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A novel rare mutation, homeobox B13 (HOXB13) G84E, was reported to co-segregate with prostate cancer (PCa) in hereditary PCa families and associate with PCa risk in unrelated cases and controls. In this study, we aim to compare the G84E mutation frequency among subjects of different races/ethnicities from various geographic regions in the world and to assess its risk for developing PCa, in the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial. All the 3508 subjects had initial negative prostate biopsy and were biopsied at Year 2 and 4 for detection of PCa. The G84E mutation was detected only in Caucasians, with the highest carrier frequency in Northern Europe (1.06%), followed by Western Europe (0.60%) and North America (0.31%). No mutation carrier was observed in Southern Europe, Eastern Europe, Latin America, Australia and South Africa. In Caucasians, the G84E mutation frequency was 0.99% and 0.24% in positive and negative biopsy subjects, respectively (P = 0.01). In positive biopsy subjects, the frequency was significantly higher in subjects with a positive family history than those without (4.31% versus 0.34%, P = 0.002). In the 4 year follow-up, the PCa detection rate was 53.8% among the 13 mutation carriers and 22.0% among 3186 non-carriers, relative risk = 2.45 (95% confidence interval: 1.48-4.07). All mutation carriers shared a common haplotype, suggesting a founder effect. In Finland, the G84E mutation was estimated to occur in the year 1792 (95% credible interval: 1735-1831). In conclusion, the G84E mutation of HOXB13, a relatively recent mutation that likely occurred in Northern Europe, significantly increases risk for PCa.

Circulating androgen levels are often used as indicators of physiological or pathological conditions. More than half of the variance for circulating androgen levels is thought to be genetically influenced. A genome-wide association study (GWAS) has identified two loci, SHBG at 17p13 and FAM9B at Xp22, for serum testosterone (T) levels; however, these explain only a small fraction of inter-individual variability. To identify additional genetic determinants of androgen levels, a GWAS of baseline serum T and dihydrotestosterone (DHT) levels was conducted in 3225 men of European ancestry from the REduction by DUtasteride of Prostate Cancer Events (REDUCE) study. Cross-validation was used to confirm the observed associations between the drug (n = 1581) and placebo (n = 1644) groups of REDUCE. In addition to confirming the associations of two known loci with serum T levels (rs727428 in SHBG: P = 1.26 × 10(-12); rs5934505 in FAM9B: P = 1.61 × 10(-8)), we identified a new locus, JMJD1C at 10q21 that was associated with serum T levels at a genome-wide significance level (rs10822184: P = 1.12 × 10(-8)). We also observed that the SHBG locus was associated with serum DHT levels (rs727428: P = 1.47 × 10(-11)). Moreover, two additional variants in SHBG [rs72829446, in strong linkage equilibrium with the missense variant D356N (rs6259), and rs1799941] were also independently associated with circulating androgen levels in a statistical scale. These three loci (JMJD1C, SHBG and FAM9B) were estimated to account for ~5.3 and 4.1% of the variance of serum T and DHT levels. Our findings may provide new insights into the regulation of circulating androgens and potential targets for androgen-based therapy.