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SNP Variants in Major Histocompatibility Complex Are Associated with Sarcoidosis Susceptibility—A Joint Analysis in Four European Populations
Sarcoidosis is a multiorgan inflammatory disorder with heritability estimates up to 66%. Previous studies have shown the major histocompatibility complex (MHC) region to be associated with sarcoidosis, suggesting a functional role for antigen-presenting molecules and immune mediators in the disease...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5395694/ https://www.ncbi.nlm.nih.gov/pubmed/28469621 http://dx.doi.org/10.3389/fimmu.2017.00422 |
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author | Wolin, Annika Lahtela, Elisa Laura Anttila, Verneri Petrek, Martin Grunewald, Johan van Moorsel, Coline H. M. Eklund, Anders Grutters, Jan C. Kolek, Vitezslav Mrazek, Frantisek Kishore, Amit Padyukov, Leonid Pietinalho, Anne Ronninger, Marcus Seppänen, Mikko Selroos, Olof Lokki, Marja-Liisa |
author_facet | Wolin, Annika Lahtela, Elisa Laura Anttila, Verneri Petrek, Martin Grunewald, Johan van Moorsel, Coline H. M. Eklund, Anders Grutters, Jan C. Kolek, Vitezslav Mrazek, Frantisek Kishore, Amit Padyukov, Leonid Pietinalho, Anne Ronninger, Marcus Seppänen, Mikko Selroos, Olof Lokki, Marja-Liisa |
author_sort | Wolin, Annika |
collection | PubMed |
description | Sarcoidosis is a multiorgan inflammatory disorder with heritability estimates up to 66%. Previous studies have shown the major histocompatibility complex (MHC) region to be associated with sarcoidosis, suggesting a functional role for antigen-presenting molecules and immune mediators in the disease pathogenesis. To detect variants predisposing to sarcoidosis and to identify genetic differences between patient subgroups, we studied four genes in the MHC Class III region (LTA, TNF, AGER, BTNL2) and HLA-DRA with tag-SNPs and their relation to HLA-DRB1 alleles. We present results from a joint analysis of four study populations (Finnish, Swedish, Dutch, and Czech). Patients with sarcoidosis (n = 805) were further subdivided based on the disease activity and the presence of Löfgren’s syndrome. In a joint analysis, seven SNPs were associated with non-Löfgren sarcoidosis (NL; the strongest association with rs3177928, P = 1.79E−07, OR = 1.9) and eight with Löfgren’s syndrome [Löfgren syndrome (LS); the strongest association with rs3129843, P = 3.44E−12, OR = 3.4] when compared with healthy controls (n = 870). Five SNPs were associated with sarcoidosis disease course (the strongest association with rs3177928, P = 0.003, OR = 1.9). The high linkage disequilibrium (LD) between SNPs and an HLA-DRB1 challenged the result interpretation. When the SNPs and HLA-DRB1 alleles were analyzed together, independent association was observed for four SNPs in the HLA-DRA/BTNL2 region: rs3135365 (NL; P = 0.015), rs3177928 (NL; P < 0.001), rs6937545 (LS; P = 0.012), and rs5007259 (disease activity; P = 0.002). These SNPs act as expression quantitative trait loci (eQTL) for HLA-DRB1 and/or HLA-DRB5. In conclusion, we found novel SNPs in BTNL2 and HLA-DRA regions associating with sarcoidosis. Our finding further establishes that polymorphisms in the HLA-DRA and BTNL2 have a role in sarcoidosis susceptibility. This multi-population study demonstrates that at least a part of these associations are HLA-DRB1 independent (e.g., not due to LD) and shared across ancestral origins. The variants that were independent of HLA-DRB1 associations acted as eQTL for HLA-DRB1 and/or -DRB5, suggesting a role in regulating gene expression. |
format | Online Article Text |
