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Meta-analysis and imputation identifies a 109 kb risk haplotype spanning TNFAIP3 associated with lupus nephritis and hematologic manifestations

Genes & Immunity volume 10, pages 470–477 (2009)Cite this article

Abstract

TNFAIP3 encodes the ubiquitin-modifying enzyme, A20, a key regulator of inflammatory signaling pathways. We previously reported association between TNFAIP3 variants and systemic lupus erythematosus (SLE). To further localize the risk variant(s), we performed a meta-analysis using genetic data available from two Caucasian case–control datasets (1453 total cases, 3381 total control subjects) and 713 SLE trio families. The best result was found at rs5029939 (P=1.67 × 10−14, odds ratio=2.09, 95% confidence interval 1.68–2.60). We then imputed single nucleotide polymorphisms (SNPs) from the CEU Phase II HapMap using genotypes from 431 SLE cases and 2155 control subjects. Imputation identified 11 SNPs in addition to three observed SNPs, which together, defined a 109 kb SLE risk segment surrounding TNFAIP3. When evaluating whether the rs5029939 risk allele was associated with SLE clinical manifestations, we observed that heterozygous carriers of the TNFAIP3 risk allele at rs5029939 have a twofold increased risk of developing renal or hematologic manifestations compared to homozygous non-risk subjects. In summary, our study strengthens the genetic evidence that variants in the region of TNFAIP3 influence risk for SLE, particularly in patients with renal and hematologic manifestations, and narrows the risk effect to a 109 kb DNA segment that spans the TNFAIP3 gene.

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Acknowledgements

We thank Joshua Ojwang, Joshua Cavett, Billy Herring and Adam Adler for their technical assistance. We thank all of the patients and family members who participated in this study, as well as the many referring physicians. Portions of the samples used in this study were obtained from the Lupus Family Registry and Repository (AR62277) (see http://lupus.omrf.org). This study makes use of data generated by the Wellcome Trust Case–Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113 (Wellcome Trust Case Control Consortium5). Control subjects from the National Institute of Mental Health Schizophrenia Genetics Initiative (NIMH-GI), data and biomaterials are being collected by the ‘Molecular Genetics of Schizophrenia II’ (MGS-2) collaboration. The investigators and coinvestigators are: ENH/Northwestern University, Evanston, IL, MH059571, Pablo V Gejman, MD (Collaboration Coordinator; PI), Alan R Sanders, MD; Emory University School of Medicine, Atlanta, GA, MH59587, Farooq Amin, MD (PI); Louisiana State University Health Sciences Center; New Orleans, Louisiana, MH067257, Nancy Buccola APRN, BC, MSN (PI); University of California-Irvine, Irvine, CA, MH60870, William Byerley, MD (PI); Washington University, St Louis, MO, U01, MH060879, C Robert Cloninger, MD (PI); University of Iowa, Iowa, IA, MH59566, Raymond Crowe, MD (PI), Donald Black, MD; University of Colorado, Denver, CO, MH059565, Robert Freedman, MD (PI); University of Pennsylvania, Philadelphia, PA, MH061675, Douglas Levinson MD (PI); University of Queensland, Queensland, Australia, MH059588, Bryan Mowry, MD (PI); Mt. Sinai School of Medicine, New York, NY, MH59586, Jeremy Silverman, PhD (PI). The samples were collected by V L Nimgaonkar's group at the University of Pittsburgh, as part of a multi-institutional collaborative research project with J Smoller, MD DSc and P Sklar, MD PhD (Massachusetts General Hospital; grant MH 63420). This work was supported through grants from the United States National Institutes of Health (AI063274 (PMG), AR052125 (PMG), AR043247 (KLM), AI024717 (JBH), AR062277 (JBH), AR042460 (JBH), AR049084 (JBH)), the Mary Kirkland Scholarship (JBH), the Alliance for Lupus Research (JBH), the US Department of Veterans Affairs (JBH), Lupus Foundation of Minnesota (PMG, KLM), National Arthritis Foundation (KLM) and Arthritis Foundation, Oklahoma Chapter (PMG).

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Authors and Affiliations

  1. Oklahoma Medical Research Foundation, Arthritis and Immunology Research Program, Oklahoma City, OK, USA

    J S Bates, C J Lessard, J M Leon, T Nguyen, L J Battiest, J Rodgers, K M Kaufman, J A Kelly, J B Harley, C Gray-McGuire, K L Moser & P M Gaffney

  2. Department of Pathology, The University of Oklahoma Heath Sciences Center, Oklahoma City, OK, USA

    C J Lessard, K M Kaufman & M B Humphrey

  3. Oklahoma City VA Medical Center, Oklahoma City, OK, USA

    K M Kaufman

  4. Oklahoma Medical Research Foundation, Clinical Immunology Research Program, Oklahoma City, OK, USA

    J A James

  5. Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA

    G S Gilkeson

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  1. J S Bates
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  2. C J Lessard
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Correspondence to P M Gaffney.

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Supplementary Information accompanies the paper on Genes and Immunity website (http://www.nature.com/gene)

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Bates, J., Lessard, C., Leon, J. et al. Meta-analysis and imputation identifies a 109 kb risk haplotype spanning TNFAIP3 associated with lupus nephritis and hematologic manifestations. Genes Immun 10, 470–477 (2009). https://doi.org/10.1038/gene.2009.31

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