INSERM, U906, (Institut Nationale de la Santé et de la Recherche Médicale), Laboratoire d'Immunologie et de Génétique des Maladies Parasitaires, Faculté de Médecine, Université de la Méditerranée (UM) Service de Médecine Interne, Hôpital Nord, Assistance Publique-Hôpitaux de Marseille (AP-HM), UM, Marseille, France.
J Rheumatol. 2010 Feb;37(2):351-8. doi: 10.3899/jrheum.090290. Epub 2009 Dec 23.
Systemic sclerosis (SSc) is a life-threatening autoimmune disease characterized by chronic fibrosis of the skin and internal organs. Connective tissue growth factor (CTGF) is believed to be a primary mediator of chronic fibrosis. We assessed the possible association between 7 single-nucleotide polymorphisms (SNP) in the CTGF gene and scleroderma in a French population (registration number 2006/0182).
We conducted a case-control study with 241 scleroderma patients and 269 controls. Seven SNP were genotyped using the TaqMan system. Univariate and multivariate analyses were performed. In silico electrophoretic mobility shift assay (EMSA), and reverse transcriptase polymerase chain reaction analyses were done to assess the effect of the SNP on CTGF gene expression.
The frequency of the rs9399005TT genotype was significantly lower in SSc patients than in controls. This association remained significant after adjustment for gender. An association was detected between the rs9399005 and the diffuse and limited cutaneous forms. Multivariate analysis between SSc patients and controls taking into account all 7 SNP and sex revealed that only sex and the rs9399005 SNP were associated with disease. DNA analysis by EMSA indicated that the T allele bound nuclear factors that were also bound by the C allele. The binding affinity was higher for the T allele. Analysis of the human database and experiments with human hepatocyte cell line indicated the existence of an alternative transcript containing the rs9399005 polymorphism in its 3'UTR region. In silico analysis indicated that this polymorphism may alter the structure of CTGF messenger RNA.
These findings suggest that CTGF gene polymorphisms may contribute to susceptibility to scleroderma.
系统性硬化症（SSc）是一种危及生命的自身免疫性疾病，其特征为皮肤和内脏器官的慢性纤维化。结缔组织生长因子（CTGF）被认为是慢性纤维化的主要介质。我们评估了 CTGF 基因中的 7 个单核苷酸多态性（SNP）与法国人群中硬皮病的可能关联（注册号 2006/0182）。
我们进行了一项病例对照研究，纳入了 241 例硬皮病患者和 269 名对照。使用 TaqMan 系统对 7 个 SNP 进行基因分型。进行单变量和多变量分析。进行了体外电泳迁移率变动分析（EMSA）和逆转录聚合酶链反应分析，以评估 SNP 对 CTGF 基因表达的影响。
rs9399005TT 基因型在 SSc 患者中的频率明显低于对照组。在调整性别后，这种关联仍然显著。rs9399005 与弥漫性和局限性皮肤形式之间存在关联。在考虑所有 7 个 SNP 和性别后，将 SSc 患者与对照组进行的多变量分析表明，只有性别和 rs9399005SNP 与疾病相关。通过 EMSA 的 DNA 分析表明，T 等位基因结合了核因子，C 等位基因也结合了这些核因子。T 等位基因的结合亲和力更高。对人类数据库的分析和对人肝细胞系的实验表明，在其 3'UTR 区域存在包含 rs9399005 多态性的替代转录本。计算机分析表明，这种多态性可能改变 CTGF 信使 RNA 的结构。
这些发现表明 CTGF 基因多态性可能导致硬皮病易感性。
