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Sequencing of TNFAIP3 and association of variants with multiple autoimmune diseases

Abstract

The TNFAIP3 locus at 6q23, encoding A20, has been associated with multiple autoimmune diseases (AIDs). In this study, we sequence the coding portions of the gene to identify contributing causal polymorphisms that may explain some of the observed associations. A collection of 123 individuals from the Multiple Autoimmune Disease Genetics Consortium (MADGC) collection, each with multiple AIDs (mean=2.2 confirmed diagnoses), and 397 unrelated healthy controls were used for initial sequencing. A total of 32 polymorphisms were identified in the sequencing experiments, including 16 novel and 11 coding variants. Association testing in the entire MADGC collection (1,008 Caucasians with one or more AIDs and 770 unaffected family controls) revealed association of a novel intronic insertion–deletion polymorphism with rheumatoid arthritis (RA) (odds ratio (OR)=2.48, P=0.041). Genotyping of the most common coding polymorphism, rs2230926, in the MADGC collection and additional control individuals revealed a significant association with Sjögren's syndrome (OR=3.38, P=0.038), Crohn's disease (OR=2.25, P=0.041), psoriasis (OR=0.037, P=0.036) and RA (OR=1.9, P=0.025). Finally, haplotype and additional testing of polymorphisms revealed that cases were enriched for 5′ and 3′ untranslated region variants (one-sided P-value=0.04), but not specifically for common (>2% minor allele frequency), rare, exonic, intronic, non-synonymous or synonymous variants.

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Acknowledgements

We thank all the participants in the studies featured in this manuscript. Dr Jorge R Oksenberg provided control DNA samples and Stacy J Caillier performed genotyping of these samples for rs2230926. WL was supported by a grant from the Dermatology Foundation. We also thank Drs Peter Gregersen and Timothy Behrens for their important contributions to the MADGC study (supported by N01 AI95386). LAC was also supported by K24 AR02175 and a Kirkland Scholar Award.

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Correspondence to L A Criswell.

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Musone, S., Taylor, K., Nititham, J. et al. Sequencing of TNFAIP3 and association of variants with multiple autoimmune diseases. Genes Immun 12, 176–182 (2011). https://doi.org/10.1038/gene.2010.64

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