Department of Anatomy, Histology and Forensic Medicine, University of Florence, Florence, Italy.
Ann Rheum Dis. 2012 Jun;71(6):1034-41. doi: 10.1136/annrheumdis-2011-200986. Epub 2012 Mar 8.
Caveolin-1 (CAV1) is an inhibitor of tissue fibrosis and has been implicated in the pathogenesis of systemic sclerosis (SSc). The aim of the study was to analyse the possible association of CAV1 gene single nucleotide polymorphisms (SNP) with SSc.
A total population of 3974 individuals (1355 SSc patients, 2619 controls) was studied. Genotype data for 23 SNP spanning the CAV1-CAV2 gene locus were obtained from a genome-wide scan conducted in a French population (564 SSc patients, 1776 controls). Three CAV1 SNP (rs926198, rs959173, rs9920) displaying the most significant associations with SSc and/or clinical phenotypes were then genotyped in an Italian population (791 SSc patients, 843 controls). CAV1 protein expression in skin biopsies was investigated by immunohistochemistry and western blotting.
In the French population, the CAV1 rs959173 C minor allele showed a significant protective association with susceptibility to SSc (OR 0.71, 95% CI 0.59 to 0.86, p(adjusted)=0.009), and with the subset of patients with limited cutaneous SSc (OR 0.71, 95% CI 0.56 to 0.89, p(adjusted)=0.018). The association was replicated in the Italian population and strengthened in the combined populations through Cochran-Mantel-Haenszel meta-analysis (SSc: pooled OR 0.81, 95% CI 0.71 to 0.92, p=0.0018; limited cutaneous SSc: pooled OR 0.80, 95% CI 0.69 to 0.93, p=0.0053). Genotype/protein expression correlations revealed that the rs959173 C protective allele was associated with increased CAV1 protein expression.
These results add CAV1 to the list of SSc susceptibility genes and provide further evidence for the contribution of this pathway in the fibrotic process that characterises SSc pathogenesis.
窖蛋白-1（CAV1）是组织纤维化的抑制剂，已被牵连到全身性硬皮病（SSc）的发病机制中。本研究的目的是分析 CAV1 基因单核苷酸多态性（SNP）与 SSc 之间可能存在的关联。
共研究了 3974 个人（1355 例 SSc 患者，2619 例对照）。从法国人群中进行的全基因组扫描中获得了涵盖 CAV1-CAV2 基因座的 23 个 SNP 的基因型数据（564 例 SSc 患者，1776 例对照）。然后，在意大利人群（791 例 SSc 患者，843 例对照）中对与 SSc 和/或临床表型关联最显著的三个 CAV1 SNP（rs926198、rs959173、rs9920）进行了基因分型。通过免疫组织化学和 Western blot 检测皮肤活检中的 CAV1 蛋白表达。
在法国人群中，CAV1 rs959173 C 次要等位基因与 SSc 的易感性呈显著保护性关联（OR 0.71，95%CI 0.59 至 0.86，p（调整）=0.009），并且与局限性皮肤 SSc 患者亚组呈显著保护性关联（OR 0.71，95%CI 0.56 至 0.89，p（调整）=0.018）。该关联在意大利人群中得到了复制，并通过 Cochran-Mantel-Haenszel 荟萃分析在合并人群中得到了加强（SSc：汇总 OR 0.81，95%CI 0.71 至 0.92，p=0.0018；局限性皮肤 SSc：汇总 OR 0.80，95%CI 0.69 至 0.93，p=0.0053）。基因型/蛋白表达相关性表明，rs959173 C 保护等位基因与 CAV1 蛋白表达增加相关。
这些结果将 CAV1 添加到 SSc 易感性基因列表中，并为该途径在 SSc 发病机制中纤维化过程中的作用提供了进一步的证据。
