title: Host genetics predict clinical deterioration in HCV-related cirrhosis.
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.
authors.affiliation: Liver Center, Gastrointestinal Division, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Lindsay Y
authors.initials: LY
authors.lastname: King
authors.affiliation: Liver Center, Gastrointestinal Division, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Kara B
authors.initials: KB
authors.lastname: Johnson
authors.affiliation: Biostatistics Center, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Lan
authors.initials: L
authors.lastname: Wei
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gudewicz
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Yujin
authors.initials: Y
authors.lastname: Hoshida
authors.affiliation: Liver Center, Gastrointestinal Division, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Corey
authors.affiliation: Department of Medicine, North Shore Medical Center, Salem, Massachusetts, United States of America.
authors.forename: Tokunbo
authors.initials: T
authors.lastname: Ajayi
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Nneka
authors.initials: N
authors.lastname: Ufere
authors.affiliation: Liver Center, Gastrointestinal Division, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Harvard Medical School, Boston, Massachusetts, United States of America; Inserm U1110, University of Strasbourg, Strasbourg, France.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Baumert
authors.affiliation: Liver Center, Gastrointestinal Division, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chan
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Tanabe
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Bryan C
authors.initials: BC
authors.lastname: Fuchs
authors.affiliation: Liver Center, Gastrointestinal Division, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Chung
mesh_terms: D018450:Disease Progression; D005260:Female; D060005:Genotyping Techniques; D019698:Hepatitis C, Chronic / Q000150:complications*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008103:Liver Cirrhosis / Q000150:complications / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis