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Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus.
- Source :
-
Nature genetics [Nat Genet] 2011 Mar; Vol. 43 (3), pp. 253-8. Date of Electronic Publication: 2011 Feb 20. - Publication Year :
- 2011
-
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.
- Subjects :
- Base Sequence
DNA-Binding Proteins
Female
Haplotypes
Humans
Linkage Disequilibrium
Male
Molecular Sequence Data
Tumor Necrosis Factor alpha-Induced Protein 3
Intracellular Signaling Peptides and Proteins genetics
Lupus Erythematosus, Systemic genetics
Nuclear Proteins genetics
Polymorphism, Single Nucleotide
Subjects
Details
- Language :
- English
- ISSN :
- 1546-1718
- Volume :
- 43
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Nature genetics
- Publication Type :
- Academic Journal
- Accession number :
- 21336280
- Full Text :
- https://doi.org/10.1038/ng.766