Alternative titles; symbols
DO: 0110014;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q25.3-q31.1 | {Macular degeneration, age-related, 1} | 603075 | Autosomal dominant | 3 | HMCN1 | 608548 |
| 1q31.3 | {Macular degeneration, age-related, reduced risk of} | 603075 | Autosomal dominant | 3 | CFHR3 | 605336 |
| 1q31.3 | {Macular degeneration, age-related, reduced risk of} | 603075 | Autosomal dominant | 3 | CFHR1 | 134371 |
| 19q13.32 | {?Macular degeneration, age-related} | 603075 | Autosomal dominant | 3 | APOE | 107741 |
A number sign (#) is used with this entry because susceptibility to age-related macular degeneration-1 (ARMD1) is associated with polymorphism in the hemicentin gene (HMCN1; 608548), also called FBLN6, on chromosome 1q25.3-q31.1.
Age-related macular degeneration (ARMD) is a progressive degeneration of photoreceptors and underlying retinal pigment epithelium (RPE) cells in the macula region of the retina. It is a highly prevalent disease and a major cause of blindness in the Western world. Drusen, pale excrescences of variable size, and other deposits accumulate below the RPE on the Bruch membrane; clinical and histopathologic investigations have shown that these extracellular deposits are the hallmark of early ARMD. As ARMD advances, areas of geographic atrophy of the RPE can cause visual loss, or choroidal neovascularization can occur to cause wet, or exudative, ARMD with accompanying central visual loss (summary by De et al., 2007).
Genetic Heterogeneity of Age-Related Macular Degeneration
ARMD2 (153800) is associated with mutation in the ABCR gene (601691) on chromosome 1p, and ARMD3 (608895) is caused by mutation in the FBLN5 gene (604580) on chromosome 14q31. Up to 50% of the attributable risk of age-related macular degeneration (ARMD4; 610698) appears to be explained by a polymorphism in the CFH gene (134370.0008). ARMD5 (613761) and ARMD6 (613757) are associated with mutation in the ERCC6 (609413) and RAX2 (610362) genes, respectively. ARMD7 (610149) and ARMD8 (613778), which both represent susceptibility linked to chromosome 10q26, are associated with single-nucleotide polymorphisms in the HTRA1 (602194) and ARMS2 (611313) genes, respectively. ARMD9 (611378) is associated with single-nucleotide polymorphisms in the C3 gene (120700). ARMD10 (611488) maps to chromosome 9q32 and may be associated with a polymorphism in the TLR4 gene (603030). ARMD11 (611953) is association with variation in the CST3 gene (604312); ARMD12 (613784) with variation in the CX3CR1 gene (601470); and ARMD13 (615439) with variation in the CFI gene (217030). ARMD14 (615489) is associated with variation in or near the C2 (613927) and CFB (138470) genes on chromosome 6p21. ARMD15 (615591) is associated with variation in the C9 gene (120940). There is evidence for a form of ARMD caused by mutation in the mitochondrial gene MTTL1 (590050).
A haplotype carrying deletion of the complement factor H-related genes CFHR1 (134371) and CFHR3 (605336) is also associated with reduced risk of ARMD.
Lotery and Trump (2007) reviewed the molecular biology of age-related macular degeneration and tabulated the genes associated with ARMD, including those with only positive findings versus genes for which conflicting results have been found.
Age-related macular degeneration is the most common cause of acquired visual impairment in the elderly and is estimated to affect at least 11 million individuals in the United States. U.S. studies showed that mild forms of ARMD occur in nearly 30% of those 75 years and older, and advanced forms occur in about 7% of people in this age group. Allikmets et al. (1997) noted that ARMD is divided clinically into 2 subtypes: 80% of patients have 'dry' ARMD, the hallmarks of which include 1 or more of the following: the presence of cellular debris (drusen) in or under the retinal pigment epithelium (RPE), irregularities in the pigmentation of the RPE, or geographic atrophy (GA). Twenty percent of patients have exudative or 'wet' ARMD characterized by serous detachment of the RPE or choroidal neovascularization (CNV), or both. Severe vision loss is associated most often with geographic atrophy or exudative disease.
Streiff and Babel (1963) described senile macular changes in an 80-year-old mother and her 50-year-old daughter. Because of the late onset of the abnormality, dominant inheritance is more likely, and affected members of successive generations are not likely to be observed. Braley (1966) stated that senile macular degeneration runs in families: 'Nearly every patient I have seen has had other members of the family similarly affected.' Visual disturbance without ophthalmoscopic findings may be present by age 50 and fundus changes become apparent only after age 70. Meyers and Zachary (1988) described a family in which 6 of 13 children had age-related macular degeneration; 2 of the affected sibs were identical twins in whom monozygosity was established (with 99.4% likelihood) by genetic tests.
Postel et al. (2005) compared the phenotype between 411 singleton and 125 multiplex probands with ARMD and found the clinical appearance and distribution of ARMD grades to be similar. There was no statistically significant difference in grade distribution between the 2 groups. Postel et al. (2005) concluded that singleton and multiplex ARMD data could be combined for consolidated genetic analyses.
Bok (2002) stated there was widespread agreement among ophthalmologists that numerous large drusen, when present in both eyes, represent a significant risk factor for the evolution of early ARMD into more advanced ARMD, with loss of central vision.
In a population-based cohort study, Klein et al. (2003) examined the relationship of 2 diseases associated with systemic inflammatory response, emphysema and gout, and selected markers of systemic inflammation with the 10-year incidence of age-related maculopathy. They found a modest relationship between both increased white blood cell count and emphysema and the increased 10-year incidence of lesions defining early and late age-related maculopathy.
Phipps et al. (2003) found that cone adaptational kinetics were affected early in age-related maculopathy, while the visual acuity was still good.
