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

• Published in: Nature genetics Vol. 43; no. 3; pp. 253 - 258
• Main Authors: Adrianto, Indra, Wen, Feng, Templeton, Amanda, Wiley, Graham, King, Jarrod B, Lessard, Christopher J, Bates, Jared S, Hu, Yanqing, Kelly, Jennifer A, Kaufman, Kenneth M, Guthridge, Joel M, Alarcón-Riquelme, Marta E, Anaya, Juan-Manuel, Bae, Sang-Cheol, Bang, So-Young, Boackle, Susan A, Brown, Elizabeth E, Petri, Michelle A, Gallant, Caroline, Ramsey-Goldman, Rosalind, Reveille, John D, Vila, Luis M, Criswell, Lindsey A, Edberg, Jeffrey C, Freedman, Barry I, Gregersen, Peter K, Gilkeson, Gary S, Jacob, Chaim O, James, Judith A, Kamen, Diane L, Kimberly, Robert P, Martin, Javier, Merrill, Joan T, Niewold, Timothy B, Park, So-Yeon, Pons-Estel, Bernardo A, Scofield, R Hal, Stevens, Anne M, Tsao, Betty P, Vyse, Timothy J, Langefeld, Carl D, Harley, John B, Moser, Kathy L, Webb, Carol F, Humphrey, Mary Beth, Montgomery, Courtney Gray, Gaffney, Patrick M
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.03.2011; Nature Publishing Group
• Subjects: 631/208/205; 631/208/2489/144; 692/699/249/1313/1613; Agriculture; Alliances; Animal Genetics and Genomics; Arthritis; Autoimmune diseases; Base Sequence; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Chromosomes; Disease susceptibility; DNA-Binding Proteins; Female; Fundamental and applied biological sciences. Psychology; Gene Function; Genetic aspects; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Haplotypes; Health aspects; Health sciences; Human Genetics; Humans; Intracellular Signaling Peptides and Proteins - genetics; letter; Linkage Disequilibrium; Lupus; Lupus Erythematosus, Systemic - genetics; Male; Medical sciences; MEDICIN; MEDICINE; Molecular Sequence Data; Nuclear Proteins - genetics; Polymorphism, Single Nucleotide; Quality control; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Science; Systemic lupus erythematosus; Tumor necrosis factor; Tumor Necrosis Factor alpha-Induced Protein 3; United Kingdom; Variant; Immunopathology; Connective tissue disease; Skin disease; Association; Systemic lupus erythematosus; Systemic disease; Autoimmune disease
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.766

Patrick Gaffney and colleagues perform a fine-mapping study of the TNFAIP3 region in systemic lupus erythematosus using individuals from diverse ancestral populations. They identify a putative causal variant in a region of high conservation and regulatory potential that is associated with reduced TNFAIP3 expression. 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.