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

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.

• Fecha de publicación: 2011
• Institución: Universidad del Rosario
• Repositorio: Repositorio EdocUR - U. Rosario
• Idioma: eng
• OAI Identifier: oai:repository.urosario.edu.co:10336/22638
• Acceso en línea: https://doi.org/10.1038/ng.766; https://repository.urosario.edu.co/handle/10336/22638
• Palabra clave: Immunoglobulin enhancer binding protein; Messenger rna; 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; Male; Molecular sequence data; Nuclear proteins; single nucleotide; systemic; Lupus erythematosus; Polymorphism
• License: Abierto (Texto Completo)