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Next-Generation Sequencing Identifies Extended HLA Class I and II Haplotypes Associated With Early-Onset and Late-Onset Myasthenia Gravis in Italian, Norwegian, and Swedish Populations
Genetic susceptibility to myasthenia gravis (MG) associates with specific HLA alleles and haplotypes at the class I and II regions in various populations. Previous studies have only examined alleles at a limited number of HLA loci that defined only broad serotypes or alleles defined at the protein s...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215161/ https://www.ncbi.nlm.nih.gov/pubmed/34163474 http://dx.doi.org/10.3389/fimmu.2021.667336 |
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author | Creary, Lisa E. Gangavarapu, Sridevi Caillier, Stacy J. Cavalcante, Paola Frangiamore, Rita Lie, Benedicte A. Bengtsson, Mats Harbo, Hanne Flinstad Brauner, Susanna Hollenbach, Jill A. Oksenberg, Jorge R. Bernasconi, Pia Maniaol, Angelina Hatlø Hammarström, Lennart Mantegazza, Renato Fernández-Viña, Marcelo A. |
author_facet | Creary, Lisa E. Gangavarapu, Sridevi Caillier, Stacy J. Cavalcante, Paola Frangiamore, Rita Lie, Benedicte A. Bengtsson, Mats Harbo, Hanne Flinstad Brauner, Susanna Hollenbach, Jill A. Oksenberg, Jorge R. Bernasconi, Pia Maniaol, Angelina Hatlø Hammarström, Lennart Mantegazza, Renato Fernández-Viña, Marcelo A. |
author_sort | Creary, Lisa E. |
collection | PubMed |
description | Genetic susceptibility to myasthenia gravis (MG) associates with specific HLA alleles and haplotypes at the class I and II regions in various populations. Previous studies have only examined alleles at a limited number of HLA loci that defined only broad serotypes or alleles defined at the protein sequence level. Consequently, genetic variants in noncoding and untranslated HLA gene segments have not been fully explored but could also be important determinants for MG. To gain further insight into the role of HLA in MG, we applied next-generation sequencing to analyze sequence variation at eleven HLA genes in early-onset (EO) and late-onset (LO) non-thymomatous MG patients positive for the acetylcholine receptor (AChR) antibodies and ethnically matched controls from Italy, Norway, and Sweden. For all three populations, alleles and haplotype blocks present on the ancestral haplotype AH8.1 were associated with risk in AChR-EOMG patients. HLA-B*08:01:01:01 was the dominant risk allele in Italians (OR = 3.28, P = 1.83E−05), Norwegians (OR = 3.52, P = 4.41E−16), and in Swedes HLA-B*08:01 was the primary risk allele (OR = 4.24, P <2.2E-16). Protective alleles and haplotype blocks were identified on the HLA-DRB7, and HLA-DRB13.1 class II haplotypes in Italians and Norwegians, whereas in Swedes HLA-DRB7 exhibited the main protective effect. For AChR-LOMG patients, the HLA-DRB15.1 haplotype and associated alleles were significantly associated with susceptibility in all groups. The HLA-DR13–HLA-DR–HLA-DQ haplotype was associated with protection in all AChR-LOMG groups. This study has confirmed and extended previous findings that the immunogenetic predisposition profiles for EOMG and LOMG are distinct. In addition, the results are consistent with a role for non-coding HLA genetic variants in the pathogenesis of MG. |
format | Online Article Text |
id | pubmed-8215161 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-82151612021-06-22 Next-Generation Sequencing Identifies Extended HLA Class I and II Haplotypes Associated With Early-Onset and Late-Onset Myasthenia Gravis in Italian, Norwegian, and Swedish Populations Creary, Lisa E. Gangavarapu, Sridevi Caillier, Stacy J. Cavalcante, Paola Frangiamore, Rita Lie, Benedicte A. Bengtsson, Mats Harbo, Hanne Flinstad Brauner, Susanna Hollenbach, Jill A. Oksenberg, Jorge R. Bernasconi, Pia Maniaol, Angelina Hatlø Hammarström, Lennart Mantegazza, Renato Fernández-Viña, Marcelo A. Front Immunol Immunology Genetic susceptibility to myasthenia gravis (MG) associates with specific HLA alleles