Alternative titles; symbols
HGNC Approved Gene Symbol: ASRT6
Cytogenetic location: 17q21 Genomic coordinates (GRCh38) : 17:39,800,001-52,100,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21 | {Asthma-related traits, susceptibility to, 6} | 611403 | 2 |
Asthma-related traits include clinical symptoms of asthma, such as coughing, wheezing, and dyspnea; bronchial hyperresponsiveness (BHR) as assessed by methacholine challenge test; serum IgE levels; atopy; and atopic dermatitis (Laitinen et al., 2001; Illig and Wjst, 2002; Pillai et al., 2006).
For a general phenotypic description and a discussion of genetic heterogeneity of asthma, see 600807.
Moffatt et al. (2007) characterized more than 317,000 SNPs in DNA from 994 patients with childhood-onset asthma and 1,243 nonasthmatics, using family and case-referent panels. The authors showed multiple markers on chromosome 17q21 to be strongly and reproducibly associated with childhood-onset asthma in family and case-referent panels with a combined p value of less than 10(-12). In independent replication studies the 17q21 locus showed strong association with a diagnosis of childhood asthma in 2,320 subjects from a cohort of German children (p = 0.0003) and in 3,301 subjects from the British 1958 Birth Cohort (p = 0.0005). Moffatt et al. (2007) systematically evaluated the relationship between markers of the 17q21 locus and transcript levels of genes in Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines from children in the asthma family panel used in their association study. The SNPs associated with childhood asthma were consistently and strongly associated (p less than 10(-22)) in cis with transcript levels of ORMDL3 (610075), a member of a gene family that encodes transmembrane proteins anchored in the endoplasmic reticulum. Moffatt et al. (2007) concluded that genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma. In the subset of individuals for whom expression data were available, the T nucleotide allele of SNP rs7216389, the marker most strongly associated with disease in the combined genomewide analysis, had a frequency of 62% among asthmatics compared to 52% in nonasthmatics (p = 0.005 in this sample). The additive effect of this allele corresponds to a change of 0.78 standard deviation units in ORMDL3 expression (p less than 10(-22)).
Madore et al. (2008) performed an association study with the 10 SNPs on chromosome 17q21 that showed the strongest association in a French Canadian asthmatic familial collection. Family-based association tests revealed significant associations for 8 SNPs (p = 0.017 to 0.005) and for 2 haplotypes (p = 0.0004 and 0.002, respectively), confirming chromosome 17q21 as an asthma locus.
Bouzigon et al. (2008) presented evidence that the risk of asthma conferred by genetic variants on chromosome 17q21 is restricted to early-onset asthma and is increased when there is exposure to environmental tobacco smoke in early life. They tested 36 SNPs in the 17q21 region in 1,511 subjects from 372 families. Eleven SNPs were significantly associated with asthma (p less than 0.01), of which 3 (rs8069176, rs2305480, and rs4795400) were strongly associated (p less than 0.001). Ordered-subset regression analysis led the authors to select an onset at age 4 years or younger to classify patients as having early-onset asthma. Association with early-onset asthma was highly significant (p less than 10(-5) for 4 SNPs), whereas no association was found with late-onset asthma. Bouzigon et al. (2008) observed a significant association with early-onset asthma only in subjects exposed to environmental tobacco smoke in early life (p less than 5 x 10(-5) for 6 SNPs). Under the best-fitting recessive model, homozygous status (GG) at the most strongly associated SNP (rs8069176) conferred an increase in risk by a factor of 2.9, as compared with other genotypes (AG and AA) in the group exposed to environmental tobacco smoke (p = 2.8 x 10(-6); p = 0.006 for the test for heterogeneity of the SNP effect on early-onset asthma between groups with tobacco exposure and those without such exposure). The identified SNPs span 3 genes in addition to ORMDL3: ZPBP2 (608499), IKZF3 (606221), and GSDMB (611221). Morita and Nagai (2009) questioned why there would be an association with early-onset disease rather than late-onset disease. Bouzigon et al. (2009) replied that they re-analyzed their data and found no association between any of the variants previously investigated and late-onset asthma in sibships exposed or unexposed to environmental tobacco smoke in early life.
