PNPLA3 rs738409 causes steatosis according to viral & IL28B genotypes in hepatitis C

Ann Hepatol. 2014 Jul-Aug;13(4):356-63.

Abstract

Background: Hepatitis C virus (HCV) is associated with a higher prevalence of steatosis compared to the general population.

Aim: Our aim was to assess the impact of PNPLA3 rs738409 G-allele on steatosis in HCV patients.

Material and methods: We included 474 HCV patients treated with peginterferon plus ribavirin. PNPLA3 rs738409 was genotyped and patients were classified according to alleles and genotypes. Steatosis was detected in 46.4% (220/474). Fibrosis was assessed by Scheuer score. Gene expression was analyzed in Huh7.5 and Huh7 cells using Real Time-PCR.

Results: PNPLA3 allele-G was associated with steatosis [54.1% (126/233) vs. 39% (94/241)] (p = 0.0001). In HCV-1, allele-G was related to steatosis [50.6% (82/162) vs. 32.3% (53/164)] (p = 0.001), but did not in HCV-3 [61.9% (26/42) vs. 62% (31/50)] (p = 0.993). PNPLA3 allele-G was associated with steatosis in patients with IL28B-CT/TT [57.7% (82/142) vs. 37.1% (56/151)] (p = 0.0001), but did not in IL28B-CC [47.8% (43/90) vs. 42% (37/88)] (p = 0.442). Independent variables associated with steatosis were: PNPLA3 G-allele [O.R. 1.84 (CI95%: 1.06-3.21); p = 0.007], age [O.R. 1.04 (CI95%: 1.01-1.07); p = 0.017], HCV-genotype 3 [O.R. 2.46 (CI95%: 1.30-4.65); p = 0.006], HOMA > 4 [O.R. 2.72 (CI95%: 1.27-5.82); p = 0.010]. Since PNPLA3 RNA could not be detected on PBMC from HCV patients, an in vitro analysis was performed. Huh7.5 cells infected with JFH1 had a decreased PNPLA3 gene expression (fold inhibition = 3.2 ± 0.2), while Huh7 cells presented increased PNPLA3 gene expression (fold induction = 1.5 ± 0.2).

Conclusion: PNPLA3 allele-G modulated the development of steatosis, particularly in patients with HCV-1 and IL28B-CT/TT genotype, but was not associated with SVR. Metabolic but not viral steatosis seems to be PNPLA3 regulated. Gene interaction may result in differential PNPLA3 gene expression levels in HCV infection.

MeSH terms

  • Adult
  • Antiviral Agents / therapeutic use
  • Cells, Cultured
  • Cohort Studies
  • Cross-Sectional Studies
  • Drug Therapy, Combination
  • Fatty Liver / genetics*
  • Fatty Liver / virology
  • Female
  • Gene Expression Profiling
  • Genotype
  • Hepacivirus / genetics*
  • Hepatitis C, Chronic / drug therapy
  • Hepatitis C, Chronic / genetics*
  • Hepatitis C, Chronic / virology
  • Humans
  • Interferon alpha-2
  • Interferon-alpha / therapeutic use
  • Interferons
  • Interleukins / genetics*
  • Lipase / genetics*
  • Liver / pathology*
  • Male
  • Membrane Proteins / genetics*
  • Middle Aged
  • Polyethylene Glycols / therapeutic use
  • RNA, Viral / genetics*
  • Recombinant Proteins / therapeutic use
  • Ribavirin / therapeutic use
  • Risk Factors
  • Viral Load

Substances

  • Antiviral Agents
  • interferon-lambda, human
  • Interferon alpha-2
  • Interferon-alpha
  • Interleukins
  • Membrane Proteins
  • RNA, Viral
  • Recombinant Proteins
  • Polyethylene Glycols
  • Ribavirin
  • Interferons
  • Lipase
  • adiponutrin, human
  • peginterferon alfa-2b
  • peginterferon alfa-2a