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Ancestral risk modification for multiple sclerosis susceptibility detected across the Major Histocompatibility Complex in a multi-ethnic population
The Major Histocompatibility Complex (MHC) makes the largest genetic contribution to multiple sclerosis (MS) susceptibility, with 32 independent effects across the region explaining 20% of the heritability in European populations. Variation is high across populations with allele frequency difference...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9778564/ https://www.ncbi.nlm.nih.gov/pubmed/36548255 http://dx.doi.org/10.1371/journal.pone.0279132 |
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author | Beecham, Ashley H. Amezcua, Lilyana Chinea, Angel Manrique, Clara P. Gomez, Lissette Martinez, Andrea Beecham, Gary W. Patsopoulos, Nikolaos A. Chitnis, Tanuja Weiner, Howard L. De Jager, Philip L. Burchard, Esteban G. Lund, Brett T. Fitzgerald, Kathryn C. Calabresi, Peter A. Delgado, Silvia R. Oksenberg, Jorge R. McCauley, Jacob L. |
author_facet | Beecham, Ashley H. Amezcua, Lilyana Chinea, Angel Manrique, Clara P. Gomez, Lissette Martinez, Andrea Beecham, Gary W. Patsopoulos, Nikolaos A. Chitnis, Tanuja Weiner, Howard L. De Jager, Philip L. Burchard, Esteban G. Lund, Brett T. Fitzgerald, Kathryn C. Calabresi, Peter A. Delgado, Silvia R. Oksenberg, Jorge R. McCauley, Jacob L. |
author_sort | Beecham, Ashley H. |
collection | PubMed |
description | The Major Histocompatibility Complex (MHC) makes the largest genetic contribution to multiple sclerosis (MS) susceptibility, with 32 independent effects across the region explaining 20% of the heritability in European populations. Variation is high across populations with allele frequency differences and population-specific risk alleles identified. We sought to identify MHC-specific MS susceptibility variants and assess the effect of ancestral risk modification within 2652 Latinx and Hispanic individuals as well as 2435 Black and African American individuals. We have identified several novel susceptibility alleles which are rare in European populations including HLA-B*53:01, and we have utilized the differing linkage disequilibrium patterns inherent to these populations to identify an independent role for HLA-DRB1*15:01 and HLA-DQB1*06:02 on MS risk. We found a decrease in Native American ancestry in MS cases vs controls across the MHC, peaking near the previously identified MICB locus with a decrease of ~5.5% in Hispanics and ~0.4% in African Americans. We have identified several susceptibility variants, including within the MICB gene region, which show global ancestry risk modification and indicate ancestral differences which may be due in part to correlated environmental factors. We have also identified several susceptibility variants for which MS risk is modified by local ancestry and indicate true ancestral genetic differences; including HLA-DQB1*06:02 for which MS risk for European allele carriers is almost two times the risk for African allele carriers. These results validate the importance of investigating MS susceptibility at an ancestral level and offer insight into the epidemiology of MS phenotypic diversity. |
format | Online Article Text |
id | pubmed-9778564 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-97785642022-12-23 Ancestral risk modification for multiple sclerosis susceptibility detected across the Major Histocompatibility Complex in a multi-ethnic population Beecham, Ashley H. Amezcua, Lilyana Chinea, Angel Manrique, Clara P. Gomez, Lissette Martinez, Andrea Beecham, Gary W. Patsopoulos, Nikolaos A. Chitnis, Tanuja Weiner, Howard L. De Jager, Philip L. Burchard, Esteban G. Lund, Brett T. Fitzgerald, Kathryn C. Calabresi, Peter A. Delgado, Silvia R. Oksenberg, Jorge R. McCauley, Jacob L. PLoS One Research Article The Major Histocompatibility Complex (MHC) makes the largest genetic contribution to multiple sclerosis (MS) susceptibility, with 32 independent effects across the region explaining 20% of the heritability in European populations. Variation is high across populations with allele frequency differences and population-specific risk alleles identified. We sought to identify MHC-specific MS susceptibility variants and assess the effect of ancestral risk modification within 2652 Latinx and Hispanic individuals as well as 2435 Black and African American individuals. We have identified several novel susceptibility alleles which are rare in European populations including HLA-B*53:01, and we have utilized the differing linkage disequilibrium patterns inherent to these populations to identify an independent role for HLA-DRB1*15:01 and HLA-DQB1*06:02 on MS risk. We found a decrease in Native American ancestry in MS cases vs controls across the MHC, peaking near the previously identified MICB locus with a decrease of ~5.5% in Hispanics and ~0.4% in African Americans. We have identified several susceptibility variants, including within the MICB gene region, which show global ancestry risk modification and indicate ancestral differences which may be due in part to correlated environmental factors. We have also identified several susceptibility variants for which MS risk is modified by local ancestry and indicate true ancestral genetic differences; including HLA-DQB1*06:02 for which MS risk for European allele carriers is almost two times the risk for African allele carriers. These results validate the importance of investigating MS susceptibility at an ancestral level and offer insight into the epidemiology of MS phenotypic diversity. Public Library of Science 2022-12-22 /pmc/articles/PMC9778564/ /pubmed/36548255 http://dx.doi.org/10.1371/journal.pone.0279132 Text en © 2022 Beecham et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Beecham, Ashley H. Amezcua, Lilyana Chinea, Angel Manrique, Clara P. Gomez, Lissette Martinez, Andrea Beecham, Gary W. Patsopoulos, Nikolaos A. Chitnis, Tanuja Weiner, Howard L. De Jager, Philip L. Burchard, Esteban G. Lund, Brett T. Fitzgerald, Kathryn C. Calabresi, Peter A. Delgado, Silvia R. Oksenberg, Jorge R. McCauley, Jacob L. Ancestral risk modification for multiple sclerosis susceptibility detected across the Major Histocompatibility Complex in a multi-ethnic population |
title | Ancestral risk modification for multiple sclerosis susceptibility detected across the Major Histocompatibility Complex in a multi-ethnic population |
title_full | Ancestral risk modification for multiple sclerosis susceptibility detected across the Major Histocompatibility Complex in a multi-ethnic population |
title_fullStr | Ancestral risk modification for multiple sclerosis susceptibility detected across the Major Histocompatibility Complex in a multi-ethnic population |
title_full_unstemmed | Ancestral risk modification for multiple sclerosis susceptibility detected across the Major Histocompatibility Complex in a multi-ethnic population |
title_short | Ancestral risk modification for multiple sclerosis susceptibility detected across the Major Histocompatibility Complex in a multi-ethnic population |
title_sort | ancestral risk modification for multiple sclerosis susceptibility detected across the major histocompatibility complex in a multi-ethnic population |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9778564/ https://www.ncbi.nlm.nih.gov/pubmed/36548255 http://dx.doi.org/10.1371/journal.pone.0279132 |
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