Genetic basis for systemic sclerosis

Among the connective tissue diseases, systemic sclerosis is an orphan disease in which diffuse connective tissue alterations lead to multi-organ involvement. Environmental factors implicated in triggering this multifactorial disease include crystalline silica, chlorine solvents, welding vapors, and various other solvents. Clustering within families indicates a role for genetic factors. Although concordance for the disease among identical twins is low, concordance for autoantibodies associated with systemic sclerosis and for fibroblast gene expression profiles is higher. Because multiplex families are rare, association and candidate gene strategies are the most appropriate methods for investigating the genetics of systemic sclerosis. The most consistent data relate to the involvement of fibrosis genes, most notably the TGF-β regulation pathway, secreted protein acid and rich in cysteine (SPARC) genes, and the fibrillin-1 gene (FBN1). Several variants of genes for cytokines or their receptors may be involved. Data on the vasculopathy characteristic of systemic sclerosis are somewhat conflicting. Investigations into the genetics of systemic sclerosis may shed light on the complex pathophysiology of this disease, help to identify factors that predict organ involvement, and suggest new treatment strategies.