Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
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
_version_ 1783710192363372544
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
work_keys_str_mv AT crearylisae nextgenerationsequencingidentifiesextendedhlaclassiandiihaplotypesassociatedwithearlyonsetandlateonsetmyastheniagravisinitaliannorwegianandswedishpopulations
AT gangavarapusridevi nextgenerationsequencingidentifiesextendedhlaclassiandiihaplotypesassociatedwithearlyonsetandlateonsetmyastheniagravisinitaliannorwegianandswedishpopulations
AT caillierstacyj nextgenerationsequencingidentifiesextendedhlaclassiandiihaplotypesassociatedwithearlyonsetandlateonsetmyastheniagravisinitaliannorwegianandswedishpopulations
AT cavalcantepaola nextgenerationsequencingidentifiesextendedhlaclassiandiihaplotypesassociatedwithearlyonsetandlateonsetmyastheniagravisinitaliannorwegianandswedishpopulations
AT frangiamorerita nextgenerationsequencingidentifiesextendedhlaclassiandiihaplotypesassociatedwithearlyonsetandlateonsetmyastheniagravisinitaliannorwegianandswedishpopulations
AT liebenedictea nextgenerationsequencingidentifiesextendedhlaclassiandiihaplotypesassociatedwithearlyonsetandlateonsetmyastheniagravisinitaliannorwegianandswedishpopulations
AT bengtssonmats nextgenerationsequencingidentifiesextendedhlaclassiandiihaplotypesassociatedwithearlyonsetandlateonsetmyastheniagravisinitaliannorwegianandswedishpopulations
AT harbohanneflinstad nextgenerationsequencingidentifiesextendedhlaclassiandiihaplotypesassociatedwithearlyonsetandlateonsetmyastheniagravisinitaliannorwegianandswedishpopulations
AT braunersusanna nextgenerationsequencingidentifiesextendedhlaclassiandiihaplotypesassociatedwithearlyonsetandlateonsetmyastheniagravisinitaliannorwegianandswedishpopulations
AT hollenbachjilla nextgenerationsequencingidentifiesextendedhlaclassiandiihaplotypesassociatedwithearlyonsetandlateonsetmyastheniagravisinitaliannorwegianandswedishpopulations
AT oksenbergjorger nextgenerationsequencingidentifiesextendedhlaclassiandiihaplotypesassociatedwithearlyonsetandlateonsetmyastheniagravisinitaliannorwegianandswedishpopulations
AT bernasconipia nextgenerationsequencingidentifiesextendedhlaclassiandiihaplotypesassociatedwithearlyonsetandlateonsetmyastheniagravisinitaliannorwegianandswedishpopulations
AT maniaolangelinahatlø nextgenerationsequencingidentifiesextendedhlaclassiandiihaplotypesassociatedwithearlyonsetandlateonsetmyastheniagravisinitaliannorwegianandswedishpopulations
AT hammarstromlennart nextgenerationsequencingidentifiesextendedhlaclassiandiihaplotypesassociatedwithearlyonsetandlateonsetmyastheniagravisinitaliannorwegianandswedishpopulations
AT mantegazzarenato nextgenerationsequencingidentifiesextendedhlaclassiandiihaplotypesassociatedwithearlyonsetandlateonsetmyastheniagravisinitaliannorwegianandswedishpopulations
AT fernandezvinamarceloa nextgenerationsequencingidentifiesextendedhlaclassiandiihaplotypesassociatedwithearlyonsetandlateonsetmyastheniagravisinitaliannorwegianandswedishpopulations