Verlaan et al. (2009) performed functional assays of candidate disease-linked variants in the chromosome 17q12-q21 region and identified allele-specific differences in nucleosome distribution, an allele-specific association with the insulator protein CTCF (604167), and weak promoter activity for rs12936231. The authors stated that overall, their findings demonstrated a common disease allele linked to changes in CTCF binding and nucleosome occupancy leading to altered domainwide cis-regulation involving ZPBP2, GSDMB, and ORMDL3. In association studies of 4 candidate SNPs (rs12936231, rs8067378, rs9303277, and rs7216389) in 3 family-based childhood asthma cohorts, all 4 SNPs demonstrated significant evidence for association (p = 8.74 x 10(-7) to 4.95 x 10(-8)) in each of the cohorts, and haplotype association analysis confirmed a strong association of the overexpressed-associated haplotype with asthma risk (p = 8.62 x 10(-8)). Verlaan et al. (2009) noted that strong linkage disequilibrium between these markers precluded recognition of 1 variant over the others as the definitive risk locus, because the combined evidence for association was very similar across markers.
In a genomewide association study of childhood asthma, Sleiman et al. (2010) replicated the previously reported association on chromosome 17q21.
Moffatt et al. (2010) carried out a genomewide association study of 10,365 persons with physician-diagnosed asthma and 16,110 unaffected persons, all of whom were matched for ancestry. They used random-effects pooled analysis to test for association in the overall study population and in subgroups of subjects with childhood-onset asthma (defined as asthma developing before 16 years of age), later-onset asthma, severe asthma, and occupational asthma. The strongest association, of the ORMDL3/GSDMB locus on chromosome 17q21, was specific to childhood-onset disease (rs2305480, P = 6 x 10(-23)).
In 2 cohorts of children born to parents with respiratory allergies or asthma, Caliskan et al. (2013) tested genotypes of 5 asthma-associated SNPs at the 17q21 locus, including rs9303277, rs11557467, rs12936231, rs2290400, and rs7216389, for associations with asthma and with human rhinovirus (HRV) and respiratory syncytial virus (RSV) wheezing illnesses, and for interactions between 17q21 genotypes and HRV and RSV wheezing illnesses with respect to the risk of asthma. Associations of 7q21 variants with asthma were restricted to children who had had HRV wheezing illnesses, resulting in a significant interaction effect with respect to the risk of asthma. Expression levels of the 17q21 genes ORMDL3 (610075) and GSDMB (611221) were significantly increased in HRV-stimulated peripheral blood mononuclear cells (PBMCs) compared to unstimulated PBMCs, but the relative increase was not associated with 17q21 genotype.
Bouzigon, E., Corda, E., Aschard, H., Dizier, M. H., Boland, A., Bousquet, J., Chateigner, N., Gormand, F., Just, J., Le Moual, N., Scheinmann, P., Siroux, V., Vervloet, D., Zelenika, D., Pin, I., Kauffmann, F., Lathrop, M., Demenais, F. Effect of 17q21 variants and smoking exposure in early-onset asthma. New Eng. J. Med. 359: 1985-1994, 2008. [PubMed: 18923164] [Full Text: https://doi.org/10.1056/NEJMoa0806604]
Bouzigon, E., Siroux, V., Demenais, F. Authors reply to Morita and Nagai. (Letter) New Eng. J. Med. 360: 1255-1256, 2009. [PubMed: 19297581] [Full Text: https://doi.org/10.1056/NEJMc082444]
