Arismendi Maria, Giraud Matthieu, Ruzehaji Nadira, Dieudé Philippe, Koumakis Eugenie, Ruiz Barbara, Airo Paolo, Cusi Daniele, Matucci-Cerinic Marco, Salvi Erika, Cuomo Giovanna, Hachulla Eric, Diot Elisabeth, Caramaschi Paola, Riccieri Valeria, Avouac Jérôme, Kayser Cristiane, Allanore Yannick
Paris Descartes University, INSERM U1016, Institut Cochin, Sorbonne Paris Cité, Paris, France.
CAPES Foundation, Ministry of Education of Brazil, Brasília, DF, 70040-020, Brazil.
Arthritis Res Ther. 2015 Mar 21;17(1):71. doi: 10.1186/s13075-015-0572-y.
Systemic 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.
Sixteen 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).
We observed an association between PLCL2 rs1372072 (odds ratio (OR) = 1.22, 95% confidence interval (CI) 1.12 to 1.33, P adj = 7.22 × 10(-5)), nuclear factor-kappa-B (NF-κB) rs7665090 (OR = 1.15, 95% CI 1.06 to 1.25, P adj = 0.01), and IRF8 rs11117432 (OR = 0.75, 95% CI 0.67 to 0.86, P adj = 2.49 × 10(-4)) with SSc susceptibility. Furthermore, phenotype stratification showed an association between rs1372072 and rs11117432 with the limited cutaneous subgroup (lcSSc) (P adj = 4.45 × 10(-4) and P adj = 0.001), whereas rs7665090 was associated with the diffuse cutaneous subtype (dcSSc) (P adj = 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.
An 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.
系统性硬化症（SSc）和原发性胆汁性肝硬化（PBC）是罕见的多基因自身免疫性疾病（AIDs），其特征为成纤维细胞功能障碍。此外，这两种疾病与其他自身免疫性疾病存在一些共同的遗传基础，自身免疫基因多效性可证明这一点。本研究旨在调查在PBC中通过大规模全基因组关联研究（GWAS）鉴定出的单核苷酸多态性（SNP）是否可能影响SSc易感性。
对来自两个欧洲人群（法国和意大利）的1616例SSc患者和3621例健康对照进行了16个PBC易感性SNP的基因分型。
我们观察到PLCL2 rs1372072（优势比（OR）=1.22，95%置信区间（CI）1.12至1.33，校正P值=7.22×10⁻⁵）、核因子-κB（NF-κB）rs7665090（OR=1.15，95%CI 1.06至1.25，校正P值=0.01）和IRF8 rs11117432（OR=0.75，95%CI 0.67至0.86，校正P值=2.49×10⁻⁴）与SSc易感性相关。此外，表型分层显示rs1372072和rs11117432与局限性皮肤亚组（lcSSc）相关（校正P值=4.45×10⁻⁴和校正P值=0.001），而rs7665090与弥漫性皮肤亚型（dcSSc）相关（校正P值=0.003）。基因型-mRNA表达相关性分析显示，IRF8保护性等位基因与SSc患者中干扰素-γ（IFN-γ）表达增加相关（P=0.03），但与患者和对照中I型干扰素（IFIT1）表达降低相关（P=0.02）。此外，我们发现NF-κB和IRF8之间存在上位性相互作用（OR=0.56，95%CI 0.00至0.74，P=4×10⁻⁴），这反过来表明IRF8的保护作用取决于NF-κB易感等位基因的存在。
对多效性基因的分析确定了两个新的SSc易感基因（NF-κB和PLCL2），并证实了IRF8位点。此外，IRF8变异影响IFN特征，我们发现IRF8和NF-κB基因变异之间的相互作用可能在SSc易感性中起作用。