Retinal angiomatous proliferation (RAP) is a neovascularization that begins in the retina and extends through the subretinal space, eventually communicating with choroidal neovascularization. It occurs in 10 to 15% of neovascular ARMD cases (Ghazi, 2002). It has a poor natural history and shows resistance to treatment with conventional laser photocoagulation (Yannuzzi et al., 2001).
Scholl et al. (2004) reported close agreement between the grading of stereoscopic color slides and digitized nonstereoscopic images. Digitized nonstereoscopic color images of the macula proved to be useful for grading age-related maculopathy (ARM) and ARMD.
In a review of epidemiologic data regarding the natural history of ARMD and its risk factors, Klein et al. (2004) found that large soft drusen associated with pigmentary abnormalities increased the risk of progression to advanced ARMD. Large soft drusen might fade over time. Advanced ARMD was more likely to be present in whites than in blacks, despite the similar prevalence of soft drusen in both groups. Neovascular ARMD was more frequent than geographic atrophy in most population-based studies in whites in America, Australia, and the Netherlands than in similar population-based studies in Iceland and Norway. After age and family history, there were few consistent relationships of risk factors to ARMD. Of these, the relationships of smoking, hypertension, and cataract surgery to advanced ARMD had been the most consistent.
Maruko et al. (2007) studied the clinical characteristics of 189 consecutive Japanese patients newly diagnosed with neovascular ARMD at one hospital and found that their features differed from those reported in white patients. In Japanese patients, there was a preponderance of polypoidal choroidal vasculopathy (PCV), male gender, unilaterality, and absence of drusen in the second eye, with the exception of RAP.
In a review on the association of cigarette smoking and ARMD, Thornton et al. (2005) found that the estimate of risk was about 2- to 3-fold higher in current smokers when compared with never smokers in 13 studies. They concluded that cigarette smoking is an important risk factor for ARMD.
Chakravarthy et al. (2007) examined the association between cigarette smoking and ARMD in 158 cases of ARMD (109 neovascular and 49 GA) in a European population. Current smokers had increased odds of neovascular ARMD or geographic atrophy, whereas for ex-smokers the odds were less. Compared with people with unilateral ARMD, those with bilateral ARMD were more likely to have a history of heavy smoking in the previous 25 years. The attributable fraction for ARMD due to smoking was 27%. Chakravarthy et al. (2007) concluded that their findings highlighted the need for increasing public awareness of the risks associated with smoking.
In a longitudinal study using the Blue Mountains Eye Study cohort in Australia, Tan et al. (2007) assessed the relationship between cardiovascular disease and cardiovascular risk factors, other than smoking, and risk of long-term incident ARMD. Increasing high-density lipoprotein (HDL) cholesterol was inversely related to incident late ARMD. Elevated total-HDL cholesterol ratio predicted late ARMD and geographic atrophy (GA). Diabetes predicted incident GA, but not neovascular ARMD. History of stroke predicted incident early ARMD and incident indistinct soft or reticular drusen. Neither pulse pressure, systolic or diastolic blood pressure reading, nor presence of hypertension at baseline was associated with incident ARMD. Tan et al. (2007) stated that their findings provided evidence of links between cardiovascular risk factors and ARMD but that further prospective evaluation of these relationships was warranted.
In a longitudinal study using the Blue Mountains Eye Study cohort, Tan et al. (2007) found that, after controlling for age, gender, and other confounding factors, statin users, compared with nonusers, had a reduced risk of developing indistinct soft drusen, the principal late ARMD precursor lesion.
Nolan et al. (2007) identified a relative lack of macular pigment as an independent risk factor for ARMD.
Pang et al. (2015) examined 230 eyes of 150 consecutive patients with neovascular AMD and 40 human donor eyes with a histopathologic diagnosis of neovascular AMD for layered, hyperreflective, subretinal pigment epithelium (sub-RPE) lines, known as the onion sign. Sixteen (7%) of the 230 eyes and 2 (5%) of the 40 donor eyes had onion signs on spectral-domain optical coherence tomography (SD-OCT). In all 16 eyes, the onion sign persisted in follow-up for up to 5 years, with fluctuations in the abundance of lines and association with intraretinal hyperreflective foci. Histologic analysis of the 2 donor eyes revealed that the hyperreflective lines correlated with clefts created by extraction of cholesterol crystals during tissue processing.
Joachim et al. (2015) reported the incidence and progression of ARMD over 15 years, beginning with 3,654 participants aged 49 years or older, and ending with 1,149 of the remaining participants, in the Blue Mountains Eye Study. The 15-year incidence was 22.7% for early ARMD and 6.8% for late ARMD; after adjusting for competing risks, early and late ARMD incidence was 15.1% and 4.1%, respectively. Women had a higher incidence of any ARMD compared with men. Risk of progression to late ARMD was strongly associated with severity of early ARMD lesions.
ARMD1
In a family studied by Klein et al. (1998), 10 members with ARMD showed the presence of large, soft, confluent drusen (see 126700) accompanied by varying degrees of RPE degeneration and/or geographic atrophy. Age at diagnosis of ARMD ranged from 54 to 77 years (average, 65 years). In the 8 affected patients with visual symptoms, onset was between age 52 and 75 years (average, 67 years). The clinical picture was described as 'a predominantly dry phenotype.'
Pras et al. (2015) studied a 3-generation Tunisian Jewish family in which 5 elderly sibs had advanced ARMD. All were first diagnosed in the seventh decade of life, and all experienced progression to severe vision impairment within 10 years. Funduscopy and optical coherence tomography showed a variety of pathology, including macular hemorrhage, large hard drusen, massive depigmentation and geographic atrophy of the RPE, and choroidal neovascularization with resultant juxtafoveal scarring. Fluorescein angiography displayed early hyperfluorescence due to the simultaneous occurrence of many large foci of 'window defect' RPE atrophy as well as 'starry sky' staining of basal laminar drusen extending peripherally. Of 9 asymptomatic offspring in the next generation of the family, 7 had normal macular appearance whereas 2 sisters, aged 39 and 48 years, exhibited altered foveal reflexes with hypopigmentation.
