Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus

• DOI: 10.1038/ng.766
• Publication Date: 2011-02-21T15:55:09Z
• Authors: Indra Adrianto; Feng Wen; Amanda Templeton; Graham Wiley; Jarrod B King; Christopher J Les...; Jared S Bates; Yanqing Hu; Jennifer A Kelly; Kenneth M Kaufman; Joel M Guthridge; Marta E Alarcón-R...; Juan-Manuel Anaya; Sang-Cheol Bae; So-Young Bang; Susan A Boackle; Elizabeth E Brown; Michelle A Petri; Caroline Gallant; Rosalind Ramsey-G...; John D Reveille; Luis M Vila; Lindsey A Criswell; Jeffrey C Edberg; Barry I Freedman; Peter K Gregersen; Gary S Gilkeson; Chaim O Jacob; Judith A James; Diane L Kamen; Robert P Kimberly; Javier Martin; Joan T Merrill; Timothy B Niewold; So-Yeon Park; Bernardo A Pons-E...; R Hal Scofield; Anne M Stevens; Betty P Tsao; Timothy J Vyse; Carl D Langefeld; John B Harley; Kathy L Moser; Carol F Webb; Mary Beth Humphrey; Courtney Gray Mon...; Patrick M Gaffney
• Keywords: single nucleotide; Male; 0301 basic medicine; Unclassified drug; Messenger rna; Hispanic; Review; Gene locus; Linkage Disequilibrium; Ethnicity; Haplotype; Lupus Erythematosus, Systemic; Priority journal; 0303 health sciences; Intracellular signaling peptides and proteins; Promoter region; Intracellular Signaling Peptides and Proteins; Nuclear Proteins; 3. Good health; DNA-Binding Proteins; Female; Human; Molecular Sequence Data; 610; Chromosome analysis; Polymorphism, Single Nucleotide; 03 medical and health sciences; Systemic lupus erythematosus; Nuclear proteins; Tumor necrosis factor alpha inducible protein 3; Molecular sequence data; 616; Genetic susceptibility; Linkage disequilibrium; Humans; African american; Polymorphism; Gene mapping; Tumor Necrosis Factor alpha-Induced Protein 3; Genetic risk; Lupus erythematosus; Asian; Gene deletion; Base Sequence; Genome analysis; systemic; Chromosome 6; Base sequence; Single nucleotide polymorphism; Immunoglobulin enhancer binding protein; Gene identification; Haplotypes; Protein subunit; Genetic association; Protein expression; Genetic variability; Transcription factor; Controlled study; Nucleotide sequence

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.