Genetic susceptibility to multiple sclerosis in African Americans
Résumé
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 MH C 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 SNP s (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.
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