ARMD is a multifactorial disorder with both genetic and environmental risk factors (Heiba et al., 1994, Seddon et al., 1997).
By linkage studies in a large family segregating ARMD (ARMD1), Klein et al. (1998) demonstrated linkage to chromosome 1q25-q31 between markers D1S466 and D1S413. Additional linkage in this family by Schultz et al. (2003) narrowed the ARMD1 candidate region to a 14.9-Mb interval between LAMB2 (150325) and D1S3469.
Genomewide Linkage Studies
In addition to the forms of ARMD mapping to chromosomes 1p, 14q, and 1q, several others have been suggested by linkage studies. Majewski et al. (2003) studied 70 families with ARMD, ranging from small nuclear families to extended multigenerational pedigrees, with 344 affected and 217 unaffected members. Both parametric and allele-sharing models were used and analyses were performed not only on complete pedigrees but also on subdivisions of the families into nuclear pedigrees. To dissect potential genetic factors responsible for differences in disease manifestation, Majewski et al. (2003) stratified the sample by 2 major phenotypes, neovascular ARMD and geographic atrophy, and by age of affected family members at the time of evaluation. In the combined sample, the following loci had a lod score exceeding 2 under at least 1 of the models considered: 1q31 (hlod = 2.07 at D1S518), 3p13 (hlod = 2.19), 4q32 (hlod = 2.66, for the subset of families with predominantly dry ARMD), 9q33 (lod = 2.01), and 10q26 (hlod = 3.06). Using correlation analysis, they found a statistically significant correlation between lod scores at 3p13 and 10q26, providing evidence for epistatic interactions between the loci and, hence, a complex basis of ARMD.
Seddon et al. (2003) performed a genomewide scan for ARMD in 158 multiplex families. Evidence of linkage was found for regions on 10 chromosomes. Significant linkage to ARMD was found for 1 marker on chromosome 2, 2 adjacent markers on chromosome 3, 2 adjacent markers on chromosome 6, and 7 contiguous markers on chromosome 8, with empirical P values of 0.00001.
Iyengar et al. (2004) conducted a genomewide scan in 34 extended families (297 individuals, 349 sib pairs) ascertained through index cases with neovascular disease of the retina or geographic atrophy. They found evidence of a major locus on 15q that presented as a weak linkage signal in a previous genome scan for ARMD, but was otherwise novel. In the present scan, they observed a total of 13 regions on 11 chromosomes, with a nominal multipoint significance level of P equal to or less than 0.01 or lod equal to or more than 1.18. Family-by-family analysis of the data suggested heterogeneity. For example, a single family individually showed linkage evidence at 8 loci, at a level of P less than 0.0001. Other tests for heterogeneity suggested that ARMD susceptibility loci on 9p24, 10q26, and 15q21 were not present in all families. In a study of candidate genes at 1q31 and 2p21, Iyengar et al. (2004) tested hemicentin-1 (608548) and EFEMP1 (601548), respectively. The SNP analysis for hemicentin-1 on 1q31 suggested that variants within or in very close proximity to this gene cause ARMD pathogenesis. In summary, they found evidence of a major ARMD locus on 15q21, which, coupled with numerous other loci segregating in these families, suggested complex oligogenic patterns of inheritance for ARMD.
In a combined analysis of 2 genomewide scans of age-related maculopathy that included 391 families and 452 affected sib pairs (Weeks et al. (2000, 2001)), Weeks et al. (2004) found linkage evidence in 4 regions: 1q31, 9p13, 10q26, and 17q25. Weeks et al. (2004) added a third set of families and performed an integrated analysis incorporating 530 families and 736 affected sib pairs. They found continued evidence of susceptibility loci within the 1q31, 10q26, and 17q25 regions. They also completed ordered subset analyses (OSAs) with apolipoprotein E (APOE; 107741) alleles, smoking history, and age at onset as stratifying covariates. Based on their OSA results, Weeks et al. (2004) hypothesized that the effect of smoking on the risk of ARMD is accentuated by a gene in the 10q26 region--a region that had been implicated in ARMD in previous studies.
Jakobsdottir et al. (2005) genotyped all nonsynonymous single-nucleotide polymorphisms (SNPs) in the critical region on 10q26 identified by Weeks et al. (2004) and found a highly significant association (P less than 0.00001) between ARMD and PLEKHA1 (607772). They concluded that this gene is primarily responsible for the evidence of linkage of age-related maculopathy to 10q26 and a major contributor to susceptibility to this disorder. The association of either a single or a double copy of the high-risk allele within the PLEKHA1 locus accounted for an odds ratio of 5.0 for ARMD and a population-attributable risk as high as 57%.
Thompson et al. (2007) investigated the role of pigmentary abnormalities (PA) and geographic atrophy (GA) in ARMD. A previous genomewide scan was reanalyzed using the rate of change along the PA/GA scale. Evidence was found for linkage to 1q25, 5p13, 6q21-23, and 11q14 (p less than 0.01). The most significant peak was found on chromosome 1, near CFH (p = 6.20 x 10(-4)). Analysis using the rate of change replicated the peaks in 5p13 and 6q21-23, suggesting that these loci might contribute to the rate of progression of PA/GA. Association analysis of CFH polymorphisms suggested that CFH might play a role in the development of pigmentary abnormalities and might modify the progression along the PA/GA scale. Thompson et al. (2007) concluded that their findings suggested a complex heterogeneous model for pigment abnormalities and geographic atrophy in ARMD.
