Genetic susceptibility to multiple sclerosis in African Americans

Abstract

Objective To explore the nature of genetic-susceptibility to multiple sclerosis (MS) in African-Americans. Background Recently, the number of genetic-associations with MS has exploded although the MS-associations of specific haplotypes within the major histocompatibility complex (MHC) have been known for decades. For example, the haplotypes HLA-DRB1*15:01~HLA-DQB1*06:02, and HLA-DRB1*03:01~ HLA-DQB1*02:01 have odds ratios (ORs) for an MS-association orders of magnitude stronger than many of these newly-discovered associations. Nevertheless, all these haplotypes are part of much larger conserved extended haplotypes (CEHs), which span both the Class I and Class II MHC regions. African-Americans are at greater risk of developing MS compared to a native Africans but at lesser risk compared to Europeans. It is the purpose of this manuscript to explore the relationship between MS-susceptibility and the CEH make-up of our African-American cohort. Design/methods The African-American (AA) cohort consisted of 1,305 patients with MS and 1,155 controls, who self-identified as being African-American. For comparison, we used the 18,492 controls and 11,144 MS-cases from the predominantly European Wellcome Trust Case Control Consortium (WTCCC) and the 28,557 phased native Africans from the multinational “Be the Match” registry. The WTCCC and the African-Americans were phased at each of five HLA loci (HLA-A, HLA-C, HLA-B, HLA-DRB1 and HLA-DQB1) and the at 11 SNPs (10 of which were in non-coding regions) surrounding the Class II region of the DRB1 gene using previously-published probabilistic phasing algorithms. Results Of the 32 most frequent CEHs, 18 (56%) occurred either more frequently or exclusively in Africans) whereas 9 (28%) occurred more frequently or exclusively in Europeans. The remaining 5 CEHs occurred in neither control group although, likely, these were African in origin. Eight of these CEHs carried the DRB1*15:03~DQB1*06:02~a36 haplotype and three carried the DRB1*15:01~DQB1*06:02~a1 haplotype. In African Americans, a single-copy of the European CEH (03:01_07:02_07:02_15:01_06:02_a1) was associated with considerable MS-risk (OR = 3.30; p = 0.0001)–similar to that observed in the WTCCC (OR = 3.25; p<10−168). By contrast, the MS-risk for the European CEH (02:01_07:02_07:02_15:01_06:02_a1) was less (OR = 1.49; ns)–again, similar to the WTCCC (OR = 2.2; p<10−38). Moreover, four African haplotypes were “protective” relative to a neutral reference, to three European CEHs, and also to the five other African CEHs. Conclusions The common CEHs in African Americans are divisible into those that are either African or European in origin, which are derived without modification from their source population. European CEHs, linked to MS-risk, in general, had similar impacts in African-Americans as they did in Europeans. By contrast, African CEHs had mixed MS-risks. For a few, the MS-risk exceeded that in a neutral-reference group whereas, for many others, these CEHs were “protective”–perhaps providing a partial rationale for the lower MS-risk in African-Americans compared to European-Americans.

Multiple sclerosis: Exploring the limits and implications of genetic and environmental susceptibility

“…‡ ‡ The same Class I or Class II haplotypes in our African American (AA) population [65]. As in the WTCCC and in other Caucasian populations [3,60,61,94], the large majority (79.6%) of this cohort of 1, 306 African American MS patients were women [65].…”

Prevalence of neuromyelitis optica spectrum disorder in the United States

“…7,22 Our findings suggest that a 28% of NMOSD patients may be Black Americans, which is more conservative than the 37% noted in a multicenter observational study of 187 patients seen at facilities in Baltimore, MD, Rochester, MN, and Dallas, TX, USA. 23 Also, our and other Afro-American prevalence estimates are remarkedly higher than those for African populations (0.004–0.2 per 100,000), 6 suggesting that genetic admixture and European ancestry may be a predisposing risk factor, which is similar to what has been observed in MS. 24,25 A notable difference with the more common MS (2018 age/sex-adjusted US prevalence 219 per 100,000) is that the prevalence of MS is higher in White Americans (284 per 100,000) than in Black Americans (226 per 100,000). 16 With respect to Asian Americans, our US prevalence estimates (9.4 per 100,000) were higher than those reported for country-specific Asian populations (e.g.…”

Multiple Sclerosis: Exploring the Limits of Genetic and Environmental Susceptibility

“…For example, the best established (and strongest) genetic associations with MS are for certain haplotypes within the HLA region on the short arm of chromosome 6 (e.g., Tables 3 & 4 A*02:01~C*05:01~B*44:02 [53][54][55][56][57]. Each of these haplotypes is well-represented in diverse human populations around the globe [71,72] and, thus, these haplotypes must be of ancient origin. Presumably, therefore, the absence of MS prior to the late 14 th (and possibly the early 19 th ) century, together with the markedly changing nature of MS over the past 200 years, points to a change in environmental conditions as the basis for the recent occurrence of MS as a clinical entity and for the changes in MS epidemiology, which have taken place over the past two centuries.…”