1. ¹Oklahoma Medical Research Foundation, Arthritis and Immunology Research Program, Oklahoma City, OK, USA
2. ²Department of Pathology, The University of Oklahoma Heath Sciences Center, Oklahoma City, OK, USA
3. ³Oklahoma City VA Medical Center, Oklahoma City, OK, USA
4. ⁴Oklahoma Medical Research Foundation, Clinical Immunology Research Program, Oklahoma City, OK, USA
5. ⁵Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA

Correspondence: Dr PM Gaffney, Oklahoma Medical Research Foundation, Arthritis and Immunology Research Program, 825 NE 13th Street, MS No. 57, Oklahoma City, OK 73104, USA. E-mail: gaffneyp@lupus.omrf.org

Received 22 December 2008; Revised 2 March 2009; Accepted 2 March 2009; Published online 23 April 2009.

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.