To identify genetic factors that modify the risk of exudative ARMD in the Japanese population, Arakawa et al. (2011) conducted a genomewide association study and a replication study using a total of 1,536 individuals with exudative AMD and 18,894 controls. In addition to CFH (rs800292, 134370.0009; p = 4.23 x 10(-15)) and ARMS2 (610149) (rs3750847, p = 8.67 x 10(-29)) loci, Arakawa et al. (2011) identified 2 new susceptibility loci for exudative AMD. The most significant association was achieved for rs13278062, a SNP located in LOC38964 397 bp upstream from TNFRSF10A (603611) on chromosome 8p21 (combined p = 1.03 x 10(-12), odds ratio = 0.73, 95% CI 0.67-0.80). The SNP rs13278062 and its surrounding region participate in regulation of TNFRSF10A transcription activity. The second most significant association was achieved for rs1713985 on chromosome 4q12 (combined p = 2.34 x 10(-8), odds ratio = 1.30), which represents a linkage disequilibrium block that includes 4 genes: REST (600571); C4ORF14; POLR2B (180661); and IGFBP7 (602867).
Associations Pending Confirmation
Kondo et al. (2010) analyzed the rs10033900 variant in 116 Japanese patients with neovascular ARMD and 189 controls and found significant association between the minor 'C' allele and a decreased disease risk (odds ratio, 0.28; p = 0.0035) in CC homozygotes. The authors noted that the rs10033900 SNP is located 2,781 bp upstream of the 3-prime untranslated region of the CFI gene (217030).
In a prospective, population-based study of 4,571 individuals aged 55 and older (the Rotterdam study) with a mean follow-up time of 7 years, Boekhoorn et al. (2007) found that ESR1 PvuII-XbaI haplotype 1 was a risk factor for late ARMD. The 2 single-nucleotide polymorphisms (SNPs) of haplotype 1 are the adjacent PvuII (rs2234693), a T-to-C transition in intron 1, and XbaI (rs9340799), a G-to-A transition located 46 bp downstream of the PvuII polymorphism. Persons with 2 copies of haplotype 1 were at 3.2 times higher risk for late ARMD than noncarriers of haplotype 1, after adjustment for age and gender. This increase was more pronounced for wet ARMD (hazard ratio 4.3) after adjustment for age, gender, smoking, and complement factor H genotype. Correction for hormone replacement therapy, blood pressure, and body mass index did not essentially alter the findings.
Fritsche et al. (2013) performed a collaborative genomewide association study of more than 17,100 advanced cases of ARMD and more than 60,000 controls. They identified 19 loci associated at p less than 5 x 10(-8), showing enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling, and angiogenesis. Their results included 7 novel loci: rs13081855, near the COL8A1 (120251) and FILIP1L (612993) genes; rs3130783, near IER3 (602996) and DDR1 (600408); rs8135665, near SLC16A8 (610409); rs334353, near TGFBR1 (190181); rs8017304, near RAD51B (602948); rs6795735, near ADAMTS9 (605421); and rs9542236, near B3GALTL (610308). The authors noted that in contrast to most other complex diseases, a genetic risk score combining SNP genotypes from all 19 loci was able to distinguish cases from controls in all samples examined, and suggested that such risk scores could be used to identify and prioritize at-risk individuals for preventive treatment.
Allikmets et al. (1997) stated that there is no reliable treatment for dry ARMD, and that only about 5% of patients with the wet subtype are candidates for laser coagulation therapy.
Borrillo et al. (2003) described a novel surgical technique for the treatment of retinal angiomatous proliferation which occurs in exudative ARMD and is resistant to treatment with conventional laser photocoagulation. Specific surgical lysis of the feeding arteriole and draining venule of the RAP lesion resulted in improved visual acuity. This was correlated with resolution of intraretinal edema and flattening of associated pigment epithelial detachment, which the authors confirmed by fluorescein angiography, optical coherence tomography, and high-speed indocyanine green angiography.
Jonas et al. (2004) reported findings suggesting that repeated intravitreal injections of triamcinolone acetonide, an antiinflammatory, might improve visual acuity in patients with exudative ARMD.
In a review of use of RNA interference (RNAi) in treatment, Kim and Rossi (2007) pointed out that one of the first applications was in the treatment of the wet form of ARMD. At the time of the report, clinical trials were underway involving direct intravitreal injection of siRNAs targeting vascular endothelial growth factor (VEGF; 192240) or its receptor (VEGFR1; 165070).
Alu-derived RNAs activate P2X7 (602566) and the NLRP3 (606416) inflammasome to cause cell death of the retinal epithelium in geographic atrophy, a type of ARMD. Fowler et al. (2014) found that nucleoside reverse transcriptase inhibitors (NRTIs) inhibit P2X7-mediated NLRP3 inflammasome activation independent of reverse transcriptase inhibition. Multiple approved and clinically relevant NRTIs prevented caspase-1 (CASP1; 147678) activation, the effector of the NLRP3 inflammasome, induced by Alu RNA. NRTIs were efficacious in mouse models of geographic atrophy, choroidal neovascularization, graft-versus-host disease, and sterile liver inflammation. Fowler et al. (2014) concluded that NRTIs might be therapeutic for both dry and wet ARMD and that these drugs work at the level of P2X7 in these systems.
Lambooij et al. (2003) demonstrated that insulin-like growth factor-1 (IGF1; 147440) and its receptor, IGF1R (147370), were present in capillary endothelial cells, retinal pigment epithelial cells, and fibroblast-like cells in choroidal neovascular membranes of age-related macular degeneration.
Axer-Siegel et al. (2004) found an association between an elevated plasma level of homocysteine and exudative neovascular ARMD but not dry ARMD.
Grisanti et al. (2004) analyzed endoglin (ENG; 131195) expression in choroidal neovascular membranes (CNVMs) surgically excised from eyes with ARMD. Endoglin expression was increased in the endothelial cells of CNVMs but was rarely associated with a concomitant expression of the proliferation marker Ki-67 (176741). The authors concluded that the elevated expression of endoglin in the surgically excised CNVMs suggested a persisting postmitotic activation in an advanced stage of neovascular tissue.
