Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
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
_version_ 1784856393542533120
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
work_keys_str_mv AT beechamashleyh ancestralriskmodificationformultiplesclerosissusceptibilitydetectedacrossthemajorhistocompatibilitycomplexinamultiethnicpopulation
AT amezcualilyana ancestralriskmodificationformultiplesclerosissusceptibilitydetectedacrossthemajorhistocompatibilitycomplexinamultiethnicpopulation
AT chineaangel ancestralriskmodificationformultiplesclerosissusceptibilitydetectedacrossthemajorhistocompatibilitycomplexinamultiethnicpopulation
AT manriqueclarap ancestralriskmodificationformultiplesclerosissusceptibilitydetectedacrossthemajorhistocompatibilitycomplexinamultiethnicpopulation
AT gomezlissette ancestralriskmodificationformultiplesclerosissusceptibilitydetectedacrossthemajorhistocompatibilitycomplexinamultiethnicpopulation
AT martinezandrea ancestralriskmodificationformultiplesclerosissusceptibilitydetectedacrossthemajorhistocompatibilitycomplexinamultiethnicpopulation
AT beechamgaryw ancestralriskmodificationformultiplesclerosissusceptibilitydetectedacrossthemajorhistocompatibilitycomplexinamultiethnicpopulation
AT patsopoulosnikolaosa ancestralriskmodificationformultiplesclerosissusceptibilitydetectedacrossthemajorhistocompatibilitycomplexinamultiethnicpopulation
AT chitnistanuja ancestralriskmodificationformultiplesclerosissusceptibilitydetectedacrossthemajorhistocompatibilitycomplexinamultiethnicpopulation
AT weinerhowardl ancestralriskmodificationformultiplesclerosissusceptibilitydetectedacrossthemajorhistocompatibilitycomplexinamultiethnicpopulation
AT dejagerphilipl ancestralriskmodificationformultiplesclerosissusceptibilitydetectedacrossthemajorhistocompatibilitycomplexinamultiethnicpopulation
AT burchardestebang ancestralriskmodificationformultiplesclerosissusceptibilitydetectedacrossthemajorhistocompatibilitycomplexinamultiethnicpopulation
AT lundbrettt ancestralriskmodificationformultiplesclerosissusceptibilitydetectedacrossthemajorhistocompatibilitycomplexinamultiethnicpopulation
AT fitzgeraldkathrync ancestralriskmodificationformultiplesclerosissusceptibilitydetectedacrossthemajorhistocompatibilitycomplexinamultiethnicpopulation
AT calabresipetera ancestralriskmodificationformultiplesclerosissusceptibilitydetectedacrossthemajorhistocompatibilitycomplexinamultiethnicpopulation
AT delgadosilviar ancestralriskmodificationformultiplesclerosissusceptibilitydetectedacrossthemajorhistocompatibilitycomplexinamultiethnicpopulation
AT oksenbergjorger ancestralriskmodificationformultiplesclerosissusceptibilitydetectedacrossthemajorhistocompatibilitycomplexinamultiethnicpopulation
AT mccauleyjacobl ancestralriskmodificationformultiplesclerosissusceptibilitydetectedacrossthemajorhistocompatibilitycomplexinamultiethnicpopulation