Genetic susceptibility to multiple sclerosis in African Americans.

<h4>Objective</h4>To explore the nature of genetic-susceptibility to multiple sclerosis (MS) in African-Americans.<h4>Background</h4>Recently, the number of genetic-associations with MS has exploded although the MS-associations of specific haplotypes within the major histocom...

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Autores principales:	Douglas S Goodin, Jorge R Oksenberg, Venceslas Douillard, Pierre-Antoine Gourraud, Nicolas Vince
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Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5007f76cad9a410e8f2bfcb38fb132da
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spelling	oai:doaj.org-article:5007f76cad9a410e8f2bfcb38fb132da2021-12-02T20:15:07ZGenetic susceptibility to multiple sclerosis in African Americans.1932-620310.1371/journal.pone.0254945https://doaj.org/article/5007f76cad9a410e8f2bfcb38fb132da2021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0254945https://doaj.org/toc/1932-6203<h4>Objective</h4>To explore the nature of genetic-susceptibility to multiple sclerosis (MS) in African-Americans.<h4>Background</h4>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-DRB115:01~HLA-DQB106:02, and HLA-DRB103:01~ HLA-DQB102:01 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.<h4>Design/methods</h4>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.<h4>Results</h4>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 DRB115:03~DQB106:02~a36 haplotype and three carried the DRB115:01~DQB106:02~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.<h4>Conclusions</h4>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.Douglas S GoodinJorge R OksenbergVenceslas DouillardPierre-Antoine GourraudNicolas VincePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 8, p e0254945 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Douglas S Goodin Jorge R Oksenberg Venceslas Douillard Pierre-Antoine Gourraud Nicolas Vince Genetic susceptibility to multiple sclerosis in African Americans.
description	<h4>Objective</h4>To explore the nature of genetic-susceptibility to multiple sclerosis (MS) in African-Americans.<h4>Background</h4>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-DRB115:01~HLA-DQB106:02, and HLA-DRB103:01~ HLA-DQB102:01 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.<h4>Design/methods</h4>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.<h4>Results</h4>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 DRB115:03~DQB106:02~a36 haplotype and three carried the DRB115:01~DQB106:02~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.<h4>Conclusions</h4>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.
format	article
author	Douglas S Goodin Jorge R Oksenberg Venceslas Douillard Pierre-Antoine Gourraud Nicolas Vince
author_facet	Douglas S Goodin Jorge R Oksenberg Venceslas Douillard Pierre-Antoine Gourraud Nicolas Vince
author_sort	Douglas S Goodin
title	Genetic susceptibility to multiple sclerosis in African Americans.
title_short	Genetic susceptibility to multiple sclerosis in African Americans.
title_full	Genetic susceptibility to multiple sclerosis in African Americans.
title_fullStr	Genetic susceptibility to multiple sclerosis in African Americans.
title_full_unstemmed	Genetic susceptibility to multiple sclerosis in African Americans.
title_sort	genetic susceptibility to multiple sclerosis in african americans.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/5007f76cad9a410e8f2bfcb38fb132da
work_keys_str_mv	AT douglassgoodin geneticsusceptibilitytomultiplesclerosisinafricanamericans AT jorgeroksenberg geneticsusceptibilitytomultiplesclerosisinafricanamericans AT venceslasdouillard geneticsusceptibilitytomultiplesclerosisinafricanamericans AT pierreantoinegourraud geneticsusceptibilitytomultiplesclerosisinafricanamericans AT nicolasvince geneticsusceptibilitytomultiplesclerosisinafricanamericans
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Genetic susceptibility to multiple sclerosis in African Americans.

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