Risk Factor For Systemic Sclerosis Research Articles

STAT4 is a genetic risk factor for systemic sclerosis having additive effects with IRF5 on disease susceptibility and related pulmonary fibrosis

Systemic sclerosis (SSc) belongs to the group of connective tissue disorders (CTDs), among which are several disorders characterized by a type I interferon (IFN) signature. The recent identification of an association between IRF5 and SSc further highlights a key role for IFN. STAT4, which encodes STAT-4, contributes to IFN signaling, and its genetic variants were found to be associated with CTDs. The aim of this study was to determine whether the STAT4 rs7574865 single-nucleotide polymorphism is associated with SSc, and whether it interacts with IRF5. Both the STAT4 rs7574865 and IRF5 rs2004640 polymorphisms were genotyped in 1,855 individuals of French Caucasian origin comprising a discovery set of 440 patients with SSc and 485 control subjects and a replication set of 445 patients with SSc and an additional 485 control subjects. STAT4 rs7574865 was shown to be associated with SSc (P=0.001, odds ratio [OR] 1.29, 95% confidence interval [95% CI] 1.11-1.51). This association was not restricted to a particular phenotype. An additive effect of the STAT4 rs7574865 T allele and the IRF5 rs2004640 T allele was observed, resulting in a multiple increased 1.28-fold risk of SSc. The OR for SSc was 2.72 (95% CI 1.86-3.99) for combinations of genotypes with >or=3 risk alleles. An additive effect was also detected for fibrosing alveolitis: carriage of at least 3 risk alleles appeared to be an independent risk factor (P=2.2x10(-4), OR 1.97, 95% CI 1.28-3.04). Our results establish STAT4 rs7574865 as a new SSc genetic susceptibility factor. STAT4 and IRF5 act with additive effects in terms of susceptibility to both SSc and SSc-related fibrosing alveolitis.

Pregnancy, microchimerism and autoimmunity: an update.

The presence of a small population of cells or DNA in one individual that derives from another genetically distinct person is referred to as microchimerism; this process may occur in course of pregnancy from mother to fetus, and vice versa. The clinical similarities between some features of autoimmune diseases and the chronic graft versus host disease, the increased incidence of autoimmune diseases observed in women after childbearing age, and the long-term persistence of microchimerism have raised the hypothesis that microchimerism could be involved in the pathogenesis of autoimmune diseases. To assess the possible relationship between pregnancy and the incidence of systemic sclerosis we performed a hospital-based case-control study. Our results, indicating a reduced risk for systemic sclerosis in women who had been pregnant in comparison with women who had not, seem to indicate that pregnancy is not a risk factor for systemic sclerosis.

HLA–DQA1*0501 is associated with diffuse systemic sclerosis in Caucasian men

Systemic sclerosis (SSc) is uncommon in men, and relatively little is known about factors contributing to its pathogenesis in this population. In the current study, we investigated HLA class II alleles in men with SSc. We also investigated the hypothesis that HLA compatibility of the mother could be a risk factor for SSc in men.Sequence-specific oligonucleotide probe typing was used to determine DQA1, DQB1, and DRB1 alleles of SSc patients (50 men and 36 parous women), healthy controls (59 men and 80 parous women), 26 mothers of men with SSc, and 44 mothers of healthy men. All study subjects were Caucasian, and allele frequencies were compared with those of Caucasian controls from the Eleventh International Histocompatibility Workshop as well as those of local controls.The DQA1*0501 allele was significantly increased among men with SSc compared with healthy men (odds ratio [OR] 2.3, P = 0.006, Pcorr = 0.04). DQA1*0501 was associated with diffuse SSc in men (OR 3.0, P = 0.004, Pcorr = 0.03), but not with limited SSc in men. Maternal HLA compatibility was not a risk factor for SSc in men.Previous studies have shown associations of DRB1 alleles with SSc, but have rarely determined DQA1 allele frequencies. Our findings indicate that a specific DQA1 allele is associated with SSc, and that DRB1 associations may be due to linkage disequilibrium with DQA1. Moreover, by analyzing genetic susceptibility according to sex, we found that the contribution of HLA genes to the risk of SSc was substantially greater in men than in parous women.