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

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-?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>A variant as the most likely functional polymorphism responsible for the association between TNFAIP3 and SLE.

SUBMITTER: Adrianto I 

PROVIDER: S-EPMC3103780 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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

Adrianto Indra I   Wen Feng F   Templeton Amanda A   Wiley Graham G   King Jarrod B JB   Lessard Christopher J CJ   Bates Jared S JS   Hu Yanqing Y   Kelly Jennifer A JA   Kaufman Kenneth M KM   Guthridge Joel M JM   Alarcón-Riquelme Marta E ME   Anaya Juan-Manuel JM   Bae Sang-Cheol SC   Bang So-Young SY   Boackle Susan A SA   Brown Elizabeth E EE   Petri Michelle A MA   Gallant Caroline C   Ramsey-Goldman Rosalind R   Reveille John D JD   Vila Luis M LM   Criswell Lindsey A LA   Edberg Jeffrey C JC   Freedman Barry I BI   Gregersen Peter K PK   Gilkeson Gary S GS   Jacob Chaim O CO   James Judith A JA   Kamen Diane L DL   Kimberly Robert P RP   Martin Javier J   Merrill Joan T JT   Niewold Timothy B TB   Park So-Yeon SY   Pons-Estel Bernardo A BA   Scofield R Hal RH   Stevens Anne M AM   Tsao Betty P BP   Vyse Timothy J TJ   Langefeld Carl D CD   Harley John B JB   Moser Kathy L KL   Webb Carol F CF   Humphrey Mary Beth MB   Montgomery Courtney Gray CG   Gaffney Patrick M PM  

Nature genetics 20110220 3

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  ...[more]