Digestive Diseases and Sciences

, Volume 57, Issue 8, pp 2213–2221

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

Authors

    • Duke Clinical Research InstituteDuke University
    • Kirby Institute for Infection and Immunity in SocietyUniversity of New South Wales
  • Alexander J. Thompson
    • Duke Clinical Research InstituteDuke University
  • Qianqian Zhu
    • Center for Human Genome VariationDuke University
  • David M. Vock
    • Duke Clinical Research InstituteDuke University
  • Mingfu Zhu
    • Center for Human Genome VariationDuke University
  • Keyur Patel
    • Duke Clinical Research InstituteDuke University
  • Stephen A. Harrison
    • Brooke Army Medical Center
  • Susanna Naggie
    • Duke Clinical Research InstituteDuke University
  • Dongliang Ge
    • Center for Human Genome VariationDuke University
  • Hans L. Tillmann
    • Duke Clinical Research InstituteDuke University
  • Thomas J. Urban
    • Center for Human Genome VariationDuke University
  • Kevin Shianna
    • Center for Human Genome VariationDuke University
  • Jacques Fellay
    • Center for Human Genome VariationDuke University
  • Zachary Goodman
    • Armed Forces Institute of Pathology
  • Stephanie Noviello
    • Schering-Plough Corporation (now Merck & Co., Inc.)
  • Lisa D. Pedicone
    • Schering-Plough Corporation (now Merck & Co., Inc.)
  • Nezam Afdhal
    • Beth Israel Deaconess Medical Center
  • Mark Sulkowski
    • Johns Hopkins University School of Medicine
  • Janice K. Albrecht
    • Schering-Plough Corporation (now Merck & Co., Inc.)
  • David B. Goldstein
    • Center for Human Genome VariationDuke University
  • John G. McHutchison
    • Duke Clinical Research InstituteDuke University
  • Andrew J. Muir
    • Duke Clinical Research InstituteDuke University
Original Article

DOI: 10.1007/s10620-012-2171-y

Cite this article as:
Clark, P.J., Thompson, A.J., Zhu, Q. et al. Dig Dis Sci (2012) 57: 2213. doi:10.1007/s10620-012-2171-y

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, SNPIL28B protein, humanPNPLA3 protein, humanAdiponutrin, humanFatty liverAbdominal obesity metabolic syndrome

Abbreviations

HCV

Hepatitis C virus

SNP

Single-nucleotide polymorphism

IL28B

Interleukin 28B

PNPLA3

Patatin-like phospholipase domain-containing 3

G1

Genotype 1

MVA

Multivariable analysis

SVR

Sustained viral response

NAFLD

Non-alcoholic fatty liver disease

Supplementary material

10620_2012_2171_MOESM1_ESM.doc (89 kb)
Supplementary material 1 (DOC 89 kb)

Copyright information

© Springer Science+Business Media, LLC 2012