To determine retinal region-specific changes in rod photoreceptor protein expression, Ethen et al. (2005) graded the distinct stages of ARMD in eye bank eyes. A significant linear decline in both arrestin (181031) and rhodopsin (180380) content correlated with progressive worsening of ARMD in the macula. In contrast, the peripheral region showed no significant correlation between degree of ARMD and the content of either protein.
In a prospective study of 251 individuals aged 60 or older who had some sign of nonexudative age-related macular dystrophy, Seddon et al. (2005) found that higher levels of CRP (123260) and IL6 (147620) were independently associated with progression of ARMD.
Chowers et al. (2006) demonstrated that transferrin expression is increased in the retinas of patients with ARMD relative to those of healthy, age-matched control patients. Mean transferrin mRNA levels were elevated 3.5- and 2.1-fold in nonneovascular (dry) and neovascular (wet) ARMD retinas, respectively. Immunohistochemistry showed more intense and widespread transferrin label in ARMD maculas, particularly in large drusen, Muller cells, and photoreceptors. Chowers et al. (2006) suggested that altered iron homeostasis is associated with ARMD.
Tamer et al. (2007) found a significant decrease of plasma dehydroepiandrosterone sulfate (DHEAS) levels in both nonexudative and exudative ARMD patients of both genders compared with age-matched controls. Regression analyses revealed an inverse correlation between serum DHEAS level and ARMD severity scale in men and in women.
De et al. (2007) found that in eyes with dry or wet ARMD, alpha-B-crystallin (CRYAB; 123590) was heterogeneously expressed by a subpopulation of RPE cells in the macular region (frequently in cells adjacent to drusen) and in areas of RPE hypertrophy associated with wet ARMD. In contrast, alpha-B-crystallin was not detected at significant levels in control RPE. De et al. (2007) concluded that accompanying the formation of drusen in early- and late-stage ARMD, RPE cells undergo change to express alpha-B-crystallin.
Bhosale et al. (2007) identified a novel carotenoid metabolite, 3-methoxyzeaxanthin (3-MZ), along with 3-prime-oxolutein and meso-zeaxanthin, in the macula of aged donors and suggested that O-methylation of carotenoids is a potential biomarker for aging and age-related ocular disorders.
In a prospective study of 27,687 women with a mean age of 54.6 years who were initially free of ARMD, with a mean follow-up of 10 years, Schaumberg et al. (2007) found that high-sensitivity CRP (hsCRP; 123260) and other biomarkers of inflammation predicted incident ARMD. Women with hsCRP levels in the highest vs lowest fifth had a more than 3-fold higher incidence of ARMD. The incidence of ARMD was also increased approximately 2-fold among women with the highest levels of ICAM1 (147840) and fibrinogen (see 134820).
In a review, Beatty et al. (2000) stated that oxidative stress, or cellular damage caused by reactive oxygen intermediates, was implicated in the pathogenesis of ARMD. They noted that the retina is particularly susceptible to oxidative stress because of its high consumption of oxygen, its high proportion of polyunsaturated fatty acids, and its exposure to visible light.
Crabb et al. (2002) developed a method for isolating microgram quantities of drusen and Bruch membrane for proteome analysis. They presented observations on oxidative protein modifications that supported the hypothesis that oxidative injury contributes to the pathogenesis of ARMD and suggested that oxidative protein modifications have a critical role in drusen formation.
Hahn et al. (2003) found that ARMD-affected maculas had statistically significant increases in the total iron level when compared with healthy maculas. The iron was present in pathologic areas, and occasionally, in relatively healthy areas, in the retinal pigment epithelium and Bruch membrane in maculas from patients who had drusen only, geographic atrophy, or exudative ARMD, They suggested that increased concentrations of iron, which generate highly reactive hydroxyl radicals via the Fenton reaction, might induce oxidative stress in the macula and lead to ARMD. Dunaief et al. (2005) reported maculopathy, clinically resembling ARMD, in a patient with retinal iron overload due to aceruloplasminemia (604290). Dunaief et al. (2005) concluded that this supported the hypothesis that retinal iron homeostasis was essential for normal retinal function and that disruption of iron homeostasis could contribute to the pathogenesis of ARMD.
Malek et al. (2003) analyzed the retinal pigment epithelium (RPE) of human donor eyes for apolipoprotein mRNA and protein. Esterified and unesterified cholesterol was present in all drusen and basal deposits of ARMD eyes and normal eyes. Both apoB and apoE but not apoC-III (107720) were found in Bruch membrane, drusen, and basal deposits, and the RPE contained apoB and apoE mRNA and protein. Malek et al. (2003) suggested that the combination of apoB mRNA and protein in RPE raised the possibility that intraocular assembly of apoB-containing lipoproteins might be a pathway involved in forming cholesterol-enriched lesions in ARMD.
Zarbin (2004) reviewed the literature concerning pathogenesis of ARMD.
De Jong (2006) reviewed age-related changes in the retinal pigment epithelium that can result in macular degeneration.
Kamei et al. (2007) noted that the accumulation of macrophages is known to be involved in the pathogenesis of ARMD. They performed immunohistochemistry on 10 surgically excised choroidal neovascular membranes from eyes with ARMD and detected oxidized lipoproteins in the membranes. Cells expressing scavenger receptors were found to be predominantly macrophages with a minority of retinal pigment epithelium. Kamei et al. (2007) concluded that macrophages might accumulate to take up oxidized lipoproteins in ARMD and that the control of oxidative stress and macrophage responses might therefore be potential treatments for ARMD.
