, J. L., Giuliani, F., Power, C., Imai, Y., Yong, V. W. Interleukin-1-beta promotes oligodendrocyte death through glutamate excitotoxicity. Ann. Neurol. 53: 588-595, 2003. [PubMed: 12730992] [Full Text: https://doi.org/10.1002/ana.10519]
Tan, Y.-V., Abad, C., Lopez, R., Dong, H., Liu, S., Lee, A., Gomariz, R. P., Leceta, J., Waschek, J. A. Pituitary adenylyl cyclase-activating polypeptide is an intrinsic regulator of Treg abundance and protects against experimental autoimmune encephalomyelitis. Proc. Nat. Acad. Sci. 106: 2012-2017, 2009. [PubMed: 19190179] [Full Text: https://doi.org/10.1073/pnas.0812257106]
Terasaki, P. I., Park, M. S., Opelz, G., Ting, A. Multiple sclerosis and high incidence of a B-lymphocyte antigen. Science 193: 1245-1247, 1976. [PubMed: 1085490] [Full Text: https://doi.org/10.1126/science.1085490]
Tienari, P. J., Peltonen, L., Palo, J. Genetic susceptibility to multiple sclerosis linked to myelin basic protein gene. Reply. (Letter) Lancet 341: 56, 1993.
Tienari, P. J., Terwilliger, J. D., Ott, J., Palo, J., Peltonen, L. Two-locus linkage analysis in multiple sclerosis (MS). Genomics 19: 320-325, 1994. [PubMed: 7514567] [Full Text: https://doi.org/10.1006/geno.1994.1064]
Tienari, P. J., Wikstrom, J., Sajantila, A., Palo, J., Peltonen, L. Genetic susceptibility to multiple sclerosis linked to myelin basic protein gene. Lancet 340: 987-991, 1992. [PubMed: 1383661] [Full Text: https://doi.org/10.1016/0140-6736(92)93007-a]
Tiwari, J. L., Hodge, S. E., Terasaki, P. I., Spence, M. A. HLA and the inheritance of multiple sclerosis: linkage analysis of 72 pedigrees. Am. J. Hum. Genet. 32: 103-111, 1980. [PubMed: 7361760]
Torkildsen, O., Knappskog, P. M., Nyland, H. I., Myhr, K.-M. Vitamin D-dependent rickets as a possible risk factor for multiple sclerosis. Arch. Neurol. 65: 809-811, 2008. [PubMed: 18541802] [Full Text: https://doi.org/10.1001/archneur.65.6.809]
Utz, U., Biddison, W. E., McFarland, H. F., McFarlin, D. E., Flerlage, M., Martin, R. Skewed T-cell receptor repertoire in genetically identical twins correlates with multiple sclerosis. Nature 364: 243-247, 1993. [PubMed: 7686632] [Full Text: https://doi.org/10.1038/364243a0]
van der Walt, A., Stankovich, J., Bahlo, M., Taylor, B. V., van der Mei, I. A. F., Foote, S. J., Kilpatrick, T. J., Rubio, J. P., Butzkueven, H. Apolipoprotein genotype does not influence MS severity, cognition, or brain atrophy. Neurology 73: 1018-1025, 2009. [PubMed: 19786693] [Full Text: https://doi.org/10.1212/WNL.0b013e3181b9c85e]
van Noort, J. M., van Sechel, A. C., Bajramovic, J. J., El Quagmiri, M., Polman, C. H., Lassmann, H., Ravid, R. The small heat-shock protein alpha-B-crystallin as candidate autoantigen in multiple sclerosis. Nature 375: 798-801, 1995. [PubMed: 7596414] [Full Text: https://doi.org/10.1038/375798a0]
