Marangoni Roberta Goncalves, Korman Benjamin D, Allanore Yannick, Dieude Philippe, Armstrong Loren L, Rzhetskaya Margarita, Hinchcliff Monique, Carns Mary, Podlusky Sofia, Shah Sanjiv J, Ruiz Barbara, Hachulla Eric, Tiev Kiet, Cracowski Jean-Luc, Varga John, Hayes M Geoffrey
Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, 240 E. Huron Street, McGaw Pavillion M230, Chicago, IL, USA.
Paris Descartes University, INSERM U1016, Institut Cochin, Sorbonne Paris Cité, Paris, France.
Arthritis Res Ther. 2015 May 19;17(1):128. doi: 10.1186/s13075-015-0641-2.
The multifunctional nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ) has potent anti-fibrotic effects, and its expression and activity are impaired in patients with systemic sclerosis (SSc). We investigated PPAR-γ gene (PPARG) single nucleotide polymorphisms (SNPs) associated with SSc.
Tag SNPs spanning PPARG were genotyped in a European ancestry US discovery cohort comprising 152 SSc patients and 450 controls, with replication of our top signal in a European cohort (1031 SSc patients and 1014 controls from France). Clinical parameters and disease severity were analyzed to evaluate clinical associations with PPARG variants.
In the discovery cohort, a single PPARG intronic SNP (rs10865710) was associated with SSc (p=0.010; odds ratio=1.52 per C allele, 95% confidence interval 1.10-2.08). This association was replicated in the French validation cohort (p=0.052; odds ratio=1.16 per C allele, 95% confidence interval 1.00-1.35). Meta-analysis of both cohorts indicated stronger evidence for association (p=0.002; odds ratio=1.22 per C allele, 95% confidence interval 1.07-1.40). The rs10865710 C allele was also associated with pulmonary arterial hypertension in the French SSc cohort (p=0.002; odds ratio=2.33 per C allele, 95% confidence interval 1.34-4.03).
A PPARG variant is associated with susceptibility to SSc, consistent with a role of PPAR-γ in the pathogenesis of SSc.
多功能核受体过氧化物酶体增殖物激活受体γ（PPAR-γ）具有强大的抗纤维化作用，其表达和活性在系统性硬化症（SSc）患者中受损。我们研究了与SSc相关的PPAR-γ基因（PPARG）单核苷酸多态性（SNP）。
在一个由152例SSc患者和450例对照组成的欧洲裔美国发现队列中，对跨越PPARG的标签SNP进行基因分型，并在一个欧洲队列（来自法国的1031例SSc患者和1014例对照）中重复验证我们的最强信号。分析临床参数和疾病严重程度，以评估与PPARG变异的临床相关性。
在发现队列中，一个单一的PPARG内含子SNP（rs10865710）与SSc相关（p=0.010；每C等位基因的优势比=1.52，95%置信区间1.10-2.08）。这种关联在法国验证队列中得到重复（p=0.052；每C等位基因的优势比=1.16，95%置信区间1.00-1.35）。两个队列的荟萃分析表明关联证据更强（p=0.002；每C等位基因的优势比=1.22，95%置信区间1.07-1.40）。rs10865710 C等位基因在法国SSc队列中也与肺动脉高压相关（p=0.002；每C等位基因的优势比=2.33，95%置信区间1.34-4.03）。
一个PPARG变异与SSc易感性相关，这与PPAR-γ在SSc发病机制中的作用一致。
