Original Article

Digestive Diseases and Sciences

, Volume 57, Issue 8, pp 2213-2221

First online:

The Association of Genetic Variants with Hepatic Steatosis in Patients with Genotype 1 Chronic Hepatitis C Infection

  • Paul J. ClarkAffiliated withDuke Clinical Research Institute, Duke UniversityKirby Institute for Infection and Immunity in Society, University of New South Wales Email author 
  • , Alexander J. ThompsonAffiliated withDuke Clinical Research Institute, Duke University
  • , Qianqian ZhuAffiliated withCenter for Human Genome Variation, Duke University
  • , David M. VockAffiliated withDuke Clinical Research Institute, Duke University
  • , Mingfu ZhuAffiliated withCenter for Human Genome Variation, Duke University
  • , Keyur PatelAffiliated withDuke Clinical Research Institute, Duke University
  • , Stephen A. HarrisonAffiliated withBrooke Army Medical Center
  • , Susanna NaggieAffiliated withDuke Clinical Research Institute, Duke University
  • , Dongliang GeAffiliated withCenter for Human Genome Variation, Duke University
    • , Hans L. TillmannAffiliated withDuke Clinical Research Institute, Duke University
    • , Thomas J. UrbanAffiliated withCenter for Human Genome Variation, Duke University
    • , Kevin ShiannaAffiliated withCenter for Human Genome Variation, Duke University
    • , Jacques FellayAffiliated withCenter for Human Genome Variation, Duke University
    • , Zachary GoodmanAffiliated withArmed Forces Institute of Pathology
    • , Stephanie NovielloAffiliated withSchering-Plough Corporation (now Merck & Co., Inc.)
    • , Lisa D. PediconeAffiliated withSchering-Plough Corporation (now Merck & Co., Inc.)
    • , Nezam AfdhalAffiliated withBeth Israel Deaconess Medical Center
    • , Mark SulkowskiAffiliated withJohns Hopkins University School of Medicine
    • , Janice K. AlbrechtAffiliated withSchering-Plough Corporation (now Merck & Co., Inc.)
    • , David B. GoldsteinAffiliated withCenter for Human Genome Variation, Duke University
    • , John G. McHutchisonAffiliated withDuke Clinical Research Institute, Duke University
    • , Andrew J. MuirAffiliated withDuke Clinical Research Institute, Duke University

Rent the article at a discount

Rent now

* Final gross prices may vary according to local VAT.

Get Access

Abstract

Background

Single-nucleotide polymorphisms (SNPs) in the IL28B and PNPLA3 gene regions have been associated with hepatic steatosis in genotype 1 (G1) chronic HCV infection but their clinical impacts remain to be determined.

Aim

We sought to validate these associations and to explore their impact on treatment response to peginterferon and ribavirin therapy.

Methods

A total of 972 G1 HCV-infected Caucasian patients were genotyped for the SNPs rs12979860 (IL28B) and rs2896019 (PNPLA3). Multivariable analysis tested IL28B and PNPLA3 for association with the presence of any steatosis (>0 %); clinically significant steatosis (>5 %); steatosis severity (grade 0–3/4); and the interacting associations of the SNPs and hepatic steatosis to sustained viral response (SVR).

Results

IL28B and PNPLA3 polymorphisms were associated with the presence of any steatosis (rs12979860, p = 1.87 × 10−7; rs2896019, p = 7.56 × 10−4); clinically significant steatosis (rs12979860, p = 1.82 × 10−3; rs2896019, p = 1.27 × 10−4); and steatosis severity (rs12979860, p = 2.05 × 10−8; rs2896019, p = 2.62 × 10−6). Obesity, hypertriglyceridemia, hyperglycemia, liver fibrosis, and liver inflammation were all independently associated with worse steatosis. Hepatic steatosis was associated with lower SVR, and this effect was attenuated by IL28B. PNPLA3 had no independent association with SVR.

Conclusions

IL28B and PNPLA3 are associated with hepatic steatosis prevalence and severity in Caucasians with G1 HCV, suggesting differing potential genetic risk pathways to steatosis. IL28B attenuates the association between steatosis and SVR. Remediable metabolic risk factors remain important, independently of these polymorphisms, and remain key therapeutic goals to achieve better outcomes for patients with HCV-associated hepatic steatosis.

Keywords

Polymorphism, single-nucleotide, SNP IL28B protein, human PNPLA3 protein, human Adiponutrin, human Fatty liver Abdominal obesity metabolic syndrome