Genetics variants in the STAT3 are associated with histological severity of nonalcoholic fatty liver disease

SOOKOIAN S; CASTANO G; FERNANDEZ GIANOTTI T; GEMMA C; MARIA SOLEDAD ROSSELLI; PIROLA CARLOS JOSÉ.

San Francisco, USA.

Congreso; Annual meetting of the American Association for the Study of Liver Diseases; 2008

AASLD

Signal Transducer and Activator of Transcription 3 (STAT3) -initially described as an acute phase protein and also as an ubiquitous transcription factor indispensable during early embryogenesis - contributes to various metabolic processes and, possibly, to the pathogenesis of certain diseases such as the metabolic syndrome. We hypothesized that STAT3 gene variants and their predicted haplotypes of linkage disequilibrium (LD) blocks may contribute to the susceptibility of nonalcoholic fatty liver disease (NAFLD). Additionally, we tested the hypothesis of a relation between gene variants and disease severity. Patients & Methods: 108 patients with NAFLD (30 males and 78 females) with features of NAFLD, and a group of 55 healthy individuals were included in a cross sectional study Hospital-based study. We selected 3 tagSNPs showing a minor allele frequency >10 % (rs2293152 C/G, rs6503695 C/T, and rs9891119 A/C) encompassing 68.55 kb in chromosome 17, representing 24 polymorphic sites (r2 >0.8). Results: In univariate analysis, there were significant differences in the allele frequency of the rs6503695 and rs9891119 between the healthy individuals and NAFLD patients (empiric P =0.021 and 0.020, respectively). The test results for the multi-marker analysis showed that haplotypes TA and CC of tagSNPs rs6503695, rs9891119 were significantly associated with NAFLD (empiric P = 0.035 and 0.015, respectively). When we tested the hypothesis of a relation between the gene variants and the clinical and histological spectrum of NAFLD by multinomial analysis, a significant association was observed with rs9891119 (P = 0.02). Using a multinomial with Logit function test, this association (chi2: 15.02, p=0.02) persisted after adjusting for HOMA (chi2: 22.36, p=0.000055) and BMI (chi2: 53.88, p=1x10-11) as independent and continuous predictor variables. In conclusion, our study suggests a potential role of the STAT3 polymorphisms and their haplotypes in susceptibility to NAFLD and disease severity. In the analysis of individual markers, rs6503695 and rs9891119 were significantly associated with the disease being the rs6503695-T and rs9891119-A allele carriers 2.3 and 2.5 fold, respectively, more likely to have NAFLD in comparison with non-carriers. The test of haplotypes based on multi-marker predictors showed that frequencies of haplotypes TA and CC of tag SNPs rs6503695 and rs9891119 in NAFLD individuals significantly differed from those in healthy subjects showing that the haplotype TA confers an almost 2-fold increase in the risk of suffering from NAFLD and haplotype CC confers a 2.5-fold protection against NAFLD.