Abstract:
: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.
journal_name
Nat Genetjournal_title
Nature geneticsauthors
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 and GENLES Networks.,Anaya JM,Bae SC,Bang SY,Boackle SA,Brown EE,Petri MA,Gallant Cdoi
10.1038/ng.766subject
Has Abstractpub_date
2011-03-01 00:00:00pages
253-8issue
3eissn
1061-4036issn
1546-1718pii
ng.766journal_volume
43pub_type
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