Vandenbroeck, K., Opdenakker, G., Goris, A., Murru, R., Billiau, A., Marrosu, M. G. Interferon-gamma gene polymorphism--associated risk for multiple sclerosis in Sardinia. Ann. Neurol. 44: 841-842, 1998. [PubMed: 9818947] [Full Text: https://doi.org/10.1002/ana.410440525]
Vitale, E., Cook, S., Sun, R., Specchia, C., Subramanian, K., Rocchi, M., Nathanson, D., Schwalb, M., Devoto, M., Rohowsky-Kochan, C. Linkage analysis conditional on HLA status in a large North American pedigree supports the presence of a multiple sclerosis susceptibility locus on chromosome 12p12. Hum. Molec. Genet. 11: 295-300, 2002. [PubMed: 11823448] [Full Text: https://doi.org/10.1093/hmg/11.3.295]
von Andrian, U. H., Engelhardt, B. Alpha-4 integrins as therapeutic targets in autoimmune disease. (Editorial) New Eng. J. Med. 348: 68-72, 2003. [PubMed: 12510047] [Full Text: https://doi.org/10.1056/NEJMe020157]
Vorechovsky, I., Kralovicova, J., Tchilian, E., Masterman, T., Zhang, Z., Ferry, B., Misbah, S., Chapel, H., Webster, D., Hellgren, D., Anvret, M., Hillert, J., Hammarstrom, L., Beverley, P. C. Does 77C-G in PTPRC modify autoimmune disorders linked to the major histocompatibility locus? Nature Genet. 29: 22-23, 2001. [PubMed: 11548742] [Full Text: https://doi.org/10.1038/ng723]
Vyse, T. J., Todd, J. A. Genetic analysis of autoimmune disease. Cell 85: 311-318, 1996. [PubMed: 8616887] [Full Text: https://doi.org/10.1016/s0092-8674(00)81110-1]
Waksman, B. H. More genes versus environment. Nature 377: 105-106, 1995. [PubMed: 7675076] [Full Text: https://doi.org/10.1038/377105a0]
Wallin, M. T., Page, W. F., Kurtzke, J. F. Multiple sclerosis in US veterans of the Vietnam era and later military service: race, sex, and geography. Ann. Neurol. 55: 65-71, 2004. [PubMed: 14705113] [Full Text: https://doi.org/10.1002/ana.10788]
Walter, M. A., Gibson, W. T., Ebers, G. C., Cox, D. W. Susceptibility to multiple sclerosis is associated with the proximal immunoglobulin heavy chain variable region. J. Clin. Invest. 87: 1266-1273, 1991. [PubMed: 1672695] [Full Text: https://doi.org/10.1172/JCI115128]
Weinshenker, B. G., Hebrink, D. D., Atkinson, E., Kantarci, O. H. Association of a tumor necrosis factor alpha polymorphism with MS susceptibility. Neurology 57: 1341-1346, 2001. [PubMed: 11591866] [Full Text: https://doi.org/10.1212/wnl.57.7.1341]
Weinshenker, B. G., Kantarci, O. H. Association of APOE polymorphisms with disease severity in MS is limited to women. (Letter) Neurology 63: 1139 only, 2004.
Wellcome Trust Case Control Consortium and The Australo-Anglo-American Spondylitis Consortium. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nature Genet. 39: 1329-1337, 2007. [PubMed: 17952073] [Full Text: https://doi.org/10.1038/ng.2007.17]
Wheeler, D., Jelinek, C., Anderson, C., Gundry, R., Irani, D., Calbresi, P., Cotter, R., Nath, A. Reply. Ann. Neurol. 62: 205 only, 2007.
