Portal de Periódicos da CAPES

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

2011; Nature Portfolio; Volume: 43; Issue: 3 Linguagem: Inglês

10.1038/ng.766

1546-1718

Indra Adrianto, Feng Wen, Amanda Templeton, Graham B. Wiley, Jarrod B. King, Christopher J. Lessard, Jared S Bates, Yanqing Hu, Jennifer A. Kelly, Kenneth M. Kaufman, Joel M. Guthridge, Marta E. Alarcón‐Riquelme, Juan‐Manuel Anaya, Sang‐Cheol Bae, So‐Young Bang, Susan A. Boackle, Elizabeth E. Brown, Michelle Petri, Caroline J. Gallant, Rosalind Ramsey‐Goldman, John D. Reveille, Luis M. Vilá, 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 Martı́n, Joan T. Merrill, Timothy B. Niewold, So Yeon Park, Bernardo A. Pons‐Estel, 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 G. Montgomery, Patrick M. Gaffney,

Immune Response and Inflammation

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.