Genetic susceptibility to systemic sclerosis from clinical aspect to genetic factor analyses.

INSERM, U906, Marseille, F-13385, France.
European Journal of Internal Medicine (Impact Factor: 2.3). 06/2009; 20(3):242-52. DOI: 10.1016/j.ejim.2008.07.012
Source: PubMed

ABSTRACT Systemic sclerosis is a rare autoimmune disease mainly characterized by vascular alteration and fibrosis involving skin but also visceral organs such as lungs, digestive tract, and heart. This disease leads to high morbidity and mortality. Its pathogenesis remains unclear, but recent attention has focus on genetic factors.
We first recall the main manifestations associated with systemic sclerosis and leading to its diagnosis and prognosis. Then we propose an overview on human genetics studies, as a number of genetic loci have been identified that appear to be associated with the disease.
Articles concerning association studies with candidate genes encoding for extracellular matrix proteins, cytokines, growth factors, chemokines, and proteins involved in vascular tone and immune regulations are presented and discussed.
Systemic sclerosis is a multigenic complex disorder. Genetic associations are observed in distinct phenotypes such as the diffuse cutaneous form or the limited form, or in association with specific autoantibody pattern. Promising candidate genes are those involved in pathways that lead to the vascular damage and fibrosis. A better knowledge of crucial mediators involved in systemic sclerosis could in the future provide new therapeutic strategies to control the disease.

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    ABSTRACT: Transforming growth factor-β1 (TGF-β1) plays an important role in the pathogenesis of systemic sclerosis (SSc). To investigate whether TGF-β1 gene promoter polymorphisms were associated with the susceptibility of SSc, we performed a meta-analysis based on all available studies through PubMed, Elsevier Science Direct, Embase, and Chinese Biomedical, China National Knowledge Infrastructure and Google Scholar with the last report up to March 15, 2013. Crude odds ratios with 95 % confidence intervals were used to estimate the strength of the association. A fixed or random effects model was adopted according to heterogeneity test. Heterogeneity among studies was evaluated using I (2) . Meta-regression was used to explore potential sources of between-study heterogeneity. Publication bias was estimated using Begg's and Egger's test. Totally, seven papers with 663 SSc patients and 908 healthy controls were subjected to the final analysis. These studies encompass seven for TGF-β1 codon 10, three for codon 25 and three for -509C/T. We failed to detect any association of these promoter polymorphism with SSc susceptibility. For TGF-β1 codon 10 polymorphism, subgroup analyses by race, genotype testing method and classification of SSc were further performed. Similarly, no association was observed. Significant heterogeneity was detected among the studies in all genetic models of TGF-β1 codon 10 polymorphism. Publication bias was absent. Taken together, our meta-analysis did not provided an evidence of confirming association between TGF-β1 (codon 10, codon 25, -509C/T) gene polymorphism and SSc. Nevertheless, due to smaller sample sizes, larger sample studies including different ethnic groups should be considered in future to confirm our results.
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    ABSTRACT: Many environmental and genetic factors have been contributed to the development of systemic sclerosis (SSc). To determine whether IL-10 gene polymorphisms are associated with SSc, we conducted a meta-analysis approach. A total of eight studies involving 1,034 SSc cases and 1,815 controls were obtained by electronic database, i.e. Embase, Blackwell, Scopus, China National Knowledge Infrastructure database, Chinese Biomedical database, Google searching. We analyzed three gene polymorphisms, including IL-10 -1082G/A (rs1800896), IL-10 -819C/T (rs1800871), IL-10 -3575T/A (rs1800890). The combined odds ratio (OR) with its 95% confidence interval (95% CI) was calculated using fixed or random effect models. We found that IL-10 819C allele might contribute to SSc susceptibility by fixed effect model and IL-10 3575A allele could be an important risk factor for SSc, especially in European descent. No significant heterogeneity were observed. Under random effect model, there was no evidence of statistically significant association between IL-10 1082G/A polymorphism and SSc. Publication bias was absent in all analyses. However, larger scale primary studies are required to further evaluate the IL-10 polymorphism and SSc.
    Molecular Biology Reports 02/2012; 39(6):6851-5. · 2.51 Impact Factor
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    ABSTRACT: OBJECTIVE:: To test the hypothesis that the subset of patients with impaired renal function who are exposed to gadolinium-containing contrast agents (GCCAs) and develop nephrogenic systemic fibrosis (NSF) have a genetic predisposition for disease. METHODS:: We examined whether an intronic single-nucleotide polymorphism (SNP) in caveolin-1 (CAV1 rs4730751) and 2 coding SNPs in transforming growth factor-beta 1 (TGFB1 rs1800471, codon 25; and rs1800470, codon 10) were associated with the NSF phenotype. RESULTS:: Forty-one patients with a history of chronic kidney disease and GCCA administration were studied, including NSF cases (n = 17) and control subjects (n = 24) without clinical or histological evidence of NSF. No significant differences in the genotype frequencies at these SNPs in TGFΒ1 and CAV1 were found between patients with NSF and subjects without NSF. CONCLUSIONS:: We conclude that polymorphisms in the genes encoding TGFΒ1 and CAV1 previously associated with the development and progression of fibrosis in several organ systems are not associated with development of NSF in this cohort of patients with renal impairment after GCCA exposure.
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May 23, 2014