Baseline vitamin D status, genetic susceptibility, and the risk of incident hepatocellular carcinoma.

High vitamin D concentrations may reduce the incidence of hepatocellular carcinoma (HCC), though results have been inconsistent. This study aimed to evaluate the association between serum 25-hydroxyvitamin D (25(OH)D) levels and HCC, and to assess whether the genetic risk of HCC modifies this association. The prospective cohort study involved 447,028 individuals free of liver diseases in the UK Biobank. Serum 25(OH)D concentrations were measured by the chemiluminescent immunoassay method. The associations were evaluated using the Cox proportional hazards model, estimating hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). Additionally, the weighted polygenic risk score (PRS) of HCC was calculated by 5 SNPs reported in a previously published genome-wide association study (GWAS). During a median follow-up of 12.5 years, 377 cases of HCC were documented. Compared to the lowest quartile of serum 25(OH)D, the HR (95% CI) of HCC was 0.52 (0.38-0.70) in the highest quartile. Per 10 nmol/L increase in serum 25(OH)D was associated with a 12% lower HCC risk (95% CI: 7%-17%). A joint effect of genetic and serum 25(OH)D on HCC risk was observed. Those with low genetic risk of HCC and the highest serum 25(OH)D had a HR (95% CI) of 0.22 (0.11-0.45) compared to those with high genetic risk of HCC and the lowest 25(OH)D serum levels, but there was no interaction (p interaction = 0.529). Our findings emphasize that higher serum 25(OH)D levels are linked to a reduced risk of HCC, indicating the potential role of 25(OH)D in the primary prevention of HCC.