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

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Adrianto I.
Wen F.
Templeton A.
Wiley G.
King J.B.
Lessard C.J.
Bates J.S.
Hu Y.
Kelly J.A.
Kaufman K.M.

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2011

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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 and gt;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-?B 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 and gt;A variant as the most likely functional polymorphism responsible for the association between TNFAIP3 and SLE. © 2011 Nature America, Inc. All rights reserved.
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Immunoglobulin enhancer binding protein , single nucleotide , Messenger rna , systemic , Protein subunit , Transcription factor , Tumor necrosis factor alpha inducible protein 3 , Unclassified drug , African american , Asian , Chromosome 6 , Chromosome analysis , Controlled study , Ethnicity , Gene deletion , Gene identification , Gene locus , Gene mapping , Genetic association , Genetic risk , Genetic susceptibility , Genetic variability , Genome analysis , Haplotype , Hispanic , Human , Nucleotide sequence , Priority journal , Promoter region , Protein expression , Review , Single nucleotide polymorphism , Systemic lupus erythematosus , Base sequence , Female , Haplotypes , Humans , Intracellular signaling peptides and proteins , Linkage disequilibrium , Lupus erythematosus , Male , Molecular sequence data , Nuclear proteins , Polymorphism
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