Systemic sclerosis: the susceptible host (genetics and environment)☆

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Organic solvents and silica

Exposure to certain environmental agents may be associated with the development of SSc. Many of the epidemiologic studies focused on exposures to organic solvents and silica dust, but the data are far from conclusive (reviewed in [6], [7], [8]). One hypothesis is that differences in the ability to deactivate environmental toxins because of genetic polymorphisms of certain metabolic enzymes may influence disease susceptibility following exposure to such agents [9], [10]. Genetic variations in

Familial aggregation

Several studies reported familial aggregation of SSc which suggested genetic contributions to disease susceptibility (reviewed in [31]). The frequency for familial SSc was previously estimated to range from 1.6% to 7% [32]. The first formal study of familial aggregation in patients who had SSc was reported by Englert and colleagues [33]. They studied a retrospective cohort of 715 patients who had SSc (710 families) and 371 age- and gender-matched general practice control families from Sydney,

Fibrillin-1 murine and human disease

The Tsk mouse is a well-characterized animal model for SSc. The Tsk/+ mouse develops dermal fibrosis without an inflammatory infiltrate, but does not develop the vascular lesions; the emphysematous changes in the lungs differ from the pulmonary fibrosis that is seen in SSc. Tsk/+ mice have increased expression of collagen types I, II, and VI genes and produce some SSc-specific autoantibodies [117]. Some studies suggested that the development of the Tsk phenotype is dependent on cell-mediated

Summary

It is becoming evident that several genetic factors participate in modulating susceptibility to SSc and its clinical manifestations. Some genes that specifically affect ECM metabolism and vascular function may be unique to SSc and scleroderma-related disorders; others, such as those genes involved in regulating immune tolerance, are likely shared with other autoimmune diseases [217]. The effect of genetic variations (or polymorphisms) that are found in most of these genes taken individually

Acknowledgements

The author gratefully acknowledges the helpful comments and suggestions by Drs. Frank C. Arnett, Maureen D. Mayes, and John D. Reveille.

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    ☆

    This work was supported by grants no. IP50-AR-44888 (NIH:NIAMS), 3M01RR02558-12S1 (NIH:NCRR) and R01AR46718-01 (NIH:NIAMS).

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