Genetic Analyses Reveal a Role for Vitamin D Insufficiency in HCV-Associated Hepatocellular Carcinoma Development

<div><p>Background</p><p>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).</p><p>Methodology/Principal Findings</p><p>Associations between <i>CYP2R1</i>, <i>GC</i>, and <i>DHCR7</i> 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 <i>CYP2R1</i> (rs1993116, rs10741657), <i>GC</i> (rs2282679), and <i>DHCR7</i> (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 (<i>P</i> = 0.07 [OR = 1.13, 95% CI = 0.99–1.28] for <i>CYP2R1</i>, <i>P</i> = 0.007 [OR = 1.56, 95% CI = 1.12–2.15] for <i>GC</i>, <i>P</i> = 0.003 [OR = 1.42, 95% CI = 1.13–1.78] for <i>DHCR7</i>; ORs for risk genotypes). In contrast, no association between these genetic variations and liver fibrosis progression rate (<i>P</i>>0.2 for each SNP) or outcome of standard therapy with pegylated interferon-α and ribavirin (<i>P</i>>0.2 for each SNP) was observed, suggesting a specific influence of the genetic determinants of 25(OH)D₃ serum levels on hepatocarcinogenesis.</p><p>Conclusions/Significance</p><p>Our data suggest a relatively weak but functionally relevant role for vitamin D in the prevention of HCV-related hepatocarcinogenesis.</p>