Role of TGF-Beta Genetic Variants in the Pathogenesis of Scleroderma

硬皮病/系统性硬化症(SSC)是一种病因不明的慢性结缔组织病。这个 已建立的SSc的特征是影响皮肤和多个内脏的广泛组织纤维化。这个 SSC纤维化的发病机制很复杂，目前尚不清楚。血管损伤和损害，以及 自身免疫反应似乎与成纤维细胞的异常激活相结合，导致进行性 纤维化症。转化生长因子β(TGF-IJ)已成为启动和/或启动和/或 纤维化反应在受累组织中的传播。只有为数不多的动力不足的研究 转化生长因子-Fc信号轴基因多态性在SSc发病机制中的作用我们建议采取 利用西北大学SSC、TGFb独特的患者资源和丰富的专业知识 生物学和遗传学研究TGFB1的两个常见的和功能相关的变体的作用 以及它的信号受体TGFBR1，在200名具有良好特征的SSc患者和400名年龄的队列中， 性别和民族状况与健康对照相匹配，以了解 转化生长因子-IJ信号通路基因多态性在SSc发生发展中的作用我们 有以下具体目标：具体目标1：我们将评估亚形之间的联系 TGFBR1*6A等位基因与皮肤干细胞及其两个亚群弥漫性皮肤干细胞(DcSSc)和局限性皮肤干细胞 SSC(ICSSC)。我们还将在病例和对照中进行TGFBR1基因的单倍型分析。特定的 目的2：我们将对另一种功能相关的转化生长因子-β信号变异体的病例和对照进行分型 途径：TGFB1 T29C，导致TGFB1循环水平升高。我们还将执行单倍型 TGFB1基因在病例和对照中的分析探索目标：作为第一个探索目标，我们将 分析两个典型的TGFBR1和TGFB1多态之间的基因-基因交互作用 从而影响转化生长因子-β信号转导。在这个目标中，我们将探索变异和风险之间的关系 硬皮病。这将使我们能够确定转化生长因子-β信号的总体水平，如 这两个变种的组合预测，将与硬皮病风险相关。作为一秒钟 探索性目的，我们将分析疾病严重程度与TGFBR1和TGFB1的关系 基因分型。

Scleroderma/systemic sclerosis (SSc) is a chronic connective tissue disease of unknown etiology. The hallmark of established SSc is widespread tissue fibrosis affecting the skin and multiple internal organs. The pathogenesis of fibrosis in SSc is complex and remains poorly understood. Vascular injury and damage, and autoimmune responses appear to be coupled with aberrant activation of fibroblasts, resulting in progressive fibrosis. Transforming Growth Factor Beta (TGF-IJ) has emerged as a central mediator of initiation and/or propagation of the fibrotic response in involved tissues. Only few underpowered studies have examined genetic polymorphisms of the TGF-fc signaling axis in the pathogenesis of SSc. We propose to take advantage of the unique patient resources and substantial expertise available at Northwestern in SSc, TGFB biology and genetics to investigate the role of two common and functionally relevant variants of TGFB1 and its signaling receptor, TGFBR1, in a cohort of 200 well characterized patients with SSc and 400 age, gender and ethnic status matched healthy controls, in order to understand the role and contribution of genetic polymorphisms of the TGF-IJ signaling pathway in the development and progression of SSc. We have the following Specific Aims: Specific Aim 1: We will assess the association between the hypomorphic TGFBR1*6A allele and SSc and its two subsets, diffuse cutaneous SSc (dcSSc) and localized cutaneous SSc (IcSSc). We will also perform haplotype analysis of the TGFBR1 gene in cases and controls. Specific Aim 2: We will genotype cases and controls for the other functionally relevant variant of the TGF-p signaling pathway: TGFB1 T29C, which results in higher TGFB1 circulating level. We will also perform haplotype analysis of the TGFB1 gene in cases and controls. Exploratory Aims: As a first exploratory aim we will analyze gene-gene interactions between the two well characterized TGFBR1 and TGFB1 polymorphisms that affect TGF-P signaling. In this Aim we will explore the relationship between the variants and risk for scleroderma. This will allow us to determine the extent to which the overall level of TGF-p signaling, as predicted by combination of these two variants, will be associated with scleroderma risk. As a second exploratory aim, we will analyze the association between disease severity and TGFBR1 as well as TGFB1 genotypes.