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疾病。的 确定的SSc的标志是影响皮肤和多个内部器官的广泛组织纤维化。的 SSc中纤维化的发病机制是复杂的并且仍然知之甚少。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，导致进行性的 纤维化转化生长因子β（TGF-β 1）已经作为启动和/或抑制肿瘤细胞增殖的中心介质出现。 纤维化反应在相关组织中的传播。只有很少的动力不足的研究 SSc发病机制中TGF-fc信号传导轴的遗传多态性。我们建议采取 独特的病人资源和大量的专业知识，在西北SSc，TGFB的优势 生物学和遗传学研究TGFB 1的两种常见和功能相关变体的作用 及其信号受体TGFBR 1，在200名特征良好的SSc患者和400名年龄， 性别和种族状况与健康对照组相匹配，以了解 SSc发生和进展中TGF-β 1信号通路的遗传多态性。我们 有以下具体目标：具体目标1：我们将评估亚形之间的关联 TGFBR 1 *6A等位基因与SSc及其两个亚群，弥漫性皮肤SSc（dcSSc）和局限性皮肤SSc（dcSSc）， SSc（IcSSc）。我们还将在病例组和对照组中进行TGFBR 1基因的单倍型分析。具体 目的2：我们将对病例和对照进行TGF-β信号传导的其他功能相关变体的基因分型。 途径：TGFB 1 T29 C，导致更高的TGFB 1循环水平。我们还将进行单倍型分析 分析病例和对照中的TGFB 1基因。探索目标：作为第一个探索目标，我们将 分析两个充分表征的TGFBR 1和TGFB 1多态性之间的基因-基因相互作用 影响TGF-β信号传导。在这个目标中，我们将探讨变异和风险之间的关系， 硬皮病这将使我们能够确定TGF-β信号传导的总体水平在多大程度上， 通过这两种变体的组合预测，将与硬皮病风险相关。作为第二 为了探索性的目的，我们将分析疾病严重程度与TGFBR 1和TGFFB 1之间的关系。 基因型

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.