Dataset Information

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]

PMID: 21336280

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Project description:ObjectiveAlthough the number of convincingly established genetic associations with systemic lupus erythematosus (SLE) has increased sharply over the last few years, refinement of these associations is required, and their potential roles in gene-gene interactions need to be further investigated. Recent genome-wide association studies (GWAS) in SLE have produced renewed interest in B cell/T cell responses and the NF-κB signaling pathway. The aim of this study was to search for possible gene-gene interactions based on identified single-nucleotide polymorphisms (SNPs), in using an approach based on the role of signaling pathways.MethodsThe SNPs in BLK, TNFSF4, TRAF1, TNFAIP3, and REL were replicated in order to evaluate genetic associations with SLE. TaqMan genotyping was conducted in 804 Chinese patients with SLE and 722 matched control subjects. A multiple logistic regression model was used to estimate the multiplicative interaction effect of the SNPs, and additive interactions were analyzed by 2×2 factorial designs. Data from a previously published GWAS conducted by the International Consortium on the Genetics of Systemic Lupus Erythematosus were derived for comparison and validation.ResultsSingle-marker analysis validated the association of BLK rs2736340 (P=4.25×10(-6)) as well as TNFSF4 rs2205960 (P=2.82×10(-5)) and TNFAIP3 rs5029939 (P=1.92×10(-3)) with SLE susceptibility in Chinese. Multiplicative interaction analysis indicated that BLK had an interactive effect with TNFSF4 in Chinese patients with SLE (P=6.57×10(-4)). Additive interaction analysis revealed interactions between TRAF1 and TNFAIP3 in both Chinese (P=2.18×10(-3)) and Caucasians (P=2.86×10(-4)). In addition, multiple tendencies toward interactions were observed, and an additive effect was observed as the number of risk genotypes increased.ConclusionThe results of this study provide evidence of the possible gene-gene interactions of BLK, TNFSF4, TRAF1, TNFAIP3, and REL in SLE, which may represent a synergic effect of T cells and B cells through the NF-κB pathway in determining immunologic aberration.

Dataset Information

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

Publications

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

Similar Datasets

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