Background: V itamin D insufficiency has been associated with the
occurrence of various types of cancer, but causal relationships remain elusive.
Methods: Associations between t he r isk o f HCV-related HCC development
and CYP2R1 , GC, and DHCR7 genotypes, which are genetic determinants of
reduced 25-OH-vitamin D3 (25[OH]D3) serum levels, were determined.
Results: A t otal of 5604 HCV-infected patients, 1279 with a nd 4325 without
progression to HCC, w ere identified. The well-known association between
25(OH)D3 s erum levels and variations in CYP2R1 ( rs1993116, rs10741657),
GC ( rs2282679), a nd DHCR7 ( rs7944926, rs12785878) g enotypes was also
apparent in patients w ith chronic hepatitis C. The same genotypes of t hese
single nucleotide polymorphisms (SNPs), w hich are associated with reduced
25(OH)D3 s erum levels, were significantly associated with HCV-associated
HCC (P=0.07 [OR=1.13] for CYP2R1 , P=0.007 [OR=1.56] for GC, P=0.003
[OR=1.42] for DHCR7; ORs for risk genotypes). In contrast, no association
between t hese genetic variations and the o utcome of antiviral therapy with
pegylated interferon-α and ribavirin ( P>0.2 for e ach SNP) or liver fibrosis
progression rate (P>0.2 for each SNP) was observed, s uggesting a specific
influence o f the genetic d eterminants of 25(OH)D3 s erum levels o n
hepatocarcinogenesis.
Conclusions: Our data suggest a relatively weak but functionally relevant role
for vitamin D in the prevention of HCV-related HCC development. Controlled
clinical trials to assess the benefit of vitamin D supplementation in HCVinfected
patients with advanced liver fibrosis or cirrhosis are warranted.