The aim of this study was to determine, through a genome-wide association study (GWAS), the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc). We... Show moreThe aim of this study was to determine, through a genome-wide association study (GWAS), the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc). We considered limited (IcSSc) and diffuse (dcSSc) cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromere (ACA), and anti-topoisomerase I (ATA). Four GWAS cohorts, comprising 2,296 SSc patients and 5,171 healthy controls, were meta-analyzed looking for associations in the selected subgroups. Eighteen polymorphisms were further tested in nine independent cohorts comprising an additional 3,175 SSc patients and 4,971 controls. Conditional analysis for associated SNPs in the HLA region was performed to explore their independent association in antibody subgroups. Overall analysis showed that non-HLA polymorphism rs11642873 in IRF8 gene to be associated at GWAS level with lcSSc (P = 2.32x10(-12), OR = 0.75). Also, rs12540874 in GRB10 gene (P = 1.27 x 10(-6), OR = 1.15) and rs11047102 in SOX5 gene (P = 1.39x10(-7), OR = 1.36) showed a suggestive association with lcSSc and ACA subgroups respectively. In the HLA region, we observed highly associated allelic combinations in the HLA-DQB1 locus with ACA (P = 1.79x10(-61), OR = 2.48), in the HLA-DPA1/B1 loci with ATA (P = 4.57x10(-76), OR = 8.84), and in NOTCH4 with ACA P = 8.84x10(-21), OR = 0.55) and ATA (P = 1.14x10(-8), OR = 0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and autoantibody subgroups. Within the HLA region, HLA-DQB1, HLA-DPA1/B1, and NOTCH4 associations with SSc are likely confined to specific auto-antibodies. These data emphasize the differential genetic components of subphenotypes of SSc. Show less
Objectives The aim of this study was to confirm the influence of TNFSF4 polymorphisms on systemic sclerosis (SSc) susceptibility and phenotypic features. Methods A total of 8 European populations... Show moreObjectives The aim of this study was to confirm the influence of TNFSF4 polymorphisms on systemic sclerosis (SSc) susceptibility and phenotypic features. Methods A total of 8 European populations of Caucasian ancestry were included, comprising 3014 patients with SSc and 3125 healthy controls. Four genetic variants of TNFSF4 gene promoter (rs1234314, rs844644, rs844648 and rs12039904) were selected as genetic markers. Results A pooled analysis revealed the association of rs1234314 and rs12039904 polymorphisms with SSc (OR 1.15, 95% CI 1.02 to 1.31; OR 1.18, 95% CI 1.08 to 1.29, respectively). Significant association of the four tested variants with patients with limited cutaneous SSc (lcSSc) was revealed (rs1234314 OR 1.22, 95% CI 1.07 to 1.38; rs844644 OR 0.91, 95% CI 0.83 to 0.99; rs844648 OR 1.10, 95% CI 1.01 to 1.20 and rs12039904 OR 1.20, 95% CI 1.09 to 1.33). Association of rs1234314, rs844648 and rs12039904 minor alleles with patients positive for anti-centromere antibodies (ACA) remained significant (OR 1.23, 95% CI 1.10 to 1.37; OR 1.12, 95% CI 1.01 to 1.25; OR 1.22, 95% CI 1.07 to 1.38, respectively). Haplotype analysis confirmed a protective haplotype associated with SSc, lcSSc and ACA positive subgroups (OR 0.88, 95% CI 0.82 to 0.96; OR 0.88, 95% CI 0.80 to 0.96; OR 0.86, 95% CI 0.77 to 0.97, respectively) and revealed a new risk haplotype associated with the same groups of patients (OR 1.14, 95% CI 1.03 to 1.26; OR 1.20, 95% CI 1.08 to 1.35; OR 1.23, 95% CI 1.07 to 1.42, respectively). Conclusions The data confirm the influence of TNFSF4 polymorphisms in SSc genetic susceptibility, especially in subsets of patients positive for lcSSc and ACA. Show less
Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs that leads to profound disability and premature death. To identify new SSc susceptibility... Show moreSystemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs that leads to profound disability and premature death. To identify new SSc susceptibility loci, we conducted the first genome-wide association study in a population of European ancestry including a total of 2,296 individuals with SSc and 5,171 controls. Analysis of 279,621 autosomal SNPs followed by replication testing in an independent case-control set of European ancestry (2,753 individuals with SSc (cases) and 4,569 controls) identified a new susceptibility locus for systemic sclerosis at CD247 (1q22-23, rs2056626, P = 2.09 x 10(-7) in the discovery samples, P = 3.39 x 10(-9) in the combined analysis). Additionally, we confirm and firmly establish the role of the MHC (P = 2.31 x 10(-18)), IRF5 (P = 1.86 x 10(-13)) and STAT4 (P = 3.37 x 10(-9)) gene regions as SSc genetic risk factors. Show less