Willer, C. J., Dyment, D. A., Risch, N. J., Sadovnick, A. D., Ebers, G. C., The Canadian Collaborative Study Group. Twin concordance and sibling recurrence rates in multiple sclerosis. Proc. Nat. Acad. Sci. 100: 12877-12882, 2003. [PubMed: 14569025] [Full Text: https://doi.org/10.1073/pnas.1932604100]
Willer, C. J., Dyment, D. A., Sadovnick, A. D., Rothwell, P. M., Murray, T. J., Ebers, G. C. Timing of birth and risk of multiple sclerosis: population based study. Brit. Med. J. 330: 120, 2005. Note: Electronic Article. [PubMed: 15585537] [Full Text: https://doi.org/10.1136/bmj.38301.686030.63]
Williams, A., Eldridge, R., McFarland, H., Houff, S., Krebs, H., McFarlin, D. Multiple sclerosis in twins. Neurology 30: 1139-1147, 1980. [PubMed: 7191511] [Full Text: https://doi.org/10.1212/wnl.30.11.1139]
Williams, K. E., Johnson, L. N. Neuroretinitis in patients with multiple sclerosis. Ophthalmology 111: 335-341, 2004. [PubMed: 15019385] [Full Text: https://doi.org/10.1016/S0161-6420(03)00663-8]
Wood, N. W., Holmans, P., Clayton, D., Robertson, N., Compston, D. A. S. No linkage or association between multiple sclerosis and the myelin basic protein gene in affected sibling pairs. J. Neurol. Neurosurg. Psychiat. 57: 1191-1194, 1994. [PubMed: 7523603] [Full Text: https://doi.org/10.1136/jnnp.57.10.1191]
Xu, C., Dai, Y., Lorentzen, J. C., Dahlman, I., Olsson, T., Hillert, J. Linkage analysis in multiple sclerosis of chromosomal regions syntenic to experimental autoimmune disease loci. Europ. J. Hum. Genet. 9: 458-463, 2001. [PubMed: 11436128] [Full Text: https://doi.org/10.1038/sj.ejhg.5200653]
Yang, Y., Liu, Y., Wei, P., Peng, H., Winger, R., Hussain, R. Z., Ben, L.-H., Cravens, P. D., Gocke, A. R., Puttaparthi, K., Racke, M. K., McTigue, D. M., Lovett-Racke, A. E. Silencing Nogo-A promotes functional recovery in demyelinating disease. Ann. Neurol. 67: 498-507, 2010. [PubMed: 20437585] [Full Text: https://doi.org/10.1002/ana.21935]
Youssef, S., Stuve, O., Patarroyo, J. C., Ruiz, P. J., Radosevich, J. L., Hur, E. M., Bravo, M., Mitchell, D. J., Sobel, R. A., Steinman, L., Zamvil, S. S. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 420: 78-84, 2002. [PubMed: 12422218] [Full Text: https://doi.org/10.1038/nature01158]
Zhou, Q., Rammohan, K., Lin, S., Robinson, N., Li, O., Liu, X., Bai, X., Yin, L., Scarberry, B., Du, P., You, M., Guan, K., Zheng, P., Liu, Y. CD24 is a genetic modifier for risk and progression of multiple sclerosis. Proc. Nat. Acad. Sci. 100: 15041-15046, 2003. Note: Erratum: Proc. Nat. Acad. Sci. 102: 8392 only, 2005. [PubMed: 14657362] [Full Text: https://doi.org/10.1073/pnas.2533866100]
Zipp, F., Weber, F., Huber, S., Sotgiu, S., Czlonkowska, A., Holler, E., Albert, E., Weiss, E. H., Wekerle, H., Hohlfeld, R. Genetic control of multiple sclerosis: increased production of lymphotoxin and tumor necrosis factor-alpha by HLA-DR2(+) T cells. Ann. Neurol. 38: 723-730, 1995. [PubMed: 7486863] [Full Text: https://doi.org/10.1002/ana.410380506]
Zwemmer, J., Uitdehaag, B., van Kamp, G., Barkhof, F., Polman, C. Association of APOE polymorphisms with disease severity in MS is limited to women. (Letter) Neurology 63: 1139 only, 2004. [PubMed: 15452327] [Full Text: https://doi.org/10.1212/wnl.63.6.1139]