Host Genetics Predict Clinical Deterioration in HCV-Related Cirrhosis

• Published in: PloS one Vol. 9; no. 12; p. e114747
• Main Authors: King, Lindsay Y., Johnson, Kara B., Zheng, Hui, Wei, Lan, Gudewicz, Thomas, Hoshida, Yujin, Corey, Kathleen E., Ajayi, Tokunbo, Ufere, Nneka, Baumert, Thomas F., Chan, Andrew T., Tanabe, Kenneth K., Fuchs, Bryan C., Chung, Raymond T.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 12.12.2014; Public Library of Science (PLoS)
• Subjects: Ascites; Bilirubin; Biopsy; Chromosomes; Cirrhosis; Clinical deterioration; Committees; Confidence intervals; Disease Progression; Encephalopathy; Epidermal growth factor; Female; Fibrosis; Gastroenterology; Gene expression; Genetics; Genotype & phenotype; Genotypes; Genotyping Techniques; Hazards; Hemorrhage; Hepatitis; Hepatitis C; Hepatitis C virus; Hepatitis C, Chronic - complications; Hepatocellular carcinoma; Hepatology; Hospitals; Human health and pathology; Humans; Hépatology and Gastroenterology; Infections; Infectious diseases; Interleukins; Kaplan-Meier Estimate; Life Sciences; Liver; Liver cancer; Liver cirrhosis; Liver Cirrhosis - complications; Liver Cirrhosis - diagnosis; Liver Cirrhosis - genetics; Liver diseases; Male; Medical records; Medical schools; Medicine; Medicine and health sciences; Middle Aged; Pathology; Patients; Phospholipase; Platelets; Polymorphism, Single Nucleotide; Prognosis; Risk; Signal transduction; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Surgery; Viruses; Vital signs; New York; United States > US; Massachusetts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0114747

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.