An allelic variant in the IRF3 gene is associated with liver cirrhosis in hepatitis C virus carriers

Abstract

Introduction: Progression to cirrhosis in hepatitis C virus (HCV) carriers is a complex trait that is modulated by a combination of both clinical and host genetic factors. Host genetics factors could play an important role in the risk of developing this phenotype. Objectives: To discover new genetic variants associated with the risk of developing cirrhosis using SNPs previously related to cholesterol metabolism and transport, fibro-genesis, immune response or viral treatment response. Patients and Methods: Three hundred thirty-seven HCV carriers with available data on liver fibrosis status (FibroScan or liver biopsy) were selected from a genotype dataset containing 442 patients. Of them, 77 (22.85%) showed cirrhosis. Plink tools were used to perform quality control of genotype data and to carry out univariate association analyses. The variables associated with cirrhosis in the univariate analyses were entered in a multivariate logistic regression model. Results: Only the SNP rs12104272, linked to IRF3 gene, was associated with cirrhosis in our sample after multiple testing corrections. A total of 330 (97.92%) patients out of 337 individuals were successfully genotyped for rs12104272. Of them, 76 (23%) were cirrhotic. In the overall population, the genotype frequencies were: 26 (7.87%) AA, 157 (47.57%) AG and 147 (44.54%) GG. A higher proportion of rs12104272 A allele carriers was observed in the non-cirrhotic group [60.63% (154 individuals)] than in the cirrhotic group [38.15% (29 individuals)]. Among patients with genotype AA/AG, the proportion of those who showed cirrhosis was 15.84% (29 patients) versus 31.97% (47 patients) with genotype GG (p = 0.0005). In the multivariate analysis adjusted for age, sex, body mass index, HIV co-infection and HCVRNA load, rs12104272 genotype AA/AG was independently associated with cirrhosis (adjusted odds ratio=0.366, 95% confidence interval=0.180-0.746, p = 0.006). The protective effect of rs12104272 AA/AG genotype was stronger in patients bearing the rs12979860 CC genotype of IL28B (adjusted odds ratio=0.069, 95% confidence interval = 0.014-0.349, p = 0.001). Conclusion: Due to its effect size, the rs12104272 SNP could have a clinical value, either alone or combined with the rs12979860 marker of IL28B, to select those individuals at low risk of cirrhosis development.