Abstract
BackgroundVitamin 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 FindingsAssociations 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/SignificanceOur data suggest a relatively weak but functionally relevant role for vitamin D in the prevention of HCV-related hepatocarcinogenesis.
Highlights
Chronic hepatitis C is associated with important morbidity, resulting in liver cirrhosis and its complications in a significant proportion of infected individuals [1]
We hypothesized that genetic determinants of 25(OH)D3 serum levels may be associated with HCVrelated hepatocellular carcinoma (HCC) if there is a causal relationship between vitamin D metabolism and HCC development in chronic hepatitis C patients
963 and 750 Swiss Hepatitis C Cohort Study (SCCS) patients were eligible to assess the impact of genetic variations in CYP2R1, GC, and DHCR7 on Fibrosis Progression Rate (FPR) and on the outcome of standard treatment with PEG-IFN-a and ribavirin, respectively
Summary
Chronic hepatitis C is associated with important morbidity, resulting in liver cirrhosis and its complications in a significant proportion of infected individuals [1]. Two genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) in the region of DEPDC5 and MICA as susceptibility loci for HCC development in patients with chronic hepatitis C [3,4] These genetic variations were strongly associated with HCV-induced HCC, with potentially important implications for the identification of patients at high risk of developing HCC, it might be challenging to translate these findings into novel therapeutic strategies for HCC. Vitamin D insufficiency is common in different populations worldwide and has been associated with the presence of various types of cancer, including HCC [5,6,7] These observations attracted considerable interest because vitamin D can be supplemented, with only infrequent side-effects and little costs. We 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)
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