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A Comprehensive Analysis of Shared Loci between Systemic Lupus Erythematosus (SLE) and Sixteen Autoimmune Diseases Reveals Limited Genetic Overlap
In spite of the well-known clustering of multiple autoimmune disorders in families, analyses of specific shared genes and polymorphisms between systemic lupus erythematosus (SLE) and other autoimmune diseases (ADs) have been limited. Therefore, we comprehensively tested autoimmune variants for assoc...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3234215/ https://www.ncbi.nlm.nih.gov/pubmed/22174698 http://dx.doi.org/10.1371/journal.pgen.1002406 |
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author | Ramos, Paula S. Criswell, Lindsey A. Moser, Kathy L. Comeau, Mary E. Williams, Adrienne H. Pajewski, Nicholas M. Chung, Sharon A. Graham, Robert R. Zidovetzki, Raphael Kelly, Jennifer A. Kaufman, Kenneth M. Jacob, Chaim O. Vyse, Timothy J. Tsao, Betty P. Kimberly, Robert P. Gaffney, Patrick M. Alarcón-Riquelme, Marta E. Harley, John B. Langefeld, Carl D. |
author_facet | Ramos, Paula S. Criswell, Lindsey A. Moser, Kathy L. Comeau, Mary E. Williams, Adrienne H. Pajewski, Nicholas M. Chung, Sharon A. Graham, Robert R. Zidovetzki, Raphael Kelly, Jennifer A. Kaufman, Kenneth M. Jacob, Chaim O. Vyse, Timothy J. Tsao, Betty P. Kimberly, Robert P. Gaffney, Patrick M. Alarcón-Riquelme, Marta E. Harley, John B. Langefeld, Carl D. |
author_sort | Ramos, Paula S. |
collection | PubMed |
description | In spite of the well-known clustering of multiple autoimmune disorders in families, analyses of specific shared genes and polymorphisms between systemic lupus erythematosus (SLE) and other autoimmune diseases (ADs) have been limited. Therefore, we comprehensively tested autoimmune variants for association with SLE, aiming to identify pleiotropic genetic associations between these diseases. We compiled a list of 446 non–Major Histocompatibility Complex (MHC) variants identified in genome-wide association studies (GWAS) of populations of European ancestry across 17 ADs. We then tested these variants in our combined Caucasian SLE cohorts of 1,500 cases and 5,706 controls. We tested a subset of these polymorphisms in an independent Caucasian replication cohort of 2,085 SLE cases and 2,854 controls, allowing the computation of a meta-analysis between all cohorts. We have uncovered novel shared SLE loci that passed multiple comparisons adjustment, including the VTCN1 (rs12046117, P = 2.02×10(−06)) region. We observed that the loci shared among the most ADs include IL23R, OLIG3/TNFAIP3, and IL2RA. Given the lack of a universal autoimmune risk locus outside of the MHC and variable specificities for different diseases, our data suggests partial pleiotropy among ADs. Hierarchical clustering of ADs suggested that the most genetically related ADs appear to be type 1 diabetes with rheumatoid arthritis and Crohn's disease with ulcerative colitis. These findings support a relatively distinct genetic susceptibility for SLE. For many of the shared GWAS autoimmune loci, we found no evidence for association with SLE, including IL23R. Also, several established SLE loci are apparently not associated with other ADs, including the ITGAM-ITGAX and TNFSF4 regions. This study represents the most comprehensive evaluation of shared autoimmune loci to date, supports a relatively distinct non–MHC genetic susceptibility for SLE, provides further evidence for previously and newly identified shared genes in SLE, and highlights the value of studies of potentially pleiotropic genes in autoimmune diseases. |
format | Online Article Text |
