Genetic susceptibility to multiple sclerosis in African Americans
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 know...
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| description | 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 |
| doi_str_mv | 10.1371/journal.pone.0254945 |
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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.sup.-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.sup.-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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0254945</identifier><identifier>PMID: 34370753</identifier><language>eng</language><publisher>San Francisco: Public Library of Science</publisher><subject>African Americans ; Algorithms ; Biology and Life Sciences ; Black or African American / genetics ; Case-Control Studies ; Consortia ; Disease susceptibility ; Drb1 protein ; Evaluation ; Gene Frequency / genetics ; Genes ; Genetic aspects ; Genetic Predisposition to Disease ; Genomes ; Haplotypes ; Haplotypes / genetics ; Health aspects ; Histocompatibility antigen HLA ; HLA-DQ beta-Chains / genetics ; HLA-DRB1 Chains / genetics ; Humans ; Life Sciences ; Major histocompatibility complex ; Medicine and Health Sciences ; Minority & ethnic groups ; Multiple sclerosis ; Multiple Sclerosis / genetics ; Neurology ; Odds Ratio ; Pathogenesis ; People and Places ; Population ; Risk ; Risk factors ; Single-nucleotide polymorphism ; White People / genetics</subject><ispartof>PloS one, 2021-08, Vol.16 (8), p.e0254945-e0254945</ispartof><rights>COPYRIGHT 2021 Public Library of Science</rights><rights>This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication: https://creativecommons.org/publicdomain/zero/1.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c599t-d8873abca2123aa79283209f0e850beb2fc0e4861eb859d1b1862f7ad1ecd4273</citedby><cites>FETCH-LOGICAL-c599t-d8873abca2123aa79283209f0e850beb2fc0e4861eb859d1b1862f7ad1ecd4273</cites><orcidid>0000-0002-5985-0822 ; 0000-0002-3767-6210 ; 0000-0002-6762-4083 ; 0000-0003-1131-9554</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8352072/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8352072/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79569,79570</link.rule.ids><backlink>$$Uhttps://inserm.hal.science/inserm-04276889$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Goodin, Douglas S.</creatorcontrib><creatorcontrib>Oksenberg, Jorge R.</creatorcontrib><creatorcontrib>Douillard, Venceslas</creatorcontrib><creatorcontrib>Gourraud, Pierre-Antoine</creatorcontrib><creatorcontrib>Vince, Nicolas</creatorcontrib><title>Genetic susceptibility to multiple sclerosis in African Americans</title><title>PloS one</title><description>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.sup.-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.sup.-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.</description><subject>African Americans</subject><subject>Algorithms</subject><subject>Biology and Life Sciences</subject><subject>Black or African American / genetics</subject><subject>Case-Control Studies</subject><subject>Consortia</subject><subject>Disease susceptibility</subject><subject>Drb1 protein</subject><subject>Evaluation</subject><subject>Gene Frequency / genetics</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genetic Predisposition to Disease</subject><subject>Genomes</subject><subject>Haplotypes</subject><subject>Haplotypes / genetics</subject><subject>Health aspects</subject><subject>Histocompatibility antigen HLA</subject><subject>HLA-DQ beta-Chains / genetics</subject><subject>HLA-DRB1 Chains / genetics</subject><subject>Humans</subject><subject>Life Sciences</subject><subject>Major histocompatibility complex</subject><subject>Medicine and Health Sciences</subject><subject>Minority & ethnic groups</subject><subject>Multiple sclerosis</subject><subject>Multiple Sclerosis / genetics</subject><subject>Neurology</subject><subject>Odds Ratio</subject><subject>Pathogenesis</subject><subject>People and Places</subject><subject>Population</subject><subject>Risk</subject><subject>Risk factors</subject><subject>Single-nucleotide polymorphism</subject><subject>White People / 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susceptibility to multiple sclerosis in African Americans</title><author>Goodin, Douglas S. ; Oksenberg, Jorge R. ; Douillard, Venceslas ; Gourraud, Pierre-Antoine ; Vince, Nicolas</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c599t-d8873abca2123aa79283209f0e850beb2fc0e4861eb859d1b1862f7ad1ecd4273</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>African Americans</topic><topic>Algorithms</topic><topic>Biology and Life Sciences</topic><topic>Black or African American / genetics</topic><topic>Case-Control Studies</topic><topic>Consortia</topic><topic>Disease susceptibility</topic><topic>Drb1 protein</topic><topic>Evaluation</topic><topic>Gene Frequency / genetics</topic><topic>Genes</topic><topic>Genetic aspects</topic><topic>Genetic Predisposition to Disease</topic><topic>Genomes</topic><topic>Haplotypes</topic><topic>Haplotypes / genetics</topic><topic>Health aspects</topic><topic>Histocompatibility antigen HLA</topic><topic>HLA-DQ beta-Chains / genetics</topic><topic>HLA-DRB1 Chains / genetics</topic><topic>Humans</topic><topic>Life Sciences</topic><topic>Major histocompatibility complex</topic><topic>Medicine and Health Sciences</topic><topic>Minority & ethnic groups</topic><topic>Multiple sclerosis</topic><topic>Multiple Sclerosis / genetics</topic><topic>Neurology</topic><topic>Odds Ratio</topic><topic>Pathogenesis</topic><topic>People and Places</topic><topic>Population</topic><topic>Risk</topic><topic>Risk factors</topic><topic>Single-nucleotide polymorphism</topic><topic>White People / genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Goodin, Douglas S.</creatorcontrib><creatorcontrib>Oksenberg, Jorge R.</creatorcontrib><creatorcontrib>Douillard, Venceslas</creatorcontrib><creatorcontrib>Gourraud, Pierre-Antoine</creatorcontrib><creatorcontrib>Vince, 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Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Goodin, Douglas S.</au><au>Oksenberg, Jorge R.</au><au>Douillard, Venceslas</au><au>Gourraud, Pierre-Antoine</au><au>Vince, Nicolas</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genetic susceptibility to multiple sclerosis in African Americans</atitle><jtitle>PloS one</jtitle><date>2021-08-09</date><risdate>2021</risdate><volume>16</volume><issue>8</issue><spage>e0254945</spage><epage>e0254945</epage><pages>e0254945-e0254945</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><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.sup.-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.sup.-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.</abstract><cop>San Francisco</cop><pub>Public Library of Science</pub><pmid>34370753</pmid><doi>10.1371/journal.pone.0254945</doi><orcidid>https://orcid.org/0000-0002-5985-0822</orcidid><orcidid>https://orcid.org/0000-0002-3767-6210</orcidid><orcidid>https://orcid.org/0000-0002-6762-4083</orcidid><orcidid>https://orcid.org/0000-0003-1131-9554</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2021-08, Vol.16 (8), p.e0254945-e0254945 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_2559640770 |
| source | Public Library of Science (PLoS) Journals Open Access; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | African Americans Algorithms Biology and Life Sciences Black or African American / genetics Case-Control Studies Consortia Disease susceptibility Drb1 protein Evaluation Gene Frequency / genetics Genes Genetic aspects Genetic Predisposition to Disease Genomes Haplotypes Haplotypes / genetics Health aspects Histocompatibility antigen HLA HLA-DQ beta-Chains / genetics HLA-DRB1 Chains / genetics Humans Life Sciences Major histocompatibility complex Medicine and Health Sciences Minority & ethnic groups Multiple sclerosis Multiple Sclerosis / genetics Neurology Odds Ratio Pathogenesis People and Places Population Risk Risk factors Single-nucleotide polymorphism White People / genetics |
| title | Genetic susceptibility to multiple sclerosis in African Americans |
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