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Polymorphism at the TNF superfamily gene TNFSF4 confers susceptibility to systemic lupus erythematosus.

ABSTRACT: Systemic lupus erythematosus (SLE) is a multisystem complex autoimmune disease of uncertain etiology (OMIM 152700). Over recent years a genetic component to SLE susceptibility has been established. Recent successes with association studies in SLE have identified genes including IRF5 (refs. 4,5) and FCGR3B. Two tumor necrosis factor (TNF) superfamily members located within intervals showing genetic linkage with SLE are TNFSF4 (also known as OX40L; 1q25), which is expressed on activated antigen-presenting cells (APCs) and vascular endothelial cells, and also its unique receptor, TNFRSF4 (also known as OX40; 1p36), which is primarily expressed on activated CD4+ T cells. TNFSF4 produces a potent co-stimulatory signal for activated CD4+ T cells after engagement of TNFRSF4 (ref. 11). Using both a family-based and a case-control study design, we show that the upstream region of TNFSF4 contains a single risk haplotype for SLE, which is correlated with increased expression of both cell-surface TNFSF4 and the TNFSF4 transcript. We hypothesize that increased expression of TNFSF4 predisposes to SLE either by quantitatively augmenting T cell-APC interaction or by influencing the functional consequences of T cell activation via TNFRSF4.

SUBMITTER: Cunninghame Graham DS

PROVIDER: S-EPMC3705866 | biostudies-literature | 2008 Jan

REPOSITORIES: biostudies-literature

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Polymorphism at the TNF superfamily gene TNFSF4 confers susceptibility to systemic lupus erythematosus.

Cunninghame Graham Deborah S DS Graham Robert R RR Manku Harinder H Wong Andrew K AK Whittaker John C JC Gaffney Patrick M PM Moser Kathy L KL Rioux John D JD Altshuler David D Behrens Timothy W TW Vyse Timothy J TJ

Nature genetics 20071202 1

Systemic lupus erythematosus (SLE) is a multisystem complex autoimmune disease of uncertain etiology (OMIM 152700). Over recent years a genetic component to SLE susceptibility has been established. Recent successes with association studies in SLE have identified genes including IRF5 (refs. 4,5) and FCGR3B. Two tumor necrosis factor (TNF) superfamily members located within intervals showing genetic linkage with SLE are TNFSF4 (also known as OX40L; 1q25), which is expressed on activated antigen-pr ...[more]

PMID: 18059267

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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.

Project description:Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease which is characterized by dysregulation of various cytokines propagating the inflammatory processes that is responsible for tissue damage. Tumor necrosis factor alpha (TNF-α) is one of the most important immunoregulatory cytokines that has been implicated in the different autoimmune diseases including SLE. Two hundred and two patients with SLE and 318 controls were included in the study. The TNF-α gene promoter region (from - 250 to - 1000 base pairs) was analyzed by direct Sanger's DNA sequencing method to find promoter variants associated with South Indian SLE patients. We have analyzed six TNF-α genetic polymorphisms including, - 863C/A (rs1800630), - 857C/T (rs1799724), - 806C/T (rs4248158), - 646G/A (rs4248160), - 572A/C (rs4248161) and - 308G/A (rs1800629) in both SLE patients and controls. We did not find association of TNF-α gene promoter SNPs with SLE patients. However, the - 863A (rs1800630) allele showed association with lupus nephritis phenotype in patients with SLE (OR: 1.62, 95%CI 1.04-2.53, P = 0.034). We found serum TNF-α level was significantly elevated in SLE cases as compared to control and found no association with any of the polymorphisms. The haplotype analysis revealed a significant protective association between the wild TNF-α alleles at positions - 863C, - 857C, - 806C, - 646G, - 572A and - 308G (CCCGAG) haplotype with lupus nephritis phenotype (OR 0.53, 95% CI 0.35-0.82, P = 0.004). Additionally, the TNF-α - 863 C/A (rs1800630) polymorphism and HLA-DRB1*07 haplotype showed significant differences between SLE patients and controls (OR 4.79, 95% CI 1.73-13.29, P = 0.0009). In conclusion, TNF-α - 863A allele (rs1800630) polymorphism is associated with increased risk of nephritis in South Indian SLE patients. We also found an interaction between HLA-DRB1*07 allele with TNF-α - 863 C/A promoter polymorphism giving supportive evidence for the tight linkage disequilibrium between TNF-α promoter SNPs and MHC class II DRB1 alleles.

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Polymorphism at the TNF superfamily gene TNFSF4 confers susceptibility to systemic lupus erythematosus.

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Polymorphism at the TNF superfamily gene TNFSF4 confers susceptibility to systemic lupus erythematosus.

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