Hormonal markers and hepatitis B virus-related hepatocellular carcinoma risk: a nested case-control study among men.
The incidence of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is higher in men than in women. We examined whether endogenous sex hormone levels or hormone-related factors might affect the risk of HCC in men. Baseline blood samples were collected from 4841 male Taiwanese HBV carriers without diagnosed HCC from 1988 through 1992. Plasma testosterone and estradiol levels and genetic polymorphisms in the hormone-related factors cytochrome P450c17 alpha (CYP17, A1 versus A2 alleles), steroid 5 alpha-reductase type II (SRD5A2, valine [V] versus leucine [L] alleles), and androgen receptor (AR, number of CAG repeats) were assayed among 119 case patients who were diagnosed with HCC during 12 years of follow-up and 238 control subjects. All statistical tests were two-sided. The risk of HCC increased with increasing concentrations of testosterone (odds ratio [OR](highest versus lowest tertile) = 2.97; 95% confidence interval [CI] = 1.54 to 5.70; P(trend) <.001) and with increasing number of the V allele of the SRD5A2 V89L polymorphism (OR(VV versus LL genotype) = 2.47; 95% CI = 1.21 to 5.03; P(trend) =.011). Fewer AR gene CAG repeats (<23 repeats) were associated with a 1.64-fold (95% CI = 1.00 to 2.68) increased risk of HCC. Although the CYP17 genotype alone did not increase the risk of HCC, there was evidence of a gene-gene interaction, because the CYP17 A1 allele statistically significantly increased the risk of HCC in the presence of fewer AR gene CAG repeats (OR = 2.51; 95% CI = 1.06 to 5.94). We found a similar interaction between the SRD5A2 VV genotype and fewer AR gene CAG repeats (OR = 5.58; 95% CI = 1.86 to 16.71). Body mass index (BMI) modified the association of HCC with testosterone and SRD5A2 genotype; in men with low BMI, multivariate-adjusted ORs for the highest tertile of testosterone versus the lowest and the SRD5A2 VV genotype versus the LL genotype were 7.63 (95% CI = 2.13 to 27.27) and 8.64 (95% CI = 2.75 to 27.14), respectively. No clear associations were found between estradiol or testosterone-to-estradiol ratio and HCC. Pathways involving androgen signaling may affect the risk of HBV-related HCC among men.