Decanini et al. (2007) examined changes of select reduction-oxidation (redox) sensitive proteins from human donor RPE at 4 stages of ARMD. The content of several antioxidant enzymes and specific proteins that facilitate refolding or degradation of oxidatively damaged proteins increased significantly in stage 3 ARMD (subjects in stage 3 had at least 1 eye with 1 or more large (125 micromole) drusen or with extensive intermediate (65-124 micromole) drusen). The proteins were involved in the primary (e.g., SOD1 and SOD2, 147450 and 147560, respectively) and secondary (e.g., heat shock proteins, see 140571) defense against oxidative damage. Additionally, the insulin pro-survival receptor exhibited disease-related upregulation. The pattern of protein changes identified supported the role of oxidative mechanisms in the pathogenesis and progression of ARMD. Decanini et al. (2007) concluded that the results helped to explain altered oxidative stress regulation and cell-survival pathways that occur in progressive stages of ARMD.
Sivaprasad et al. (2007) noted that only the C3a des Arg form of C3a is present in human plasma. They therefore studied the levels of C3a des Arg in 84 persons with a clinical diagnosis of ARMD compared with those in age-matched controls. The levels were significantly raised in the patient group compared with those in the control group. Sivaprasad et al. (2007) also found that the concentration of plasma C3a des Arg did not differ significantly between those with different CFH genotypes. The authors suggested that systemic activation of the complement system may contribute to the pathogenesis of ARMD independent of CFH polymorphism. They suggested that new treatment strategies might be aimed toward reducing systemic low grade inflammation.
Takeda et al. (2009) demonstrated that the eosinophil/mast cell chemokine receptor CCR3 (601268) is specifically expressed in choroidal neovascular endothelial cells in humans with ARMD and that despite the expression of its ligands eotaxin-1 (601156), eotaxin-2 (602495), and eotaxin-3 (604697), neither eosinophils nor mast cells are present in human choroidal neovascularization (CNV). Genetic or pharmacologic targeting of CCR3 or eotaxins inhibited injury-induced CNV in mice. CNV suppression by CCR3 blockade was due to direct inhibition of endothelial cell proliferation, and was uncoupled from inflammation since it occurred in mice lacking eosinophils or mast cells, and was independent of macrophage and neutrophil recruitment. CCR3 blockade was more effective at reducing CNV than VEGFA (192240) neutralization, which is used in the treatment of ARMD, and, unlike VEGFA blockade, is not toxic to the mouse retina. In vivo imaging with CCR3-targeting quantum dots located spontaneous CNV invisible to standard fluorescein angiography in mice before retinal invasion. Takeda et al. (2009) concluded that CCR3 targeting might reduce vision loss due to ARMD through early detection and therapeutic angioinhibition.
Kaneko et al. (2011) showed that the microRNA-processing enzyme DICER1 (606241) is reduced in the RPE of humans with geographic atrophy and that conditional ablation of DICER1, but not of 7 other microRNA processing enzymes, induces RPE degeneration in mice. DICER1 knockdown induced accumulation of Alu RNA in human RPE cells and Alu-like B1 and B2 RNAs in mouse RPE. Alu RNA was increased in the RPE of humans with geographic atrophy, and this pathogenic RNA induced human RPE cytotoxicity and RPE degeneration in mice. Antisense oligonucleotides targeting Alu/B1/B2 RNAs prevented DICER1 depletion-induced RPE degeneration despite global miRNA downregulation. DICER1 degrades Alu RNA, and this digested Alu RNA could not induce RPE degeneration in mice. Kaneko et al. (2011) concluded that their findings revealed an miRNA-independent cell survival function for DICER1 involving retrotransposon transcript degradation, showed that Alu RNA can directly cause human pathology, and identified new targets for a major cause of blindness.
Using mouse and human RPE cells and mice lacking various genes, Tarallo et al. (2012) showed that a DICER1 deficit or Alu RNA exposure activated the NLRP3 (606416) inflammasome, triggering Toll-like receptor-independent MYD88 (602170) signaling via IL18 (600953) in the RPE. Inhibition of inflammasome components, MYD88, or IL18 prevented RPE degeneration induced by DICER1 loss or Alu RNA exposure. Because RPE in human geographic atrophy contained elevated NLRP3, PYCARD (606838), and IL18, Tarallo et al. (2012) suggested targeting this pathway for prevention and/or treatment of geographic atrophy.
By stimulating peripheral blood mononuclear cells with drusen isolated from the eyes of 6 donors aged 80 to 97 years with AMD, Doyle et al. (2012) detected production of IL1B (147720) and IL18. Stimulating a monocyte cell line with drusen resulted in increased amounts of activated CASP1 (147678). Bone marrow cells from Nlrp3 -/- mice produced significantly less Il1b than wildtype cells, whereas Tnf (191160) and Il6 production was unchanged. When adducted to human serum albumin, carboxymethylpyrrole (CEP), a biomarker of AMD, primed the inflammasome. C1Q (see 120550), a component of drusen, also mediated inflammasome activation, and this activation involved the phagolysosome. Mice immunized with CEP-adducted mouse serum albumin, modeling dry AMD, developed activated macrophages in the choroid and Bruch membrane and also above the retinal pigment epithelia. Laser-induced CNV, a mouse model of wet AMD, was increased in Nlrp3 -/- mice compared with wildtype or Il1r1 (147810) -/- mice, implicating Il18 in regulation of CNV development. Doyle et al. (2012) concluded that NLRP3 is protective against the major disease pathology of AMD and suggested that strategies aimed at delivering IL18 to the eye may be beneficial in preventing progression of CNV in the context of wet AMD.
Jonasson et al. (2003) reviewed the prevalence of age-related maculopathy and ARMD in citizens of Reykjavik, Iceland, who were 50 years of age or older. Intermediate soft drusen were present in 4.8% of those 50- to 59-year-olds and in 18.2% of those 80 years and older; large soft distinct drusen were present in 1.2% of 50- to 59-year-olds and in 10.9% of those 80 years and older; and large soft, crystalline, or semisolid drusen were seen in 0.6% of 50- to 59-year-olds and 25.5% of those 80 years and older. Geographic atrophy was found in either eye in 9.2% of those 70 years and older, whereas exudative macular degeneration was found in 2.3% of those 70 years and older. The authors concluded that geographic atrophy was more common in their respondents than in other population-based studies.