and haplotypes at the class I and II regions in various populations. Previous studies have only examined alleles at a limited number of HLA loci that defined only broad serotypes or alleles defined at the protein sequence level. Consequently, genetic variants in noncoding and untranslated HLA gene segments have not been fully explored but could also be important determinants for MG. To gain further insight into the role of HLA in MG, we applied next-generation sequencing to analyze sequence variation at eleven HLA genes in early-onset (EO) and late-onset (LO) non-thymomatous MG patients positive for the acetylcholine receptor (AChR) antibodies and ethnically matched controls from Italy, Norway, and Sweden. For all three populations, alleles and haplotype blocks present on the ancestral haplotype AH8.1 were associated with risk in AChR-EOMG patients. HLA-B*08:01:01:01 was the dominant risk allele in Italians (OR = 3.28, P = 1.83E−05), Norwegians (OR = 3.52, P = 4.41E−16), and in Swedes HLA-B*08:01 was the primary risk allele (OR = 4.24, P <2.2E-16). Protective alleles and haplotype blocks were identified on the HLA-DRB7, and HLA-DRB13.1 class II haplotypes in Italians and Norwegians, whereas in Swedes HLA-DRB7 exhibited the main protective effect. For AChR-LOMG patients, the HLA-DRB15.1 haplotype and associated alleles were significantly associated with susceptibility in all groups. The HLA-DR13–HLA-DR–HLA-DQ haplotype was associated with protection in all AChR-LOMG groups. This study has confirmed and extended previous findings that the immunogenetic predisposition profiles for EOMG and LOMG are distinct. In addition, the results are consistent with a role for non-coding HLA genetic variants in the pathogenesis of MG. Frontiers Media S.A. 2021-06-07 /pmc/articles/PMC8215161/ /pubmed/34163474 http://dx.doi.org/10.3389/fimmu.2021.667336 Text en Copyright © 2021 Creary, Gangavarapu, Caillier, Cavalcante, Frangiamore, Lie, Bengtsson, Harbo, Brauner, Hollenbach, Oksenberg, Bernasconi, Maniaol, Hammarström, Mantegazza and Fernández-Viña https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Creary, Lisa E. Gangavarapu, Sridevi Caillier, Stacy J. Cavalcante, Paola Frangiamore, Rita Lie, Benedicte A. Bengtsson, Mats Harbo, Hanne Flinstad Brauner, Susanna Hollenbach, Jill A. Oksenberg, Jorge R. Bernasconi, Pia Maniaol, Angelina Hatlø Hammarström, Lennart Mantegazza, Renato Fernández-Viña, Marcelo A. Next-Generation Sequencing Identifies Extended HLA Class I and II Haplotypes Associated With Early-Onset and Late-Onset Myasthenia Gravis in Italian, Norwegian, and Swedish Populations |
title | Next-Generation Sequencing Identifies Extended HLA Class I and II Haplotypes Associated With Early-Onset and Late-Onset Myasthenia Gravis in Italian, Norwegian, and Swedish Populations |
title_full | Next-Generation Sequencing Identifies Extended HLA Class I and II Haplotypes Associated With Early-Onset and Late-Onset Myasthenia Gravis in Italian, Norwegian, and Swedish Populations |
title_fullStr | Next-Generation Sequencing Identifies Extended HLA Class I and II Haplotypes Associated With Early-Onset and Late-Onset Myasthenia Gravis in Italian, Norwegian, and Swedish Populations |
title_full_unstemmed | Next-Generation Sequencing Identifies Extended HLA Class I and II Haplotypes Associated With Early-Onset and Late-Onset Myasthenia Gravis in Italian, Norwegian, and Swedish Populations |
title_short | Next-Generation Sequencing Identifies Extended HLA Class I and II Haplotypes Associated With Early-Onset and Late-Onset Myasthenia Gravis in Italian, Norwegian, and Swedish Populations |
title_sort | next-generation sequencing identifies extended hla class i and ii haplotypes associated with early-onset and late-onset myasthenia gravis in italian, norwegian, and swedish populations |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215161/ https://www.ncbi.nlm.nih.gov/pubmed/34163474 http://dx.doi.org/10.3389/fimmu.2021.667336 |
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