Multiple sclerosis susceptibility alleles in African Americans

Abstract

Multiple sclerosis (MS) is an autoimmune demyelinating disease characterized by complex genetics and multifaceted gene-environment interactions. Compared to whites, African Americans have a lower risk for developing MS, but African Americans with MS have a greater risk of disability. These differences between African Americans and whites may represent differences in genetic susceptibility and/or environmental factors. SNPs from 12 candidate genes have recently been identified and validated with MS risk in white populations. We performed a replication study using 918 cases and 656 unrelated controls to test whether these candidate genes are also associated with MS risk in African Americans. CD6, CLEC16a, EVI5, GPC5, and TYK2 contained SNPs that are associated with MS risk in the African American dataset. EVI5 showed the strongest association outside the MHC (rs10735781, OR = 1.233, 95% CI = 1.06–1.43, P value = 0.006). In addition, RGS1 appears to affect age of onset whereas TNFRSF1A appears to be associated with disease progression. None of the tested variants showed results that were statistically in-consistent with the effects established in whites. The results are consistent with shared disease genetic mechanisms among individuals of European and African ancestry.

Replication of top markers of a genome-wide association study in multiple sclerosis in Spain

“…Interestingly, the risk allele in African Americans (G) is the same as the one now found to be associated with MS susceptibility in Spain, whereas the opposite allele (A) was originally described to be associated in Caucasian individuals. 21 The meta analysis of both GPC5 studies in Spanish and African American subjects (heterogeneity P ¼ 0.43; I 2 ¼ 0%) yielded a P MÀH o0.00001; odds ratio MÀH (95% confidence inteval) ¼ 0.83 (0.76-0.90). The initially reported odds ratio (1.361) reflects an effect stronger than this one.…”

“…Given the fact that GPC5 is associated with MS susceptibility, as well as with the response to IFN-b therapy, it is tantalizing to speculate that the IFN type I pathway might have a role in the pathogenesis of the disease, at least in a subgroup of patients. Recently, GPC5 rs9523762 results were published in African Americans, 21 though no significant association with MS was reached (P ¼ 0.154). Interestingly, the risk allele in African Americans (G) is the same as the one now found to be associated with MS susceptibility in Spain, whereas the opposite allele (A) was originally described to be associated in Caucasian individuals.…”

Multiple sclerosis genetics

“…In populations of non-European descent, studies have replicated some, but not all, non-MHC SNPs (Johnson et al, 2010). It is encouraging that at least some MS risk alleles identified in European-descended populations replicate in other racial groups and further substantiates that such risk alleles are genuine.…”

Immunological evaluation of rheumatoid arthritis patients treated with itolizumab

“…24,25 An anti-CD6 monoclonal antibody (mAb) that prevented renal and bone marrow graft rejection 26,27 was evaluated in multiple sclerosis patients, and a significant reduction in peripheral T cell counts was found. 28 More recently, the finding of CD6 as a susceptibility gene in multiple sclerosis, 29,30 as well as the overexpression of ALCAM and the presence of CD6+ T and B cells in salivary glands of patients with Sj€ ogren syndrome, 31 support the role of CD6 in pathological autoimmunity and reinforces its relevance for targeted therapy.…”