id | pubmed-5395694 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-53956942017-05-03 SNP Variants in Major Histocompatibility Complex Are Associated with Sarcoidosis Susceptibility—A Joint Analysis in Four European Populations Wolin, Annika Lahtela, Elisa Laura Anttila, Verneri Petrek, Martin Grunewald, Johan van Moorsel, Coline H. M. Eklund, Anders Grutters, Jan C. Kolek, Vitezslav Mrazek, Frantisek Kishore, Amit Padyukov, Leonid Pietinalho, Anne Ronninger, Marcus Seppänen, Mikko Selroos, Olof Lokki, Marja-Liisa Front Immunol Immunology Sarcoidosis is a multiorgan inflammatory disorder with heritability estimates up to 66%. Previous studies have shown the major histocompatibility complex (MHC) region to be associated with sarcoidosis, suggesting a functional role for antigen-presenting molecules and immune mediators in the disease pathogenesis. To detect variants predisposing to sarcoidosis and to identify genetic differences between patient subgroups, we studied four genes in the MHC Class III region (LTA, TNF, AGER, BTNL2) and HLA-DRA with tag-SNPs and their relation to HLA-DRB1 alleles. We present results from a joint analysis of four study populations (Finnish, Swedish, Dutch, and Czech). Patients with sarcoidosis (n = 805) were further subdivided based on the disease activity and the presence of Löfgren’s syndrome. In a joint analysis, seven SNPs were associated with non-Löfgren sarcoidosis (NL; the strongest association with rs3177928, P = 1.79E−07, OR = 1.9) and eight with Löfgren’s syndrome [Löfgren syndrome (LS); the strongest association with rs3129843, P = 3.44E−12, OR = 3.4] when compared with healthy controls (n = 870). Five SNPs were associated with sarcoidosis disease course (the strongest association with rs3177928, P = 0.003, OR = 1.9). The high linkage disequilibrium (LD) between SNPs and an HLA-DRB1 challenged the result interpretation. When the SNPs and HLA-DRB1 alleles were analyzed together, independent association was observed for four SNPs in the HLA-DRA/BTNL2 region: rs3135365 (NL; P = 0.015), rs3177928 (NL; P < 0.001), rs6937545 (LS; P = 0.012), and rs5007259 (disease activity; P = 0.002). These SNPs act as expression quantitative trait loci (eQTL) for HLA-DRB1 and/or HLA-DRB5. In conclusion, we found novel SNPs in BTNL2 and HLA-DRA regions associating with sarcoidosis. Our finding further establishes that polymorphisms in the HLA-DRA and BTNL2 have a role in sarcoidosis susceptibility. This multi-population study demonstrates that at least a part of these associations are HLA-DRB1 independent (e.g., not due to LD) and shared across ancestral origins. The variants that were independent of HLA-DRB1 associations acted as eQTL for HLA-DRB1 and/or -DRB5, suggesting a role in regulating gene expression. Frontiers Media S.A. 2017-04-19 /pmc/articles/PMC5395694/ /pubmed/28469621 http://dx.doi.org/10.3389/fimmu.2017.00422 Text en Copyright © 2017 Wolin, Lahtela, Anttila, Petrek, Grunewald, van Moorsel, Eklund, Grutters, Kolek, Mrazek, Kishore, Padyukov, Pietinalho, Ronninger, Seppänen, Selroos and Lokki. http://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) or licensor 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 Wolin, Annika Lahtela, Elisa Laura Anttila, Verneri Petrek, Martin Grunewald, Johan van Moorsel, Coline H. M. Eklund, Anders Grutters, Jan C. Kolek, Vitezslav Mrazek, Frantisek Kishore, Amit Padyukov, Leonid Pietinalho, Anne Ronninger, Marcus Seppänen, Mikko Selroos, Olof Lokki, Marja-Liisa SNP Variants in Major Histocompatibility Complex Are Associated with Sarcoidosis Susceptibility—A Joint Analysis in Four European Populations |
title | SNP Variants in Major Histocompatibility Complex Are Associated with Sarcoidosis Susceptibility—A Joint Analysis in Four European Populations |
title_full | SNP Variants in Major Histocompatibility Complex Are Associated with Sarcoidosis Susceptibility—A Joint Analysis in Four European Populations |
title_fullStr | SNP Variants in Major Histocompatibility Complex Are Associated with Sarcoidosis Susceptibility—A Joint Analysis in Four European Populations |
title_full_unstemmed | SNP Variants in Major Histocompatibility Complex Are Associated with Sarcoidosis Susceptibility—A Joint Analysis in Four European Populations |
title_short | SNP Variants in Major Histocompatibility Complex Are Associated with Sarcoidosis Susceptibility—A Joint Analysis in Four European Populations |
title_sort | snp variants in major histocompatibility complex are associated with sarcoidosis susceptibility—a joint analysis in four european populations |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5395694/ https://www.ncbi.nlm.nih.gov/pubmed/28469621 http://dx.doi.org/10.3389/fimmu.2017.00422 |
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