title: Meta-analysis of the TNFAIP3 region in psoriasis reveals a risk haplotype that is distinct from other autoimmune diseases.
abstract: Tumor necrosis factor alpha-inducible protein 3 (TNFAIP3) encodes a ubiquitin-modifying protein, A20, that is a critical regulator of inflammatory responses. TNFAIP3 polymorphisms are associated with the susceptibility to multiple autoimmune diseases (AIDs) including psoriasis, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis and celiac disease. In order to refine the TNFAIP3 association signal in psoriasis and identify candidate causal variants, we performed imputation and meta-analysis of the TNFAIP3 region in five European ancestry cohorts totaling 4704 psoriasis cases and 7805 controls. We identified 49 variants whose significance exceeded a corrected Bonferroni threshold, with the top variant being rs582757 (P = 6.07 × 10(-12), odds ratio (OR) = 1.23). Conditional analysis revealed a suggestive independent association at rs6918329 (P(cond) = 7.22 × 10(-5), OR = 1.15). Functional annotation of the top variants identified several with a strong evidence of regulatory potential and several within long noncoding RNAs. Analysis of TNFAIP3 haplotypes revealed that the psoriasis risk haplotype is distinct from other AIDs. Overall, our findings identify novel candidate causal variants of TNFAIP3 in psoriasis and highlight the complex genetic architecture of this locus in autoimmune susceptibility.
authors.affiliation: 1] Department of Dermatology, University of California San Francisco, San Francisco, CA, USA [2] Department of Medicine, Rosalind Russell Medical Research Center for Arthritis, University of California San Francisco, San Francisco, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Nititham
authors.affiliation: Department of Medicine, Rosalind Russell Medical Research Center for Arthritis, University of California San Francisco, San Francisco, CA, USA.
authors.forename: K E
authors.initials: KE
authors.lastname: Taylor
authors.affiliation: Department of Dermatology, University of California San Francisco, San Francisco, CA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Gupta
authors.affiliation: Department of Gastroenterology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Digestive Diseases, Shanghai, China.
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Dermatology, University of California San Francisco, San Francisco, CA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Ahn
authors.affiliation: 1] Department of Human Genetics, Genome Institute of Singapore, A*STAR, Singapore, Singapore [2] Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore [3] School of Life Sciences, Anhui Medical University, Hefei, China.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.affiliation: 1] Department of Dermatology, University of California San Francisco, San Francisco, CA, USA [2] Blood Systems Research Institute, San Francisco, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Seielstad
authors.affiliation: Division of Gastroenterology, University of California San Francisco, San Francisco, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Ma
authors.affiliation: Department of Cancer Genomics, Imperial College of London, London, UK.
authors.forename: A M
authors.initials: AM
authors.lastname: Bowcock
authors.affiliation: Department of Medicine, Rosalind Russell Medical Research Center for Arthritis, University of California San Francisco, San Francisco, CA, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Criswell
authors.affiliation: Unit of Dermatology and Venereology, Department of Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Stahle
authors.affiliation: Department of Dermatology, University of California San Francisco, San Francisco, CA, USA.
authors.forename: W
authors.identifier: 0000000178836439
authors.initials: W
authors.lastname: Liao
mesh_terms: D001327:Autoimmune Diseases / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D011565:Psoriasis / Q000235:genetics*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C426747:TNIP3 protein, human