Abstract
Single nucleotide polymorphisms (SNPs) in the epidermal growth factor (EGF, rs4444903), patatin-like phospholipase domain-containing protein 3 (PNPLA3, rs738409) genes, and near the interleukin-28B (IL28B, rs12979860) gene are linked to treatment response, fibrosis, and hepatocellular carcinoma (HCC) in chronic hepatitis C. Whether these SNPs independently or in combination predict clinical deterioration in hepatitis C virus (HCV)-related cirrhosis is unknown. We genotyped SNPs in EGF, PNPLA3, and IL28B from liver tissue from 169 patients with biopsy-proven HCV cirrhosis. We estimated risk of clinical deterioration, defined as development of ascites, encephalopathy, variceal hemorrhage, HCC, or liver-related death using Cox proportional hazards modeling. During a median follow-up of 6.6 years, 66 of 169 patients experienced clinical deterioration. EGF non-AA, PNPLA3 non-CC, and IL28B non-CC genotypes were each associated with increased risk of clinical deterioration in age, sex, and race-adjusted analysis. Only EGF non-AA genotype was independently associated with increased risk of clinical deterioration (hazard ratio [HR] 2.87; 95% confidence interval [CI] 1.31–6.25) after additionally adjusting for bilirubin, albumin, and platelets. Compared to subjects who had 0–1 unfavorable genotypes, the HR for clinical deterioration was 1.79 (95%CI 0.96–3.35) for 2 unfavorable genotypes and 4.03 (95%CI 2.13–7.62) for unfavorable genotypes for all three loci (Ptrend<0.0001). In conclusion, among HCV cirrhotics, EGF non-AA genotype is independently associated with increased risk for clinical deterioration. Specific PNPLA3 and IL28B genotypes also appear to be associated with clinical deterioration. These SNPs have potential to identify patients with HCV-related cirrhosis who require more intensive monitoring for decompensation or future therapies preventing disease progression.
Highlights
Chronic hepatitis C (CHC) is the most common cause of liver-related death and liver transplantation in the United States [1]
We found significant associations between epidermal growth factor (EGF), IL28B, and PNPLA3 genotypes and the risk of clinical deterioration in patients with hepatitis C virus (HCV)-related cirrhosis
These results suggest that genetic variation at the EGF locus is independently associated with clinical deterioration in patients with CHC and provides prognostic information beyond known clinical predictors
Summary
Chronic hepatitis C (CHC) is the most common cause of liver-related death and liver transplantation in the United States [1]. The rate of progression of hepatitis C virus (HCV) infection is variable, likely due to a combination of host genetic and environmental factors. Attempts have been made to develop risk scores to predict the risk of disease progression for individual patients. Such scores have incorporated both clinical variables and genetic data [4]. While the patatin-like phospholipase domain-containing protein 3 (PNPLA3) SNP rs738409 has mainly been studied in nonalcoholic fatty liver disease (NAFLD) [13], studies in patients with CHC have shown an association with steatosis, fibrosis [14, 15], and HCC [15, 16], data are conflicting [17]
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