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 fourfold 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.