In regression models, SNPs were analyzed using an additive model (none, one or two copies of the minor allele were coded 0, 1 and 2, respectively, assuming greater effect with increased copy number of the minor allele), unless otherwise specified. Results Patient Characteristics Out of a total of 3,648 patients enrolled in the SCCS, 1661 patients read me with known duration of infection were included in the primary analyses of the present study based on the selection criteria defined above. Out of these patients, 50 individuals developed HCC. The three additional cohorts included a total number of 1229 patients with chronic hepatitis C and HCC, as well as 2714 patients with chronic hepatitis C without HCC at the time of the analysis. Thus, the primary analysis of the present study included 1279 chronic hepatitis C patients with HCC and 4325 without HCC.

Baseline characteristics of these patients are summarized in Table 1. Table 1 Baseline characteristics of included patients. In addition, 963 and 750 SCCS patients were eligible to assess the impact of genetic variations in CYP2R1, GC, and DHCR7 on FPR and on the outcome of standard treatment with PEG-IFN-�� and ribavirin, respectively. Serum levels of 25(OH)D3 were only available in a minority for 496 SCCS patients. Association between Genetic Determinants of 25(OH)D3 Serum Levels and HCV-induced HCC Median 25(OH)D3 serum levels in patients with chronic hepatitis C with or without HCC in the SCCS were 12.7 and 14.3 ng/mL, (range 4.9�C40.9 and 3.9�C76.9) respectively (P=0.19, values available in 496 patients).

However, 25(OH)D3 serum levels fluctuate strongly during seasons and as a consequence of numerous circumstances such as exposure to sunlight, nutrition, accompanying diseases, vitamin D supplementation and others. We therefore believe that genetic variants in CYP2R1, GC, and DHCR7, with their proven impact on 25(OH)D3 serum levels, should be used as surrogates for long-term 25(OH)D3 serum levels. Hence, we genotyped the most relevant tagging SNPs for these loci (rs1993116/rs10741657 for CYP2R1, rs2282679 for GC, rs7944926/rs12785878 for DHCR7; data on LD and Hardy Weinberg equilibrium for these SNPs are shown in Table S1), and assessed their association with HCV-related HCC. Table 2 summarizes results of the primary analysis for associations between HCV-related HCC and genetic variations Anacetrapib in CYP2R1, GC, and DHCR7 in the four independent patient cohorts. In the combined analyses of these cohorts, the strongest association with HCV-induced HCC was found for GC (P=0.007, OR=1.56, 95% CI=1.12�C2.15) and DHCR7 (P=0.003, OR=1.42, 95% CI=1.13�C1.78), whereas CYP2R1 was almost significantly associated with HCV-induced HCC (P=0.07, OR=1.13, 95% CI=0.99�C1.28).