Scleroderma/systemic sclerosis (SSc) is a chronic connective tissue disease of unknown etiology. Thehallmark of established SSc is widespread tissue fibrosis affecting the skin and multiple internal organs. Thepathogenesis of fibrosis in SSc is complex and remains poorly understood. Vascular injury and damage, andautoimmune responses appear to be coupled with aberrant activation of fibroblasts, resulting in progressivefibrosis. Transforming Growth Factor Beta (TGF-IJ) has emerged as a central mediator of initiation and/orpropagation of the fibrotic response in involved tissues. Only few underpowered studies have examinedgenetic polymorphisms of the TGF-fc signaling axis in the pathogenesis of SSc. We propose to takeadvantage of the unique patient resources and substantial expertise available at Northwestern in SSc, TGFBbiology and genetics to investigate the role of two common and functionally relevant variants of TGFB1and 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 ofgenetic polymorphisms of the TGF-IJ signaling pathway in the development and progression of SSc. Wehave the following Specific Aims:
Specific Aim 1 : We will assess the association between the hypomorphicTGFBR1*6A allele and SSc and its two subsets, diffuse cutaneous SSc (dcSSc) and localized cutaneousSSc (IcSSc). We will also perform haplotype analysis of the TGFBR1 gene in cases and controls.
SpecificAim 2 : We will genotype cases and controls for the other functionally relevant variant of the TGF-p signalingpathway: TGFB1 T29C, which results in higher TGFB1 circulating level. We will also perform haplotypeanalysis of the TGFB1 gene in cases and controls. Exploratory Aims: As a first exploratory aim we willanalyze gene-gene interactions between the two well characterized TGFBR1 and TGFB1 polymorphismsthat affect TGF-P signaling. In this Aim we will explore the relationship between the variants and risk forscleroderma. This will allow us to determine the extent to which the overall level of TGF-p signaling, aspredicted by combination of these two variants, will be associated with scleroderma risk. As a secondexploratory aim, we will analyze the association between disease severity and TGFBR1 as well as TGFB1genotypes.
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