1. Sequencing of TNFAIP3 and association of variants with multiple autoimmune diseases
- Author
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Lindsey A. Criswell, Pui-Yan Kwok, Ernest T. Lam, Catherine Chu, Stacy L. Musone, Wilson Liao, Joanne Nititham, Kimberly E. Taylor, Annie Poon, and Averil Ma
- Subjects
Genotype ,Immunology ,Locus (genetics) ,Biology ,Polymorphism, Single Nucleotide ,Article ,Autoimmune Diseases ,Gene Frequency ,Genetics ,Humans ,Genetic Predisposition to Disease ,Allele ,Allele frequency ,Genotyping ,Alleles ,Tumor Necrosis Factor alpha-Induced Protein 3 ,Genetics (clinical) ,Base Sequence ,Haplotype ,Intracellular Signaling Peptides and Proteins ,Nuclear Proteins ,Odds ratio ,DNA-Binding Proteins ,Minor allele frequency - Abstract
The TNFAIP3 locus at 6q23, encoding A20, has been associated with multiple autoimmune diseases (AIDs). Here, we sequence the coding portions of the gene in order 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. Thirty-two 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 (OR = 2.48, p = 0.041). Genotyping of the most common coding polymorphism, rs2230926, in the MADGC collection and additional control individuals revealed 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 rheumatoid arthritis (OR = 1.9, p = 0.025). Lastly, haplotype and additional testing of polymorphisms revealed that cases were enriched for 5’ and 3’ untranslated region (UTR) variants (one-sided p-value=0.04), but not specifically for common (>2% MAF), rare, exonic, intronic, non-synonymous, or synonymous variants.
- Published
- 2011
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