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Immunoglobulin M gene association with autoantibody reactivity and type 1 diabetes

Several lines of evidence show that autoimmune responses evolving in type 1 diabetes (T1D) patients include the generation of multi-reactive autoantibody (AutoAb) repertoires, but their role in T1D pathogenesis remains elusive. We tested the hypothesis that variants at the immunoglobulin heavy chain...

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Autores principales: Rolim, Inês, Duarte, Nádia, Barata, Gabriela, Costa, João, Gardete-Correia, Luís, Boavida, José, Duarte, Rui, Raposo, João, Peerally, Zulmira, Catarino, Manuela, Penha-Gonçalves, Carlos
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486809/
https://www.ncbi.nlm.nih.gov/pubmed/28534223
http://dx.doi.org/10.1007/s00251-017-0999-1
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author Rolim, Inês
Duarte, Nádia
Barata, Gabriela
Costa, João
Gardete-Correia, Luís
Boavida, José
Duarte, Rui
Raposo, João
Peerally, Zulmira
Catarino, Manuela
Penha-Gonçalves, Carlos
author_facet Rolim, Inês
Duarte, Nádia
Barata, Gabriela
Costa, João
Gardete-Correia, Luís
Boavida, José
Duarte, Rui
Raposo, João
Peerally, Zulmira
Catarino, Manuela
Penha-Gonçalves, Carlos
author_sort Rolim, Inês
collection PubMed
description Several lines of evidence show that autoimmune responses evolving in type 1 diabetes (T1D) patients include the generation of multi-reactive autoantibody (AutoAb) repertoires, but their role in T1D pathogenesis remains elusive. We tested the hypothesis that variants at the immunoglobulin heavy chain (IGH) locus are genetic determinants of AutoAbs against pancreatic antigens and contribute to T1D susceptibility. With this aim, two independent study designs were used: a case-control study and a family-based cohort comprising a total of 240 T1D patients, 172 first-degree relatives (mother and/or father), and 130 unrelated healthy controls living in Portugal. We found that three SNPs in the IGH locus show suggestive association with T1D with the highest nominal association at rs1950942 (in the IGHM-IGHJ gene region) in both the case-control study (P = 9.35E−03) and the family-based cohort (P = 3.08E−03). These SNPs were also associated with IgG AutoAbs against pancreatic antigens and with AutoAb multi-reactivity in T1D patients. Notably, we found that the SNP with the highest association with T1D susceptibility and IgG autoantibody reactivity (rs1950942) was also associated with anti-GAD IgM reactivity in T1D patients (P = 5.98E−03) and in non-affected parents (P = 4.17E−03). This finding implies that IGH association with autoreactive IgM is detectable irrespective of disease status. These results suggest that genetic variants at the IgM gene region of the IGH locus contribute to antibody autoreactivity and are associated with T1D. We propose that the control of autoantibody generation by IGH polymorphisms is a component of the complex architecture of T1D genetic susceptibility. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00251-017-0999-1) contains supplementary material, which is available to authorized users.
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spelling pubmed-54868092017-07-11 Immunoglobulin M gene association with autoantibody reactivity and type 1 diabetes Rolim, Inês Duarte, Nádia Barata, Gabriela Costa, João Gardete-Correia, Luís Boavida, José Duarte, Rui Raposo, João Peerally, Zulmira Catarino, Manuela Penha-Gonçalves, Carlos Immunogenetics Original Article Several lines of evidence show that autoimmune responses evolving in type 1 diabetes (T1D) patients include the generation of multi-reactive autoantibody (AutoAb) repertoires, but their role in T1D pathogenesis remains elusive. We tested the hypothesis that variants at the immunoglobulin heavy chain (IGH) locus are genetic determinants of AutoAbs against pancreatic antigens and contribute to T1D susceptibility. With this aim, two independent study designs were used: a case-control study and a family-based cohort comprising a total of 240 T1D patients, 172 first-degree relatives (mother and/or father), and 130 unrelated healthy controls living in Portugal. We found that three SNPs in the IGH locus show suggestive association with T1D with the highest nominal association at rs1950942 (in the IGHM-IGHJ gene region) in both the case-control study (P = 9.35E−03) and the family-based cohort (P = 3.08E−03). These SNPs were also associated with IgG AutoAbs against pancreatic antigens and with AutoAb multi-reactivity in T1D patients. Notably, we found that the SNP with the highest association with T1D susceptibility and IgG autoantibody reactivity (rs1950942) was also associated with anti-GAD IgM reactivity in T1D patients (P = 5.98E−03) and in non-affected parents (P = 4.17E−03). This finding implies that IGH association with autoreactive IgM is detectable irrespective of disease status. These results suggest that genetic variants at the IgM gene region of the IGH locus contribute to antibody autoreactivity and are associated with T1D. We propose that the control of autoantibody generation by IGH polymorphisms is a component of the complex architecture of T1D genetic susceptibility. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00251-017-0999-1) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2017-05-22 2017 /pmc/articles/PMC5486809/ /pubmed/28534223 http://dx.doi.org/10.1007/s00251-017-0999-1 Text en © The Author(s) 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Article
Rolim, Inês
Duarte, Nádia
Barata, Gabriela
Costa, João
Gardete-Correia, Luís
Boavida, José
Duarte, Rui
Raposo, João
Peerally, Zulmira
Catarino, Manuela
Penha-Gonçalves, Carlos
Immunoglobulin M gene association with autoantibody reactivity and type 1 diabetes
title Immunoglobulin M gene association with autoantibody reactivity and type 1 diabetes
title_full Immunoglobulin M gene association with autoantibody reactivity and type 1 diabetes
title_fullStr Immunoglobulin M gene association with autoantibody reactivity and type 1 diabetes
title_full_unstemmed Immunoglobulin M gene association with autoantibody reactivity and type 1 diabetes
title_short Immunoglobulin M gene association with autoantibody reactivity and type 1 diabetes
title_sort immunoglobulin m gene association with autoantibody reactivity and type 1 diabetes
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486809/
https://www.ncbi.nlm.nih.gov/pubmed/28534223
http://dx.doi.org/10.1007/s00251-017-0999-1
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