Androgen-receptor gene CAG repeats, plasma testosterone levels, and risk of hepatitis B-related hepatocellular carcinoma

Background: Worldwide, hepatocellular carcinoma (HCC) is more prevalent in men than in women, suggesting that sex hormones and/or X-chromosome-linked genes may be involved in hepatocarcinogenesis. We investigated the association of a trinucleotide (CAG) repeat in the androgen receptor (AR) gene (located on the X chromosome) termed "AR-CAG repeats," levels of plasma testosterone, and the risk of HCC in Taiwanese men. Chronic hepatitis B virus (HBV) infection, which is associated with risk of HCC, is hyperendemic in Taiwan. Methods: We compared the number of AR-CAG repeats in 285 HBV carriers with HCC and in 349 HBV carriers without HCC. We also conducted a nested case-control study on participants in a cohort study. Blood was collected prospectively from 110 case patients and 239 control subjects and was used to determine the number of AR-CAG repeats and plasma testosterone level. All statistical tests were two-sided. Results: The overall odds ratio (OR) for HCC was 1.72 (95% confidence interval [CI] = 1.03-2.89) for HBV carriers with 20 or fewer AR-CAG repeats compared with those with more than 24 repeats. This association was observed only in patients with late-onset HCC (OR = 2.37; 95% CI = 1.28-4.38). In the nested case-control study, HBV carriers in the highest tertile of testosterone levels had a statistically significantly increased risk of HCC (OR = 2.06; 95% CI = 1.14-3.70) compared with those in the lowest tertile. Elevated testosterone was more strongly associated with early-onset (OR = 4.67;95% CI = 1.41-15.38) than late-onset disease. HBV carriers with 20 or fewer AR-CAG repeats and higher testosterone levels had a four-fold increase in HCC risk compared with those with more than 24 repeats and testosterone levels in the lowest tertile. Conclusions: Higher levels of androgen signaling, reflected by higher testosterone levels and 20 or fewer AR-CAG repeats, may be associated with an increased risk of HBV-related HCC in men.