Genetic factors in systemic sclerosis

Maureen D Mayes,Maria Trojanowska

doi:10.1186/ar2189

Abstract

A number of genetic loci have been identified that appear to be associated with systemic sclerosis (SSc; scleroderma). There is mounting evidence suggesting that these genetic associations may in fact be associated with distinct phenotypes in SSc based on autoantibody pattern rather than with SSc as a single disease entity. This may ultimately have implications for approaches to therapy as well as responses to therapy. The most promising candidate genes are those involved in pathways that lead to the vascular damage and fibrosis that are the hallmarks of this disease. There is uncertainty, however, regarding the nature of the key pathological mechanisms that link these two disease processes. Recent studies have focused on Fli1 (friend leukaemia integration 1), a transcription factor that is found in immune cells, fibroblasts, and endothelial cells that regulates collagen gene function and angiogenesis. Fli1 is dysregulated in SSc skin and dermal blood vessels, and appears to play a pathological role in SSc skin fibrosis and vessel degeneration. Whether this dysregulation is due to genetic polymorphisms in the Fli1 pathway or to epigenetic mechanisms is not clear.

Highlights

It is the generally accepted dogma that autoimmune disease requires an external trigger to act upon a genetically susceptible host
It focuses on studies conducted to determine the role played by a particular gene product, Fli1, whose dysregulation appears to contribute to the complex pathogenesis of systemic sclerosis (SSc) in a number of ways
We recently completed a study of 1,100 patients in which we looked at several human leucocyte antigen (HLA) class II associations and were able to verify the findings of multiple previous studies

Summary

Introduction

It is the generally accepted dogma that autoimmune disease requires an external trigger to act upon a genetically susceptible host. There are conflicting reports on the association of SPARC (secreted protein, acidic and rich in cysteine) polymorphisms with SSc [12,13] This lack of confirmation may be due to the fact that Zhou and coworkers [12] studied the Choctaw Indians, a relatively inbred group with homogeneous disease expression, whereas Lagan and coworkers [13] studied a more heterogeneous scleroderma cohort. Staining of microvessels in the homozygous Fli1∆CTA mice compared with Fli1+/+ mice revealed downregulation of a number of proteins that are known to be involved in endothelial-mural interactions These included smooth muscle actin, desmin and platelet-derived growth factor receptor β. Work in cancer has shown that if pericytes are not present, such vessels do not survive [36]

Conclusion

14. Gregersen PK: Pathways to gene identification in rheumatoid arthritis

Findings

33. Hanahan D