Abstract
IntroductionSystemic sclerosis (SSc) and primary biliary cirrhosis (PBC) are rare polygenic autoimmune diseases (AIDs) characterized by fibroblast dysfunction. Furthermore, both diseases share some genetic bases with other AIDs, as evidenced by autoimmune gene pleiotropism. The present study was undertaken to investigate whether single-nucleotide polymorphisms (SNPs) identified by a large genome-wide association study (GWAS) in PBC might contribute to SSc susceptibility.MethodsSixteen PBC susceptibility SNPs were genotyped in a total of 1,616 patients with SSc and 3,621 healthy controls from two European populations (France and Italy).ResultsWe observed an association between PLCL2 rs1372072 (odds ratio (OR) = 1.22, 95% confidence interval (CI) 1.12 to 1.33, Padj = 7.22 × 10−5), nuclear factor-kappa-B (NF-κB) rs7665090 (OR = 1.15, 95% CI 1.06 to 1.25, Padj = 0.01), and IRF8 rs11117432 (OR = 0.75, 95% CI 0.67 to 0.86, Padj = 2.49 × 10−4) with SSc susceptibility. Furthermore, phenotype stratification showed an association between rs1372072 and rs11117432 with the limited cutaneous subgroup (lcSSc) (Padj = 4.45 × 10−4 and Padj = 0.001), whereas rs7665090 was associated with the diffuse cutaneous subtype (dcSSc) (Padj = 0.003). Genotype-mRNA expression correlation analysis revealed that the IRF8 protective allele was associated with increased interferon-gamma (IFN-γ) expression (P = 0.03) in patients with SSc but decreased type I IFN (IFIT1) expression in patients and controls (P = 0.02). In addition, we found an epistatic interaction between NF-κB and IRF8 (OR = 0.56, 95% CI 0.00 to 0.74, P = 4 × 10−4) which in turn revealed that the IRF8 protective effect is dependent on the presence of the NF-κB susceptibility allele.ConclusionsAn analysis of pleiotropic genes identified two new susceptibility genes for SSc (NF-κB and PLCL2) and confirmed the IRF8 locus. Furthermore, the IRF8 variant influenced the IFN signature, and we found an interaction between IRF8 and NF-κB gene variants that might play a role in SSc susceptibility.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0572-y) contains supplementary material, which is available to authorized users.
Highlights
Systemic sclerosis (SSc) and primary biliary cirrhosis (PBC) are rare polygenic autoimmune diseases (AIDs) characterized by fibroblast dysfunction
Among the single-nucleotide polymorphisms (SNPs) of interest, minor allele frequencies (MAFs) range from 11% to 44%; we provide a power calculation for these two MAFs
We first evaluated the French sample and observed six loci for which a nominal P value was reached: PLCL2 rs1372072 odds ratios (ORs) = 1.22, 95% confidence interval (CI) 1.10 to 1.36, P = 1.97 × 10−4; TIMMDC1 rs2293370 OR = 0.84, 95% CI 0.73 to 0.96, P = 1.46 × 10−2; IL12A rs485499 OR = 0.88, 95% CI 0.79 to 0.99, P = 3.37 × 10−2; NF-kB rs7665090 OR = 1.12, 95% CI 1.01 to 1.25, P = 2.47 × 10−2; IL7R rs860413 OR = 0.89, 95% CI 0.79 to 1.00, P = 5.77 × 10−2; and IRF8 rs11117432 OR = 0.68, 95% CI 0.68 to 0.93, P = 6.52 × 10−3
Summary
Systemic sclerosis (SSc) and primary biliary cirrhosis (PBC) are rare polygenic autoimmune diseases (AIDs) characterized by fibroblast dysfunction. Both diseases share some genetic bases with other AIDs, as evidenced by autoimmune gene pleiotropism. A recent GWAS carried out in patients with PBC identified 12 new loci involved in disease susceptibility and highlighted the importance of type I interferon (IFN), nuclear factor-kappa-B (NF-κB), and Toll-like receptor (TLR) signaling [7] in its pathogenesis. Given the evidence of shared autoimmune genes between SSc and other AIDs, we investigated the association of 16 single-nucleotide polymorphisms (SNPs), recently identified as susceptibility factors for PBC, with SSc and its subphenotypes
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