Sequencing of TNFAIP3 and association of variants with multiple autoimmune diseases

• Published in: Genes and immunity Vol. 12; no. 3; pp. 176 - 182
• Main Authors: Musone, S L, Taylor, K E, Nititham, J, Chu, C, Poon, A, Liao, W, Lam, E T, Ma, A, Kwok, P-Y, Criswell, L A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-04-2011; Nature Publishing Group
• Subjects: 3' Untranslated regions; 631/208/205; 631/208/2489/144; 631/208/457/649; 692/699/249/1313; Alleles; Autoimmune diseases; Autoimmune Diseases - genetics; Base Sequence; Biomedical and Life Sciences; Biomedicine; Cancer Research; Chromosome 6; Consortia; Crohn's disease; Crohns disease; Diagnosis; DNA sequencing; DNA-Binding Proteins; Gene deletion; Gene Expression; Gene Frequency; Gene loci; Genetic aspects; Genetic Predisposition to Disease - genetics; Genetics; Genotype; Genotyping; Haplotypes; Human Genetics; Humans; Immunology; Inflammatory bowel disease; Insertion; Intracellular Signaling Peptides and Proteins - genetics; Nuclear Proteins - genetics; Nucleotide sequencing; original-article; Polymorphism; Polymorphism, Single Nucleotide - genetics; Psoriasis; Rheumatoid arthritis; Risk factors; Single nucleotide polymorphisms; Sjogren's syndrome; Tumor Necrosis Factor alpha-Induced Protein 3; United States; United States > US; San Francisco California; California; TNFAIP3; autoimmunity; resequencing; a20; genetic association study
• ISSN: 1466-4879; 1476-5470
• DOI: 10.1038/gene.2010.64

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.