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High Resolution Haplotype Analyses of Classical HLA Genes in Families With Multiple Sclerosis Highlights the Role of HLA-DP Alleles in Disease Susceptibility
Multiple sclerosis (MS) susceptibility shows strong genetic associations with HLA alleles and haplotypes. We genotyped 11 HLA genes in 477 non-Hispanic European MS patients and their 954 unaffected parents using a validated next-generation sequencing (NGS) methodology. HLA haplotypes were assigned u...
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/PMC8240666/ https://www.ncbi.nlm.nih.gov/pubmed/34211458 http://dx.doi.org/10.3389/fimmu.2021.644838 |
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author | Osoegawa, Kazutoyo Creary, Lisa E. Montero-Martín, Gonzalo Mallempati, Kalyan C. Gangavarapu, Sridevi Caillier, Stacy J. Santaniello, Adam Isobe, Noriko Hollenbach, Jill A. Hauser, Stephen L. Oksenberg, Jorge R. Fernández-Viňa, Marcelo A. |
author_facet | Osoegawa, Kazutoyo Creary, Lisa E. Montero-Martín, Gonzalo Mallempati, Kalyan C. Gangavarapu, Sridevi Caillier, Stacy J. Santaniello, Adam Isobe, Noriko Hollenbach, Jill A. Hauser, Stephen L. Oksenberg, Jorge R. Fernández-Viňa, Marcelo A. |
author_sort | Osoegawa, Kazutoyo |
collection | PubMed |
description | Multiple sclerosis (MS) susceptibility shows strong genetic associations with HLA alleles and haplotypes. We genotyped 11 HLA genes in 477 non-Hispanic European MS patients and their 954 unaffected parents using a validated next-generation sequencing (NGS) methodology. HLA haplotypes were assigned unequivocally by tracing HLA allele transmissions. We explored HLA haplotype/allele associations with MS using the genotypic transmission disequilibrium test (gTDT) and multiallelic TDT (mTDT). We also conducted a case-control (CC) study with all patients and 2029 healthy unrelated ethnically matched controls. We performed separate analyses of 54 extended multi-case families by reviewing transmission of haplotype blocks. The haplotype fragment including DRB5*01:01:01~DRB1*15:01:01:01 was significantly associated with predisposition (gTDT: p < 2.20e-16; mTDT: p =1.61e-07; CC: p < 2.22e-16) as reported previously. A second risk allele, DPB1*104:01 (gTDT: p = 3.69e-03; mTDT: p = 2.99e-03; CC: p = 1.00e-02), independent from the haplotype bearing DRB1*15:01 was newly identified. The allele DRB1*01:01:01 showed significant protection (gTDT: p = 8.68e-06; mTDT: p = 4.50e-03; CC: p = 1.96e-06). Two DQB1 alleles, DQB1*03:01 (gTDT: p = 2.86e-03; mTDT: p = 5.56e-02; CC: p = 4.08e-05) and DQB1*03:03 (gTDT: p = 1.17e-02; mTDT: p = 1.16e-02; CC: p = 1.21e-02), defined at two-field level also showed protective effects. The HLA class I block, A*02:01:01:01~C*03:04:01:01~B*40:01:02 (gTDT: p = 5.86e-03; mTDT: p = 3.65e-02; CC: p = 9.69e-03) and the alleles B*27:05 (gTDT: p = 6.28e-04; mTDT: p = 2.15e-03; CC: p = 1.47e-02) and B*38:01 (gTDT: p = 3.20e-03; mTDT: p = 6.14e-03; CC: p = 1.70e-02) showed moderately protective effects independently from each other and from the class II associated factors. By comparing statistical significance of 11 HLA loci and 19 haplotype segments with both untruncated and two-field allele names, we precisely mapped MS candidate alleles/haplotypes while eliminating false signals resulting from ‘hitchhiking’ alleles. We assessed genetic burden for the HLA allele/haplotype identified in this study. This family-based study including the highest-resolution of HLA alleles proved to be powerful and efficient for precise identification of HLA genotypes associated with both, susceptibility and protection to development of MS. |
format | Online Article Text |
