Genetic analyses reveal a role for vitamin D insufficiency in HCV-associated hepatocellular carcinoma development

PLoS One. 2013 May 29;8(5):e64053. doi: 10.1371/journal.pone.0064053. Print 2013.

Abstract

Background: Vitamin D insufficiency has been associated with the occurrence of various types of cancer, but causal relationships remain elusive. We therefore aimed to determine the relationship between genetic determinants of vitamin D serum levels and the risk of developing hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC).

Methodology/principal findings: Associations between CYP2R1, GC, and DHCR7 genotypes that are determinants of reduced 25-hydroxyvitamin D (25[OH]D3) serum levels and the risk of HCV-related HCC development were investigated for 1279 chronic hepatitis C patients with HCC and 4325 without HCC, respectively. The well-known associations between CYP2R1 (rs1993116, rs10741657), GC (rs2282679), and DHCR7 (rs7944926, rs12785878) genotypes and 25(OH)D3 serum levels were also apparent in patients with chronic hepatitis C. The same genotypes of these single nucleotide polymorphisms (SNPs) that are associated with reduced 25(OH)D3 serum levels were found to be associated with HCV-related HCC (P = 0.07 [OR = 1.13, 95% CI = 0.99-1.28] for CYP2R1, P = 0.007 [OR = 1.56, 95% CI = 1.12-2.15] for GC, P = 0.003 [OR = 1.42, 95% CI = 1.13-1.78] for DHCR7; ORs for risk genotypes). In contrast, no association between these genetic variations and liver fibrosis progression rate (P>0.2 for each SNP) or outcome of standard therapy with pegylated interferon-α and ribavirin (P>0.2 for each SNP) was observed, suggesting a specific influence of the genetic determinants of 25(OH)D3 serum levels on hepatocarcinogenesis.

Conclusions/significance: Our data suggest a relatively weak but functionally relevant role for vitamin D in the prevention of HCV-related hepatocarcinogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antiviral Agents / therapeutic use
  • Carcinoma, Hepatocellular / complications
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / virology
  • Child
  • Cholestanetriol 26-Monooxygenase / genetics
  • Cohort Studies
  • Cytochrome P450 Family 2
  • Female
  • Gene Frequency
  • Genotype
  • Hepacivirus*
  • Hepatitis C, Chronic / complications
  • Hepatitis C, Chronic / drug therapy
  • Hepatitis C, Chronic / genetics*
  • Humans
  • Linkage Disequilibrium
  • Liver Neoplasms / complications
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / virology
  • Male
  • Middle Aged
  • Oxidoreductases Acting on CH-CH Group Donors / genetics
  • Polymorphism, Single Nucleotide
  • Vitamin D / analogs & derivatives
  • Vitamin D / blood
  • Vitamin D Deficiency / blood
  • Vitamin D Deficiency / genetics*
  • Vitamin D-Binding Protein / genetics
  • Young Adult

Substances

  • Antiviral Agents
  • Vitamin D-Binding Protein
  • Vitamin D
  • 25-hydroxyvitamin D
  • Cytochrome P450 Family 2
  • CYP2R1 protein, human
  • Cholestanetriol 26-Monooxygenase
  • Oxidoreductases Acting on CH-CH Group Donors
  • 7-dehydrocholesterol reductase

Grant support

This work was supported by the Swiss National Science Foundation (3100A0-122447 to DM, 32003B-127613 to PYB as well as 3347C0-108782/1 and 33CSC0-108782/2 to the SCCS), the Leenaards Foundation (to PYB), the European Community's FP7 (260844, to PYB), and the Santos-Suarez Foundation (to PYB). CML is supported by the Deutsche Forschungsgemeinschaft (LA 2806/2-1), by the Johann Wolfgang Goethe University (Förderung Nachwuchsforscher 2012), and by the Deutsche Leberstifung (S163/10087/2012). TB was supported by the German Competence Network for Viral Hepatitis (Hep-Net), funded by the German Ministry of Education and Research (BMBF, Grant No. 01 KI 0437, Project No. 10.1.3 and Core Project No. 10.1 Genetic host factors in viral hepatitis and Genetic Epidemiology Group in viral hepatitis), and by the BMBF Project: Host and viral determinants for susceptibility and resistance to hepatitis C virus infection (Grant No. 01KI0787). HDN and US were funded by the Deutsche Krebshilfe (107865). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.