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Adrianto I Wen F Templeton A Wiley G King JB Lessard CJ Bates JS Hu Y Kelly JA Kaufman KM Guthridge JM Alarcón-Riquelme ME;BIOLUPUS GENLES Networks Anaya JM Bae SC Bang SY Boackle SA Brown EE Petri MA Gallant C Ramsey-Goldman R Reveille JD Vila LM Criswell LA Edberg JC Freedman BI Gregersen PK Gilkeson GS Jacob CO James JA Kamen DL Kimberly RP Martin J Merrill JT Niewold TB Park SY Pons-Estel BA Scofield RH Stevens AM Tsao BP Vyse TJ Langefeld CD Harley JB Moser KL Webb CF Humphrey MB 《Nature genetics》2011,43(3):253-258
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. 相似文献
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