Caliskan, M., Bochkov, Y. A., Kreiner-Moller, E., Bonnelykke, K., Stein, M. M., Du, G., Bisgaard, H., Jackson, D. J., Gern, J. E., Lemanske, R. F., Nicolae, D. L., Ober, C. Rhinovirus wheezing illness and genetic risk of childhood-onset asthma. New Eng. J. Med. 368: 1398-1407, 2013. [PubMed: 23534543] [Full Text: https://doi.org/10.1056/NEJMoa1211592]
Illig, T., Wjst, M. Genetics of asthma and related phenotypes. Paediat. Resp. Rev. 3: 47-51, 2002. [PubMed: 12065182] [Full Text: https://doi.org/10.1053/prrv.2002.0185]
Laitinen, T., Daly, M. J., Rioux, J. D., Kauppi, P., Laprise, C., Petays, T., Green, T., Cargill, M., Haahtela, T., Lander, E. S., Laitinen, L. A., Hudson, T. J., Kere, J. A susceptibility locus for asthma-related traits on chromosome 7 revealed by genome-wide scan in a founder population. Nature Genet. 28: 87-91, 2001. [PubMed: 11326283] [Full Text: https://doi.org/10.1038/ng0501-87]
Madore, A.-M., Tremblay, K., Hudson, T. J., Laprise, C. Replication of an association between 17q21 SNPs and asthma in a French-Canadian familial collection. Hum. Genet. 123: 93-95, 2008. [PubMed: 17992541] [Full Text: https://doi.org/10.1007/s00439-007-0444-x]
Moffatt, M. F., Gut, I. G., Demenais, F., Strachen, D. P., Bouzigon, E., Heath, S., von Mutius, E., Farrall, M., Lathrop, M., Cookson, W. O. C. M. A large-scale, consortium-based genomewide association study of asthma. New Eng. J. Med. 363: 1211-1221, 2010. [PubMed: 20860503] [Full Text: https://doi.org/10.1056/NEJMoa0906312]
Moffatt, M. F., Kabesch, M., Liang, L., Dixon, A. L., Strachan, D., Heath, S., Depner, M., von Berg, A., Bufe, A., Rietschel, E., Heinzmann, A., Simma, B., and 12 others. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 448: 470-473, 2007. [PubMed: 17611496] [Full Text: https://doi.org/10.1038/nature06014]
Morita, H., Nagai, R. Smoking exposure, 17q21 variants, and early-onset asthma. (Letter) New Eng. J. Med. 360: 1255 only, 2009. [PubMed: 19297581] [Full Text: https://doi.org/10.1056/NEJMc082444]
Pillai, S. G., Chiano, M. N., White, N. J., Speer, M., Barnes, K. C., Carlsen, K., Gerritsen, J., Helms, P., Lenney, W., Silverman, M., Sly, P., Sundy, J., and 13 others. A genome-wide search for linkage to asthma phenotypes in the genetics of asthma international network families: evidence for a major susceptibility locus on chromosome 2p. Europ. J. Hum. Genet. 14: 307-316, 2006. Note: Erratum: Europ. J. Hum. Genet. 15: 714 only, 2007. [PubMed: 16391567] [Full Text: https://doi.org/10.1038/sj.ejhg.5201532]
Sleiman, P. M. A., Flory, J., Imielinski, M., Bradfield, J. P., Annaiah, K., Willis-Owen, S. A. G., Wang, K., Rafaels, N. M., Michel, S., Bonnelykke, K., Zhang, H., Kim, C. E., and 30 others. Variants of DENND1B associated with asthma in children. New Eng. J. Med. 362: 36-44, 2010. Note: Erratum: New Eng. J. Med. 363: 994 only, 2010. Erratum: New Eng. J. Med. 366: 672 only, 2012. [PubMed: 20032318] [Full Text: https://doi.org/10.1056/NEJMoa0901867]
Verlaan, D. J., Berlivet, S., Hunninghake, G. M., Madore, A.-M., Lariviere, M., Moussette, S., Grundberg, E., Kwan, T., Ouimet, M., Ge, B., Hoberman, R., Swiatek, M., and 14 others. Allele-specific chromatin remodeling in the ZPBP2/ GSDMB/ORMDL3 locus associated with the risk of asthma and autoimmune disease. Am. J. Hum. Genet. 85: 377-393, 2009. [PubMed: 19732864] [Full Text: https://doi.org/10.1016/j.ajhg.2009.08.007]