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      Differential Genetic Associations for Systemic Lupus Erythematosus Based on Anti–dsDNA Autoantibody Production

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          Abstract

          Systemic lupus erythematosus (SLE) is a clinically heterogeneous, systemic autoimmune disease characterized by autoantibody formation. Previously published genome-wide association studies (GWAS) have investigated SLE as a single phenotype. Therefore, we conducted a GWAS to identify genetic factors associated with anti–dsDNA autoantibody production, a SLE–related autoantibody with diagnostic and clinical importance. Using two independent datasets, over 400,000 single nucleotide polymorphisms (SNPs) were studied in a total of 1,717 SLE cases and 4,813 healthy controls. Anti–dsDNA autoantibody positive (anti–dsDNA +, n = 811) and anti–dsDNA autoantibody negative (anti–dsDNA –, n = 906) SLE cases were compared to healthy controls and to each other to identify SNPs associated specifically with these SLE subtypes. SNPs in the previously identified SLE susceptibility loci STAT4, IRF5, ITGAM, and the major histocompatibility complex were strongly associated with anti–dsDNA + SLE. Far fewer and weaker associations were observed for anti–dsDNA – SLE. For example, rs7574865 in STAT4 had an OR for anti–dsDNA + SLE of 1.77 (95% CI 1.57–1.99, p = 2.0E-20) compared to an OR for anti–dsDNA – SLE of 1.26 (95% CI 1.12–1.41, p = 2.4E-04), with p heterogeneity<0.0005. SNPs in the SLE susceptibility loci BANK1, KIAA1542, and UBE2L3 showed evidence of association with anti–dsDNA + SLE and were not associated with anti–dsDNA – SLE. In conclusion, we identified differential genetic associations with SLE based on anti–dsDNA autoantibody production. Many previously identified SLE susceptibility loci may confer disease risk through their role in autoantibody production and be more accurately described as autoantibody propensity loci. Lack of strong SNP associations may suggest that other types of genetic variation or non-genetic factors such as environmental exposures have a greater impact on susceptibility to anti–dsDNA – SLE.

          Author Summary

          Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can involve virtually any organ system. SLE patients produce antibodies that bind to their own cells and proteins (autoantibodies) which can cause irreversible organ damage. One particular SLE–related autoantibody directed at double-stranded DNA (anti–dsDNA) is associated with kidney involvement and more severe disease. Previous genome-wide association studies (GWAS) in SLE have studied SLE itself, not particular SLE manifestations. Therefore, we conducted this GWAS of anti–dsDNA autoantibody production to identify genetic associations with this clinically important autoantibody. We found that many previously identified SLE–associated genes are more strongly associated with anti–dsDNA autoantibody production than SLE itself, and they may be more accurately described as autoantibody propensity genes. No strong genetic associations were observed for SLE patients who do not produce anti–dsDNA autoantibodies, suggesting that other factors may have more influence in developing this type of SLE. Further investigation of these autoantibody propensity genes may lead to greater insight into the causes of autoantibody production and organ damage in SLE.

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          Most cited references13

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          Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus.

          M Hochberg (1997)
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            A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer.

            We conducted a genome-wide association study (GWAS) of breast cancer by genotyping 528,173 SNPs in 1,145 postmenopausal women of European ancestry with invasive breast cancer and 1,142 controls. We identified four SNPs in intron 2 of FGFR2 (which encodes a receptor tyrosine kinase and is amplified or overexpressed in some breast cancers) that were highly associated with breast cancer and confirmed this association in 1,776 affected individuals and 2,072 controls from three additional studies. Across the four studies, the association with all four SNPs was highly statistically significant (P(trend) for the most strongly associated SNP (rs1219648) = 1.1 x 10(-10); population attributable risk = 16%). Four SNPs at other loci most strongly associated with breast cancer in the initial GWAS were not associated in the replication studies. Our summary results from the GWAS are available online in a form that should speed the identification of additional risk loci.
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              STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus.

              Rheumatoid arthritis is a chronic inflammatory disease with a substantial genetic component. Susceptibility to disease has been linked with a region on chromosome 2q. We tested single-nucleotide polymorphisms (SNPs) in and around 13 candidate genes within the previously linked chromosome 2q region for association with rheumatoid arthritis. We then performed fine mapping of the STAT1-STAT4 region in a total of 1620 case patients with established rheumatoid arthritis and 2635 controls, all from North America. Implicated SNPs were further tested in an independent case-control series of 1529 patients with early rheumatoid arthritis and 881 controls, all from Sweden, and in a total of 1039 case patients and 1248 controls from three series of patients with systemic lupus erythematosus. A SNP haplotype in the third intron of STAT4 was associated with susceptibility to both rheumatoid arthritis and systemic lupus erythematosus. The minor alleles of the haplotype-defining SNPs were present in 27% of chromosomes of patients with established rheumatoid arthritis, as compared with 22% of those of controls (for the SNP rs7574865, P=2.81x10(-7); odds ratio for having the risk allele in chromosomes of patients vs. those of controls, 1.32). The association was replicated in Swedish patients with recent-onset rheumatoid arthritis (P=0.02) and matched controls. The haplotype marked by rs7574865 was strongly associated with lupus, being present on 31% of chromosomes of case patients and 22% of those of controls (P=1.87x10(-9); odds ratio for having the risk allele in chromosomes of patients vs. those of controls, 1.55). Homozygosity of the risk allele, as compared with absence of the allele, was associated with a more than doubled risk for lupus and a 60% increased risk for rheumatoid arthritis. A haplotype of STAT4 is associated with increased risk for both rheumatoid arthritis and systemic lupus erythematosus, suggesting a shared pathway for these illnesses. Copyright 2007 Massachusetts Medical Society.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                March 2011
                March 2011
                3 March 2011
                : 7
                : 3
                : e1001323
                Affiliations
                [1 ]Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America
                [2 ]ITGR Human Genetics, Genentech, South San Francisco, California, United States of America
                [3 ]Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, Manhasset, New York, United States of America
                [4 ]Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
                [5 ]Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden
                [6 ]Andalusian Center for Genomics and Oncological Research, Pfizer-University of Granada-Junta de Andalucía, Granada, Spain
                [7 ]Arthritis and Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
                [8 ]Department of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
                [9 ]US Department of Veterans Affairs Medical Center and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America
                [10 ]Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
                [11 ]Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
                [12 ]Allegheny-Singer Research Institute, Pittsburgh, Pennsylvania, United States of America
                [13 ]Department of Biostatistical Sciences, Wake Forest University Health Sciences, Wake Forest, North Carolina, United States of America
                Brigham and Women's Hospital, United States of America
                Author notes

                Conceived and designed the experiments: SAC LAC. Performed the experiments: SAC KET JN. Analyzed the data: SAC KET. Contributed reagents/materials/analysis tools: SAC KET RRG JN ATL WAO COJ MEAR BPT JBH PMG KLM MP FYD MIK SM PKG CDL TWB LAC. Wrote the paper: SAC LAC.

                ¶ For membership of The International Consortium on the Genetics of Systemic Lupus Erythematosus please see the Acknowledgments.

                Article
                10-PLGE-RA-NV-3614R3
                10.1371/journal.pgen.1001323
                3048371
                21408207
                99c4d637-f1c6-4b36-b029-4b6e4623c942
                This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
                History
                : 10 July 2010
                : 31 January 2011
                Page count
                Pages: 11
                Categories
                Research Article
                Genetics and Genomics/Complex Traits
                Immunology/Autoimmunity
                Rheumatology/Systemic Lupus Erythematosos

                Genetics
                Genetics

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