Association of TNFSF4 (OX40L) polymorphisms with susceptibility to systemic sclerosis.

OBJECTIVE: It is increasingly being appreciated that multiple autoimmune diseases share common susceptibility genes. The tumour necrosis factor ligand superfamily member 4 gene (TNFSF4, OX40L), which encodes for the T cell costimulatory molecule OX40 ligand, has been identified as a susceptibility gene for the development of systemic lupus erythematosus (SLE). Accordingly, the aim of the current study was to investigate the possible association of the TNFSF4 gene region with systemic sclerosis (SSc), an autoimmune disease that leads to the development of cutaneous and visceral fibrosis. METHODS: A total of 9 single nucleotide polymorphisms (SNPs) in the TNFSF4 gene region, previously associated with susceptibility to SLE, were tested for association with SSc in a collection of 1059 patients with SSc and 698 controls. RESULTS: Case-control comparisons revealed a significant association between susceptibility to SSc and the minor alleles at SNPs rs1234314 (OR 1.20, 95% CI 1.04 to 1.4, p(FDR)=0.019), rs2205960 (OR 1.24, 95% CI 1.10 to 1.50, p(FDR)=0.019) and rs844648 (OR 1.16, 95% CI 1.01 to 1.30, p(FDR)=0.032). The minor allele at rs844644 was protective (OR 0.84, 95% CI 0.70 to 0.97, p(FDR)=0.038). Analysis of subsets of patients with SSc demonstrated significant associations of the TNFSF4 SNPs with limited and diffuse SSc as well as specific SNPs that were associated with SSc-associated autoantibodies. Finally, the analyses suggest a potential interaction between two TNFSF4 SNPs, rs2205960 and rs844648, with regards to SSc susceptibility. CONCLUSIONS: Polymorphisms in the TNFSF4 gene region are associated with susceptibility to SSc and its clinical and autoantibody subsets. TNFSF4 may be another gene that confers risk to multiple autoimmune diseases.

Association of the C8orf13-BLK region with systemic sclerosis in North-American and European populations.

OBJECTIVE: Genetic studies in the systemic sclerosis (SSc), an autoimmune disease that clinically manifests with dermal and internal organ fibrosis and small vessel vasculopathy, have identified multiple susceptibility genes including HLA-class II, PTPN22, IRF5, and STAT4 which have also been associated with other autoimmune diseases, such as systemic lupus erythematosus (SLE). These data suggest that there are common autoimmune disease susceptibility genes. The current report sought to determine if polymorphisms in the C8orf13-BLK region (chromosome 8p23.1-B lymphoid tyrosine kinase), which is associated with SLE, are associated also with SSc. METHODS: Two variants in the C8orf13-BLK region (rs13277113 & rs2736340) were tested for association with 1050 SSc cases and 694 controls of North Americans of European descent and replicated in a second series 589 SSc cases and 722 controls from Spain. RESULTS: The "T" allele at rs2736340 variant was associated with SSc in both the U.S. and Spanish case-control series (P = 6.8 x 10(-5), OR 1.27, 95% CI 1.1-1.4). The "A" allele at rs13277113 variant was associated with SSc in the U.S. series only (P = 3.6 x 10(-4), OR 1.32, 95% CI 1.1-1.6) and was significant in the combined analyses of the two series (P = 2.0 x 10(-3); OR 1.20, 95% CI 1.1-1.3). Both variants demonstrated an association with the anti-centromere antibody (P = 2.2 x 10(-6) and P = 5.5 x 10(-4), respectively) and limited SSc (P = 3.3 x 10(-5) and P = 2.9 x 10(-3), respectively) in the combined analysis. Peripheral blood gene expression profiles suggest that B-cell receptor and NFkappaB signaling are dysregulated based on the risk haplotype of these variants. CONCLUSION: We identify and replicate the association of the C8orf13-BLK region as a novel susceptibility factor for SSc, placing it in the category of common autoimmune disease susceptibility genes.