Jonasson et al. (2005) examined the age- and gender-specific 5-year incidence of age-related maculopathy and ARMD in citizens of Reykjavik. Geographic atrophy was the predominant type of ARMD in Iceland, and the ratio of geographic atrophy to neovascular ARMD was higher than in racially similar populations.
Gupta et al. (2007) examined the prevalence of ARMD in a rural population in northern India. Of the 1,101 participants for whom fundus photographs were available, 28.8% had ungradable fundus images due to cataract. Including all with ungradable images in the denominator, the prevalence of soft drusen was 34.0%; of soft indistinct drusen, 2.2%; and of pigmentary irregularity, 10.8%. There were 15 patients (1.4%) with late-stage ARMD with the prevalence rising from 0.4% in the 50- to 59-year age range to 4.6% in those aged 70 years or older. Gupta et al. (2007) stated that the prevalence of late ARMD in this population was similar to that encountered in Western settings.
In affected individuals in the large 3-generation family with ARMD1 reported by Klein et al. (1998), Schultz et al. (2003) identified a mutation in the FBLN6 (hemicentin) gene (Q5345R; 608548.0001). They found the mutation in 7 of 288 additional unrelated ARMD individuals who also shared flanking haplotypes spanning 1 Mb, but also in 4 of 174 unaffected control subjects ranging in age from 57 to 89 years, suggesting incomplete penetrance. However, Fisher et al. (2007) found that the Q5345R substitution occurred as a low-frequency polymorphism (0.0026) in a control population. The findings suggested that this polymorphism may confer susceptibility to ARMD in a small set of patients but does not contribute substantially to disease.
Schultz et al. (2005) reviewed the literature regarding the role of hemicentin in ARMD, the results of association studies for the Q5345R mutation, and the linkage evidence for an ARMD locus on 1q31. They concluded that the data could be reconciled if additional disease-producing mutations are identified in the HMCN1 gene or if a second more common risk factor for ARMD is located in the same region.
In a 3-generation Tunisian Jewish family with ARMD, Pras et al. (2015) performed exome sequencing and identified a heterozygous 1-bp deletion in the HMCN1 gene (c.4162delC; 608548.0002) that segregated with disease and was not found in 100 ethnically matched controls or in in-house and public exome databases. Two sisters in the third generation who exhibited subclinical foveal alterations were heterozygous for the mutation, whereas 7 other offspring in that generation with normal ocular examinations did not carry the mutation.
Association with HLA
Goverdhan et al. (2005) investigated whether HLA genotypes were associated with ARMD. They genotyped class I HLA-A (142800), -B (142830), and -Cw (see 142840) and class II DRB1 (142857) and DQB1 (604305) in 200 patients with ARMD, as well as in controls. Allele Cw*0701 correlated positively with ARMD, whereas alleles B*4001 and DRB1*1301 were negatively associated. These HLA associations were independent of any linkage disequilibrium. Goverdhan et al. (2005) concluded that HLA polymorphisms influenced the development of ARMD and proposed modulation of choroidal immune function as a possible mechanism for this effect.
Modifier Genes
Yang et al. (2008) presented evidence that rs3775291 in the TLR3 gene (603029) was associated with protection from progression to geographic atrophy in patients with age-related macular degeneration. However, Allikmets et al. (2009) and Edwards et al. (2009) could not replicate the findings of Yang et al. (2008). Neither group found an association between rs3775291 and protection against geographic atrophy in age-related macular degeneration in independent studies comprising 1,080 and 880 patients, respectively.
Ocular neovascularization is the leading cause of blindness in developed countries and often causes rapid loss of vision in age-related macular degeneration. Acute visual loss is most often due to hemorrhage from new vessels that have extended from the choroid into the subretinal space. Growth of abnormal vessels beneath the retina in age-related macular degeneration is known as subretinal neovascularization (SRN). Smith et al. (2000) reported an angiogenic phenotype in heterozygous Bst mice that was age-related, clinically evident, and resembled human SRN. Thus, this represented a spontaneous, genetically determined model of SRN.
Krzystolik et al. (2002) evaluated the safety and efficacy of intravitreal injections of an antigen-binding fragment of a recombinant humanized monoclonal antibody (rhuFab) directed toward vascular endothelial growth factor (VEGF; 192240) in a monkey model of choroidal neovascularization (CNV). They found that intravitreal rhuFab VEGF injections prevented formation of clinically significant CNV in cynomolgus monkeys and decreased leakage of already-formed CNV with no significant toxic effects. The authors concluded that their study provided the nonclinical proof of principle for ongoing clinical studies of intravitreally-injected rhuFab VEGF in patients with CNV due to age-related macular degeneration.
Dithmar et al. (2001) examined the histologic, histochemical, and ultrastructural changes in Bruch membrane in mice on a high-fat diet, with and without laser photochemical injury. They found that electron-lucent debris accumulates in murine Bruch membrane, and the amount correlates with age and high-fat diet. Laser photochemical injury of the retinal pigment epithelium may result in the appearance of basal laminar deposit-like deposition in eyes with electron-lucent debris. The basal laminar deposit-like deposits in this model were similar to the basal laminar deposits that occur in ARMD and represent an animal model for ARMD.
Espinosa-Heidmann et al. (2004) studied the development of basal laminar deposits in the eyes of transgenic mice that overexpressed apoB100 (see 107730). The mice were fed a high-fat diet and their eyes were exposed to blue-green light. The results suggested that age and high-fat diet predisposed to the formation of basal laminar deposits by altering hepatic and/or RPE lipid metabolism in ways more complicated than plasma hyperlipidemia alone. Vitamin E-treated mice showed minimal formation of basal laminar deposits.