id | pubmed-3234215 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-32342152011-12-15 A Comprehensive Analysis of Shared Loci between Systemic Lupus Erythematosus (SLE) and Sixteen Autoimmune Diseases Reveals Limited Genetic Overlap Ramos, Paula S. Criswell, Lindsey A. Moser, Kathy L. Comeau, Mary E. Williams, Adrienne H. Pajewski, Nicholas M. Chung, Sharon A. Graham, Robert R. Zidovetzki, Raphael Kelly, Jennifer A. Kaufman, Kenneth M. Jacob, Chaim O. Vyse, Timothy J. Tsao, Betty P. Kimberly, Robert P. Gaffney, Patrick M. Alarcón-Riquelme, Marta E. Harley, John B. Langefeld, Carl D. PLoS Genet Research Article In spite of the well-known clustering of multiple autoimmune disorders in families, analyses of specific shared genes and polymorphisms between systemic lupus erythematosus (SLE) and other autoimmune diseases (ADs) have been limited. Therefore, we comprehensively tested autoimmune variants for association with SLE, aiming to identify pleiotropic genetic associations between these diseases. We compiled a list of 446 non–Major Histocompatibility Complex (MHC) variants identified in genome-wide association studies (GWAS) of populations of European ancestry across 17 ADs. We then tested these variants in our combined Caucasian SLE cohorts of 1,500 cases and 5,706 controls. We tested a subset of these polymorphisms in an independent Caucasian replication cohort of 2,085 SLE cases and 2,854 controls, allowing the computation of a meta-analysis between all cohorts. We have uncovered novel shared SLE loci that passed multiple comparisons adjustment, including the VTCN1 (rs12046117, P = 2.02×10(−06)) region. We observed that the loci shared among the most ADs include IL23R, OLIG3/TNFAIP3, and IL2RA. Given the lack of a universal autoimmune risk locus outside of the MHC and variable specificities for different diseases, our data suggests partial pleiotropy among ADs. Hierarchical clustering of ADs suggested that the most genetically related ADs appear to be type 1 diabetes with rheumatoid arthritis and Crohn's disease with ulcerative colitis. These findings support a relatively distinct genetic susceptibility for SLE. For many of the shared GWAS autoimmune loci, we found no evidence for association with SLE, including IL23R. Also, several established SLE loci are apparently not associated with other ADs, including the ITGAM-ITGAX and TNFSF4 regions. This study represents the most comprehensive evaluation of shared autoimmune loci to date, supports a relatively distinct non–MHC genetic susceptibility for SLE, provides further evidence for previously and newly identified shared genes in SLE, and highlights the value of studies of potentially pleiotropic genes in autoimmune diseases. Public Library of Science 2011-12-08 /pmc/articles/PMC3234215/ /pubmed/22174698 http://dx.doi.org/10.1371/journal.pgen.1002406 Text en Ramos et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Ramos, Paula S. Criswell, Lindsey A. Moser, Kathy L. Comeau, Mary E. Williams, Adrienne H. Pajewski, Nicholas M. Chung, Sharon A. Graham, Robert R. Zidovetzki, Raphael Kelly, Jennifer A. Kaufman, Kenneth M. Jacob, Chaim O. Vyse, Timothy J. Tsao, Betty P. Kimberly, Robert P. Gaffney, Patrick M. Alarcón-Riquelme, Marta E. Harley, John B. Langefeld, Carl D. A Comprehensive Analysis of Shared Loci between Systemic Lupus Erythematosus (SLE) and Sixteen Autoimmune Diseases Reveals Limited Genetic Overlap |
title | A Comprehensive Analysis of Shared Loci between Systemic Lupus Erythematosus (SLE) and Sixteen Autoimmune Diseases Reveals Limited Genetic Overlap |
title_full | A Comprehensive Analysis of Shared Loci between Systemic Lupus Erythematosus (SLE) and Sixteen Autoimmune Diseases Reveals Limited Genetic Overlap |
title_fullStr | A Comprehensive Analysis of Shared Loci between Systemic Lupus Erythematosus (SLE) and Sixteen Autoimmune Diseases Reveals Limited Genetic Overlap |
title_full_unstemmed | A Comprehensive Analysis of Shared Loci between Systemic Lupus Erythematosus (SLE) and Sixteen Autoimmune Diseases Reveals Limited Genetic Overlap |
title_short | A Comprehensive Analysis of Shared Loci between Systemic Lupus Erythematosus (SLE) and Sixteen Autoimmune Diseases Reveals Limited Genetic Overlap |
title_sort | comprehensive analysis of shared loci between systemic lupus erythematosus (sle) and sixteen autoimmune diseases reveals limited genetic overlap |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3234215/ https://www.ncbi.nlm.nih.gov/pubmed/22174698 http://dx.doi.org/10.1371/journal.pgen.1002406 |
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