id | pubmed-8240666 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-82406662021-06-30 High Resolution Haplotype Analyses of Classical HLA Genes in Families With Multiple Sclerosis Highlights the Role of HLA-DP Alleles in Disease Susceptibility Osoegawa, Kazutoyo Creary, Lisa E. Montero-Martín, Gonzalo Mallempati, Kalyan C. Gangavarapu, Sridevi Caillier, Stacy J. Santaniello, Adam Isobe, Noriko Hollenbach, Jill A. Hauser, Stephen L. Oksenberg, Jorge R. Fernández-Viňa, Marcelo A. Front Immunol Immunology Multiple sclerosis (MS) susceptibility shows strong genetic associations with HLA alleles and haplotypes. We genotyped 11 HLA genes in 477 non-Hispanic European MS patients and their 954 unaffected parents using a validated next-generation sequencing (NGS) methodology. HLA haplotypes were assigned unequivocally by tracing HLA allele transmissions. We explored HLA haplotype/allele associations with MS using the genotypic transmission disequilibrium test (gTDT) and multiallelic TDT (mTDT). We also conducted a case-control (CC) study with all patients and 2029 healthy unrelated ethnically matched controls. We performed separate analyses of 54 extended multi-case families by reviewing transmission of haplotype blocks. The haplotype fragment including DRB5*01:01:01~DRB1*15:01:01:01 was significantly associated with predisposition (gTDT: p < 2.20e-16; mTDT: p =1.61e-07; CC: p < 2.22e-16) as reported previously. A second risk allele, DPB1*104:01 (gTDT: p = 3.69e-03; mTDT: p = 2.99e-03; CC: p = 1.00e-02), independent from the haplotype bearing DRB1*15:01 was newly identified. The allele DRB1*01:01:01 showed significant protection (gTDT: p = 8.68e-06; mTDT: p = 4.50e-03; CC: p = 1.96e-06). Two DQB1 alleles, DQB1*03:01 (gTDT: p = 2.86e-03; mTDT: p = 5.56e-02; CC: p = 4.08e-05) and DQB1*03:03 (gTDT: p = 1.17e-02; mTDT: p = 1.16e-02; CC: p = 1.21e-02), defined at two-field level also showed protective effects. The HLA class I block, A*02:01:01:01~C*03:04:01:01~B*40:01:02 (gTDT: p = 5.86e-03; mTDT: p = 3.65e-02; CC: p = 9.69e-03) and the alleles B*27:05 (gTDT: p = 6.28e-04; mTDT: p = 2.15e-03; CC: p = 1.47e-02) and B*38:01 (gTDT: p = 3.20e-03; mTDT: p = 6.14e-03; CC: p = 1.70e-02) showed moderately protective effects independently from each other and from the class II associated factors. By comparing statistical significance of 11 HLA loci and 19 haplotype segments with both untruncated and two-field allele names, we precisely mapped MS candidate alleles/haplotypes while eliminating false signals resulting from ‘hitchhiking’ alleles. We assessed genetic burden for the HLA allele/haplotype identified in this study. This family-based study including the highest-resolution of HLA alleles proved to be powerful and efficient for precise identification of HLA genotypes associated with both, susceptibility and protection to development of MS. Frontiers Media S.A. 2021-05-25 /pmc/articles/PMC8240666/ /pubmed/34211458 http://dx.doi.org/10.3389/fimmu.2021.644838 Text en Copyright © 2021 Osoegawa, Creary, Montero-Martín, Mallempati, Gangavarapu, Caillier, Santaniello, Isobe, Hollenbach, Hauser, Oksenberg and Fernández-Viňa 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 Osoegawa, Kazutoyo Creary, Lisa E. Montero-Martín, Gonzalo Mallempati, Kalyan C. Gangavarapu, Sridevi Caillier, Stacy J. Santaniello, Adam Isobe, Noriko Hollenbach, Jill A. Hauser, Stephen L. Oksenberg, Jorge R. Fernández-Viňa, Marcelo A. High Resolution Haplotype Analyses of Classical HLA Genes in Families With Multiple Sclerosis Highlights the Role of HLA-DP Alleles in Disease Susceptibility |
title | High Resolution Haplotype Analyses of Classical HLA Genes in Families With Multiple Sclerosis Highlights the Role of HLA-DP Alleles in Disease Susceptibility |
title_full | High Resolution Haplotype Analyses of Classical HLA Genes in Families With Multiple Sclerosis Highlights the Role of HLA-DP Alleles in Disease Susceptibility |
title_fullStr | High Resolution Haplotype Analyses of Classical HLA Genes in Families With Multiple Sclerosis Highlights the Role of HLA-DP Alleles in Disease Susceptibility |
title_full_unstemmed | High Resolution Haplotype Analyses of Classical HLA Genes in Families With Multiple Sclerosis Highlights the Role of HLA-DP Alleles in Disease Susceptibility |
title_short | High Resolution Haplotype Analyses of Classical HLA Genes in Families With Multiple Sclerosis Highlights the Role of HLA-DP Alleles in Disease Susceptibility |
title_sort | high resolution haplotype analyses of classical hla genes in families with multiple sclerosis highlights the role of hla-dp alleles in disease susceptibility |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240666/ https://www.ncbi.nlm.nih.gov/pubmed/34211458 http://dx.doi.org/10.3389/fimmu.2021.644838 |
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