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

Indra Adrianto, Feng Wen, Amanda Templeton, Graham 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 A. Petri, Caroline Gallant, Rosalind Ramsey-GoldmanJohn 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-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 Gray Montgomery, Patrick M. Gaffney

Research output: Contribution to journalReview articlepeer-review

226 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)253-258
Number of pages6
JournalNature Genetics
Issue number3
StatePublished - Mar 2011

All Science Journal Classification (ASJC) codes

  • Genetics


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