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PMID: 22174698 Published · ppublish English Journal Article Meta-Analysis Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

A comprehensive analysis of shared loci between systemic lupus erythematosus (SLE) and sixteen autoimmune diseases reveals limited genetic overlap.

PLoS genetics ·Vol. 7 ·No. 12 ·2011-12-00 ·Pages e1002406

Ramos PS, Criswell LA, Moser KL, Comeau ME, Williams AH, Pajewski NM, Chung SA, Graham RR, Zidovetzki R, Kelly JA, Kaufman KM, Jacob CO, Vyse TJ, Tsao BP, Kimberly RP, Gaffney PM, Alarcón-Riquelme ME, Harley JB, Langefeld CD, International Consortium on the Genetics of Systemic Erythematosus

Abstract

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.

MeSH Terms
Arthritis, Rheumatoid/genetics Autoimmune Diseases/genetics Case-Control Studies Cohort Studies Colitis, Ulcerative/genetics Crohn Disease/genetics Diabetes Mellitus, Type 1/genetics Genetic Pleiotropy Genetic Predisposition to Disease/genetics Genome-Wide Association Study Humans Interleukin-2 Receptor alpha Subunit/genetics Lupus Erythematosus, Systemic/genetics OX40 Ligand/genetics Polymorphism, Single Nucleotide Receptors, Interleukin/genetics V-Set Domain-Containing T-Cell Activation Inhibitor 1/genetics Whites/genetics
Chemicals
IL23R protein, human IL2RA protein, human Interleukin-2 Receptor alpha Subunit OX40 Ligand Receptors, Interleukin TNFSF4 protein, human V-Set Domain-Containing T-Cell Activation Inhibitor 1 VTCN1 protein, human
Authors & Affiliations
20 authors, click to expand affiliations / ORCID
Ramos Paula S
Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America. [email protected]
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
International Consortium on the Genetics of Systemic Erythematosus
Investigators
9 investigators, click to expand
Alarcón-Riquelme Marta E
Criswell Lindsey A
Harley John B
Jacob Chaim O
Kimberly Robert P
Langefeld Carl D
Moser Kathy L
Tsao Betty P
Vyse Timothy J
Conflict of Interest

RRG is an employee of Genentech.

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Article Info
Journal
PLoS genetics
Abbr.
PLoS Genet
ISSN
1553-7404
DOI
10.1371/journal.pgen.1002406
Email
[email protected]
Published
2011-12-00
Epub
2011-00-08
Pages
e1002406
Language
English
Region
United States
NLM ID
101239074
PMCID
PMC3234215
Subset
IM
Grants
NIAMS NIH HHS · AR049084 · United States
NIAMS NIH HHS · AR053308 · United States
NIAID NIH HHS · R56 AI063274 · United States
NIAMS NIH HHS · P30 AR053483 · United States
NCRR NIH HHS · KL2 RR024130 · United States
NIAMS NIH HHS · R01 AR033062 · United States
NCRR NIH HHS · RR024130 · United States
NIAMS NIH HHS · AR445650 · United States
NIAMS NIH HHS · AR33062 · United States
NIAID NIH HHS · AI024717 · United States
NIAMS NIH HHS · P01 AR049084 · United States
NIAMS NIH HHS · P60 AR053308 · United States
NIAID NIH HHS · R01 AI063274 · United States
NIAMS NIH HHS · AR49084 · United States
NCRR NIH HHS · M01 RR000079 · United States
NIAMS NIH HHS · AR043814 · United States
NCRR NIH HHS · P20 RR020143 · United States
NIAMS NIH HHS · AR044804 · United States
NIAMS NIH HHS · AR042460 · United States
NCRR NIH HHS · RR020143 · United States
NIAMS NIH HHS · AR043247 · United States
NIAMS NIH HHS · N01 AR062277 · United States
NIAID NIH HHS · AI063274 · United States
NIAMS NIH HHS · R01 AR043814 · United States
NIAID NIH HHS · R37 AI024717 · United States
NIAMS NIH HHS · R01 AR042460 · United States
Wellcome Trust · 085492 · United Kingdom
NIAID NIH HHS · R01 AI024717 · United States
NIAMS NIH HHS · K24 AR002175 · United States
NCRR NIH HHS · M01 RR-000079 · United States
NIAMS NIH HHS · AR02175 · United States
External Links
PubMed source DOI: 10.1371/journal.pgen.1002406 PMC Full Text View journal details
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