A Functional Polymorphism in the Epidermal Growth Factor Gene Independently Predicts Clinical Decompensation in HCV-Related Cirrhosis

Background and Aims: Several single nucleotide polymorphisms (SNPs), including rs4444903 in the epidermal growth factor (EGF) gene, rs12979860 near the interleukin-28B (IL28B) gene, and rs738409 in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene, have been linked to treatment response, steatosis, fibrosis, and development of hepatocellular carcinoma (HCC) in chronic hepatitis C (HCV). No study has comprehensively examined the effects of these SNPs on the natural history of HCV-related cirrhosis. Methods: We performed a retrospective cohort study of 169 subjects with chronic HCV and biopsy-proven cirrhosis who had long term followup for clinical events. Formalin-fixed, paraffin-embedded liver biopsy specimens were genotyped for EGF, IL28B, and PNPLA3 using a TaqMan assay with commercial probes and primers. Cox proportional hazards modeling was used to determine the hazard ratio for clinical decompensation, defined as the development of ascites, encephalopathy, variceal hemorrhage, HCC, or cirrhosis-related death. Results: During a median followup of 6.6 years, 66 patients (39%) experienced clinical decompensation. On univariate analysis, EGF non-A/A, PNPLA3 non-C/C, and IL28B non-C/C genotypes were each associated with increased risk of decompensation. In multivariable Cox regression modeling, EGF non-A/A genotype was independently associated with an increased rate of clinical decompensation (HR = 3.00, p = 0.005). Conclusions: HCV cirrhotics with the EGF A/G and G/G genotypes at rs4444903, a functional polymorphism associated with higher intrahepatic EGF levels, have an increased risk of clinical decompensation. Further study of the predictive value of EGF genotyping in patients with earlier stages and other etiologies of liver disease is warranted.