Cousins et al. (2003) found that female gender in aged mice and estrogen deficiency in middle-aged mice appeared to increase the severity of sub-RPE deposit formation. Loss of RPE matrix metalloproteinase-2 (MMP2; 120360) activity correlated with deposit severity, with estrogen-deficient mice expressing less MMP2 than ovary-intact control mice. However, estrogen supplementation at the dosages used in the study did not appear to protect against formation of sub-RPE deposits.
Danciger et al. (2003) performed a quantitative genetics study on 8-month-old progeny from an intercross between 2 strains of albino mice. They identified 3 highly significant quantitative trait loci (QTLs) on mouse chromosomes 6, 10, and 16. The strongest and most highly significant QTL on chromosome 6 accounted for 30% of the total genetic effect, with a lod score of 13.5. Because none of the age-related retinal degeneration QTLs was homologous to human chromosomal loci so far implicated in ARMD, each of these murine QTLs represented a new gene for potential study, particularly the gene on chromosome 6.
Imamura et al. (2006) generated Sod1 (147450)-null mice and observed age-related changes of the retina similar to the key elements of human ARMD, including drusen, thickened Bruch's membrane, and choroidal neovascularization. The number of drusen increased with age, and exposure of young Sod1 -/- mice to excess light induced drusen. The RPE of the null mice showed signs of oxidative damage, and there was disruption of beta-catenin (116806)-mediated cell adhesions. Imamura et al. (2006) suggested that oxidative stress may play a causative role in ARMD and that the Sod1 -/- mouse provides a model of ARMD.
Malek et al. (2005) described a mouse model that combined 3 known ARMD risk factors: advanced age, high fat cholesterol-rich (HF-C) diet, and apolipoprotein E (107741) genotype. Eyes of aged, targeted replacement mice expressing human apoE2, apoE3, or apoE4 and maintained on an HF-C diet showed apoE isoform-dependent pathologies of differential severity: apoE4 mice were the most severely affected. They developed a constellation of changes that mimicked the pathology associated with human ARMD. These alterations included diffuse subretinal pigment epithelial deposits, drusenoid deposits, thickened Bruch membrane, and atrophy, hypopigmentation, and hyperpigmentation of the retinal pigment epithelium. In extreme cases, apoE4 mice also developed choroidal neovascularization, a hallmark of exudative ARMD. Neither age nor HF-C diet alone was sufficient to elicit these changes. The findings implicated the human apoE4 allele as a susceptibility gene for ARMD and supported the hypothesis that common pathogenic mechanisms may underlie ARMD.
Li et al. (2007) studied biochemical alterations in the retinas of very low density lipoprotein receptor (VLDLR; 192977) knockout mice, an animal model of retinal angiomatous proliferation (Heckenlively et al., 2003). Expression of the angiogenic factors VEGF (192240) and FGF2 (134920) was significantly greater in the area of retinal neovascularization. Mueller cells around the lesion were activated, as indicated by increased expression of glial fibrillary acidic protein (137780). Expression of the proinflammatory cytokine IL18 (600953) and the inflammation mediator intercellular adhesion molecule-1 (ICAM1; 147840) was increased before significant intraretinal neovascularization. Furthermore, phosphorylation of Akt (164730) and mitogen-activated protein kinase (176948) and translocalization of NF-kappa-B (164011) were greater in Vldlr knockout mouse retinas. Li et al. (2007) concluded that an inflammatory process is involved in the development of neovascularization in the Vldlr knockout mouse retina.
Clinical trials of siRNA targeting vascular endothelial growth factor A (VEGFA; 192240) or its receptor VEGFR1 (also called FLT1, 165070), in patients with blinding choroidal neovascularization (CNV) from age-related macular degeneration, are premised on gene silencing by means of intracellular RNAi. Kleinman et al. (2008) showed instead in 2 animal models that CNV inhibition is an siRNA-class effect: 21-nucleotide or longer siRNAs targeting nonmammalian genes, nonexpressed genes, nongenomic sequences, pro- and antiangiogenic genes, and RNAi-incompetent siRNAs all suppressed choroidal neovascularization in mice comparably to siRNA targeting Vegfa or Vegfr1 without off-target RNAi or interferon-alpha/beta activation. Nontargeted (against nonmammalian genes) and targeted (against Vegfa or Vegfr1) siRNA suppressed CNV via cell surface toll-like receptor-3 (TLR3; 603029), its adaptor TRIF (607601), and induction of interferon-gamma (IFNG; 147570) and interleukin-12 (see 161560). Nontargeted siRNA suppressed dermal neovascularization in mice as effectively as Vegfa siRNA. siRNA-induced inhibition of neovascularization required a minimum length of 21 nucleotides, a bridging necessity in a modeled 2:1 TLR3-RNA complex. Choroidal endothelial cells from people expressing the TLR3 coding variant 412FF were refractory to extracellular siRNA-induced cytotoxicity, facilitating individualized pharmacogenetic therapy. Multiple human endothelial cell types expressed surface TLR3, indicating that generic siRNAs might treat angiogenic disorders that affect 8% of the world's population, and that siRNAs might induce unanticipated vascular or immune effects.
In the eyes of transgenic mice overexpressing human apoB100 in the RPE, Fujihara et al. (2009) observed ultrastructural changes consistent with early human ARMD, including loss of basal infoldings and accumulation of cytoplasmic vacuoles in the RPE and basal laminar deposits containing long-spacing collagen and heterogeneous debris in Bruch membrane. In apoB100 mice given a high-fat diet, basal linear-like deposits were identified in 12-month-old mice. Linear regression analysis showed that the genotype was a stronger influencing factor than high-fat diet in producing ARMD-like lesions.
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