Association of interleukin 23 receptor polymorphisms with anti-topoisomerase-I positivity and pulmonary hypertension in systemic sclerosis.

OBJECTIVE: IL23R has been identified as a susceptibility gene for development of multiple autoimmune diseases. We investigated the possible association of IL23R with systemic sclerosis (SSc), an autoimmune disease that leads to the development of cutaneous and visceral fibrosis. METHODS: We tested 9 single-nucleotide polymorphisms (SNP) in IL23R for association with SSc in a cohort of 1402 SSc cases and 1038 controls. IL23R SNP tested were previously identified as SNP showing associations with inflammatory bowel disease. RESULTS: Case-control comparisons revealed no statistically significant differences between patients and healthy controls with any of the IL23R polymorphisms. Analyses of subsets of SSc patients showed that rs11209026 (Arg381Gln variant) was associated with anti-topoisomerase I antibody (ATA)-positive SSc (p = 0.001)) and rs11465804 SNP was associated with diffuse and ATA-positive SSc (p = 0.0001, p = 0.0026, respectively). These associations remained significant after accounting for multiple comparisons using the false discovery rate method. Wild-type genotype at both rs11209026 and rs11465804 showed significant protection against the presence of pulmonary hypertension (PHT). (p = 3x10(-5), p = 1x10(-5), respectively). CONCLUSION: Polymorphisms in IL23R are associated with susceptibility to ATA-positive SSc and protective against development of PHT in patients with SSc.

Polymorphisms in TBX21 and STAT4 increase the risk of systemic sclerosis: evidence of possible gene-gene interaction and alterations in Th1/Th2 cytokines.

OBJECTIVE: Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs. Dysregulation of the immune system, including the Th1/Th2 cytokine balance, is central to the pathogenesis of SSc. This study was undertaken to investigate the hypothesis that single-nucleotide polymorphisms (SNPs) in TBX21 and STAT4, both of which are critical transcription factors that regulate the Th1/Th2 balance, are associated with SSc susceptibility. METHODS: We tested SNPs in TBX21 and STAT4 for association with SSc in 2 independent cohorts, the SSc Registry cohort (880 SSc cases and 507 controls) and the University of Texas SSc cohort (522 cases and 531 controls). Additional white control genotypes were obtained from public repositories. We also investigated for gene-gene interactions. Plasma cytokines and whole blood gene expression profiles were examined to determine functional effects of these SNPs. RESULTS: Multiple SNPs in TBX21 and STAT4 were found to be associated with SSc. In a combined analysis of 902 SSc patients and 4,745 controls, TT genotyping of the TBX21 rs11650354 variant revealed a recessive pattern for disease susceptibility (Pcorr=1.4x10(-15), odds ratio 3.37, 95% confidence interval 2.4-4.6). In an analysis of 1,039 SSc patients and 3,322 controls, the A allele of the STAT4 variant rs11889341 was associated with increased SSc susceptibility in a dominant pattern (Pcorr=2.4x10(-5), odds ratio 1.29, 95% confidence interval 1.2-1.5). Furthermore, we identified gene-gene interaction among the TBX21 and STAT4 variants, such that the STAT4 genotype increased the risk of SSc only in the TBX21 CC genotype group. SSc patients carrying the TBX21 CC genotype had higher interleukin-6 (IL-6) and tumor necrosis factor alpha levels, and those with the TT genotype had elevated IL-2, IL-5, IL-4, and IL-13 (Th2) levels, compared with controls. Whole blood expression profiles revealed dysregulation of type I interferon pathways in the CC group and T cell pathways in the TT group of the TBX21 SNP. CONCLUSION: The present results, from studies of 2 independent cohorts, indicate that SNPs in TBX21 and STAT4 contribute uniquely and interactively to SSc susceptibility, leading to altered cytokine balance and immune dysregulation.