DO: 2377;
Cytogenetic location: 5p13.2 Genomic coordinates (GRCh38): 5:33,800,001-38,400,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5p13.2 | {Multiple sclerosis, susceptibility to, 3} | 612595 | 2 |
Multiple sclerosis-3 (MS3) is a chronic inflammatory disease of the central nervous system (CNS) characterized by multifocal demyelination (summary by Kallio et al., 2009).
For a discussion of genetic heterogeneity of multiple sclerosis, see MS1 (126200).
Association with the IL7R Gene
Gregory et al. (2007) found a significant association between a T-to-C SNP (rs6897932; thr244 to ile) in the transmembrane domain of the IL7R gene (146661) on chromosome 5p13 and susceptibility to multiple sclerosis. The findings were observed in 1,055 individuals with MS (P = 0.0006 for the C allele) and replicated in 3 independent European populations or populations of European descent comprising 438, 1,338, and 1,077 patients, respectively. A combined analysis of all the family-based and case-control data sets resulted in a p value of 2.9 x 10(-7). Functional expression studies showed that the C allele of rs6897932 affects alternative splicing of exon 6, leading to increased skipping of the exon and increased production of soluble IL7R in individuals carrying the risk allele. This results in decreased expression of membrane-bound IL7R, thus causing decreased IL7 (146660)/IL7R signaling.
Among 1,210 patients with MS from Nordic countries, Lundmark et al. (2007) found an association between disease development and several SNPs in the IL7R gene (rs6897932, rs6871748, and rs2303137). All were significant after Bonferroni correction. Further analyses, including estimation of haplotype frequencies, indicated that rs6897932 was most strongly associated with risk of MS. Lundmark et al. (2007) also found increased expression of IL7R mRNA in cerebrospinal fluid of MS individuals compared to controls.
In a multistage genomewide association study involving a total of 1,540 MS family trios, 2,322 case subjects, and 5,418 control subjects, the International Multiple Sclerosis Genetics Consortium (2007) confirmed significant association of rs6897932 with MS.
O'Doherty et al. (2008) studied 2 independent case-control collections from Olmsted County, Minnesota, and Belfast, Northern Ireland, involving 208 MS patients and 413 controls, and 463 MS patients and 532 controls, respectively. Association of the rs6897932 C allele with MS was confirmed in the Olmsted County group but not in the Belfast group.
D'Netto et al. (2009) found an association between MS and rs6897932 in a case-control study of 211 MS patients and 182 unrelated controls (OR, 1.54; p = 0.013). However, there was no significant association between the SNP and MS in the 211 patients and 521 unaffected relatives from 43 multiplex MS families.
Fang et al. (2011) found a significant association between the C allele of rs6897932 and the CC genotype among 107 Japanese patients with conventional MS compared to 158 controls. The frequency of the C allele was 90.65% in patients with conventional MS and 79.75% in controls (OR of 2.46, corrected p value of 0.0020). The frequency of the CC genotype was 81.31% in patients with conventional MS and 63.29% in controls (OR of 2.52, corrected p value of 0.0048). Similar results were obtained when the patients were categorized as non-NMO (neuromyelitis optica) MS. No association was observed between this SNP and patients with opticospinal MS or NMO. Fang et al. (2011) concluded that this SNP is a strong risk factor for non-NMO MS and conventional MS in the Asian population.
Association with the C7 Gene
In Southern Ostrobothnia, Finland, the prevalence and familial occurrence of multiple sclerosis are exceptionally high. Kallio et al. (2009) screened haplotypes at chromosome 5p15-q11 risk region in 72 Finnish MS cases, the majority of which share distant genealogic relatedness due to origin from Southern Ostrobothnia. Haplotype analysis over the 45-Mb risk region in Finnish MS families revealed only modest association for the IL7R gene (p = 0.04), whereas most significant association was found with an 8-SNP haplotype covering the C7 gene (217070) and the HEATR7B2 gene (p = 0.0001), located 5.1-Mb centromeric of the IL7R gene. An independent sample of Finnish isolate MS patients showed significant association (p = 4.0 x 10(-4)) with a 24-SNP haplotype, and the combined data set showed significant linkage to the C7-HEATR7B2 region (p = 3.2 x 10(-6), corrected p = 0.012, OR = 2.73). In serum and plasma from 20 Finnish MS patients and 32 unaffected controls, terminal complement complex, which includes C7, showed increased activity in individuals with the identified risk haplotype. The authors reported that the C7-HEATR7B2 and IL7R loci were not in linkage disequilibrium. Kallio et al. (2009) noted that studies with more heterogeneous populations from Finland, Norway, Sweden, and the U.S. showed suggestive association with other C7-HEATR7B2 risk haplotypes.
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]
Fang, L., Isobe, N., Yoshimura, S., Yonekawa, T., Matsushita, T., Masaki, K., Doi, H., Ochi, K., Miyamoto, K., Kawano, Y., Kira, J. Interleukin-7 receptor alpha gene polymorphism influences multiple sclerosis risk in Asians. Neurology 76: 2125-2127, 2011. [PubMed: 21670443] [Full Text: https://doi.org/10.1212/WNL.0b013e31821f466c]
Gregory, S. G., Schmidt, S., Seth, P., Oksenberg, J. R., Hart, J., Prokop, A., Caillier, S. J., Ban. M., Goris, A., Barcellos, L. F., Lincoln, R., McCauley, J. L., Sawcer, S. J., Compston, D. A. S., Dubois, B., Hauser, S. L., Garcia-Blanco, M. A., Pericak-Vance, M. A., Haines, J. L., Multiple Sclerosis Genetics Group. Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis. Nature Genet. 39: 1083-1091, 2007. [PubMed: 17660817] [Full Text: https://doi.org/10.1038/ng2103]
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]
Kallio, S. P., Jakkula, E., Purcell, S., Suvela, M., Koivisto, K., Tienari, P. J., Elovaara, I., Pirttila, T., Reunanen, M., Bronnikov, D., Viander, M., Meri, S., and 10 others. Use of a genetic isolate to identify rare disease variants: C7 on 5p associated with MS. Hum. Molec. Genet. 18: 1670-1683, 2009. [PubMed: 19221116] [Full Text: https://doi.org/10.1093/hmg/ddp073]
Lundmark, F., Duvefelt, K., Iacobaeus, E., Kockum, I., Wallstrom, E., Khademi, M., Oturai, A., Ryder, L. P., Saarela, J., Harbo, H. F., Celius, E. G., Salter, H., Olsson, T., Hillert, J. Variation in interleukin 7 receptor alpha chain (IL7R) influences risk of multiple sclerosis. Nature Genet. 39: 1108-1113, 2007. [PubMed: 17660816] [Full Text: https://doi.org/10.1038/ng2106]
O'Doherty, C., Kantarci, O., Vandenbroeck, K. IL7RA polymorphisms and susceptibility to multiple sclerosis. (Letter) New Eng. J. Med. 358: 753-754, 2008. [PubMed: 18272905] [Full Text: https://doi.org/10.1056/NEJMc0707553]