OBJECTIVES: /st> The TRAF1-C5 locus has recently been identified as a genetic risk factor for rheumatoid arthritis (RA). Since genetic risk factors tend to overlap with several autoimmune... Show moreOBJECTIVES: /st> The TRAF1-C5 locus has recently been identified as a genetic risk factor for rheumatoid arthritis (RA). Since genetic risk factors tend to overlap with several autoimmune diseases, a study was undertaken to investigate whether this region is associated with type 1 diabetes (TID), celiac disease (CD), systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). METHODS: /st> The most consistently associated SNP, rs10818488, was genotyped in a total of 735 patients with T1D, 1049 with CD, 367 with SSc, 746 with SLE and 3494 ethnically- and geographically-matched healthy individuals. The replication sample set consisted of 99 patients with T1D, 272 with SLE and 482 healthy individuals from Crete. RESULTS: /st> A significant association was detected between the rs10818488 A allele and T1D (OR 1.14, p=0.027) and SLE (OR 1.16, p=0.016), which was replicated in 99 patients with T1D, 272 with SLE and 482 controls from Crete (OR 1.64, p=0.002; OR 1.43, p=0.002, respectively). Joint analysis of all patients with T1D (N=961) and all patients with SLE (N=1018) compared with 3976 healthy individuals yielded an allelic common OR of 1.19 (p=0.002) and 1.22 (p=2.6x10(-4)), respectively. However, combining our dataset with the T1D sample set from the WTCCC resulted in a non-significant association (OR 1.06, p=0.087). In contrast, previously unpublished results from the SLEGEN study showed a significant association of the same allele (OR 1.19, p=0.0038) with an overall effect of 1.22 (p=1.02x10(-6)) in a total of 1577 patients with SLE and 4215 healthy individuals. CONCLUSION: /st> A significant association was found for the TRAF1-C5 locus in SLE, implying that this region lies in a pathway relevant to multiple autoimmune diseases. Show less
Objectives The TRAF1-C5 locus has recently been identified as a genetic risk factor for rheumatoid arthritis (RA). Since genetic risk factors tend to overlap with several autoimmune diseases, a... Show moreObjectives The TRAF1-C5 locus has recently been identified as a genetic risk factor for rheumatoid arthritis (RA). Since genetic risk factors tend to overlap with several autoimmune diseases, a study was undertaken to investigate whether this region is associated with 1 diabetes (TID), celiac disease (CD), systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). Methods The most consistently associated SNP, rs10818488, was genotyped in a total of 735 patients with T1D, 1049 with CD, 367 with SSc, 746 with SLE and 3494 ethnically- and geographically-matched healthy individuals. The replication sample set consisted of 99 patients with T1D, 272 with SLE and 482 healthy individuals from Crete. Results A significant association was detected between the rs10818488 A allele and T1D (OR 1.14, p=0.027) and SLE (OR 1.16, p=0.016), which was replicated in 99 patients with T1D, 272 with SLE and 482 controls from Crete (OR 1.64, p=0.002; OR 1.43, p=0.002, respectively). Joint analysis of all patients with T1D (N=961) and all patients with SLE (N=1018) compared with 3976 healthy individuals yielded an allelic common OR of 1.19 (p=0.002) and 1.22 (p=2.6x10(-4)), respectively. However, combining our dataset with the T1D sample set from the WTCCC resulted in a nonsignificant association (OR 1.06, p=0.087). In contrast, previously unpublished results from the SLEGEN study showed a significant association of the same allele (OR 1.19, p=0.0038) with an overall effect of 1.22 (p=1.02x10(-6)) in a total of 1577 patients with SLE and 4215 healthy individuals. Conclusion A significant association was found for the TRAF1-C5 locus in SLE, implying that this region lies in a pathway relevant to multiple autoimmune diseases. Show less
