title: Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus.
abstract: Systemic lupus erythematosus (SLE, MIM152700) is an autoimmune disease characterized by self-reactive antibodies resulting in systemic inflammation and organ failure. TNFAIP3, encoding the ubiquitin-modifying enzyme A20, is an established susceptibility locus for SLE. By fine mapping and genomic re-sequencing in ethnically diverse populations, we fully characterized the TNFAIP3 risk haplotype and identified a TT>A polymorphic dinucleotide (deletion T followed by a T to A transversion) associated with SLE in subjects of European (P = 1.58 × 10(-8), odds ratio = 1.70) and Korean (P = 8.33 × 10(-10), odds ratio = 2.54) ancestry. This variant, located in a region of high conservation and regulatory potential, bound a nuclear protein complex composed of NF-κB subunits with reduced avidity. Further, compared with the non-risk haplotype, the haplotype carrying this variant resulted in reduced TNFAIP3 mRNA and A20 protein expression. These results establish this TT>A variant as the most likely functional polymorphism responsible for the association between TNFAIP3 and SLE.
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
authors.forename: Indra
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authors.lastname: Jacob
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authors.lastname: Niewold
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authors.lastname: Park
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authors.lastname: Pons-Estel
authors.forename: R Hal
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authors.lastname: Scofield
authors.forename: Anne M
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authors.lastname: Stevens
authors.forename: Betty P
authors.initials: BP
authors.lastname: Tsao
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authors.lastname: Vyse
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
authors.forename: Kathy L
authors.initials: KL
authors.lastname: Moser
authors.forename: Carol F
authors.initials: CF
authors.lastname: Webb
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Humphrey
authors.forename: Courtney Gray
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authors.lastname: Montgomery
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authors.lastname: Gaffney
mesh_terms: D001483:Base Sequence; D004268:DNA-Binding Proteins; D005260:Female; D006239:Haplotypes; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D015810:Linkage Disequilibrium; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3