Prostate Cancer Mortality Associated with Aggregate Polymorphisms in Androgen-Regulating Genes: The Atherosclerosis...

Genetic variations in androgen metabolism may influence prostate cancer (PC) prognosis. Clinical studies consistently linked PC prognosis with four single nucleotide polymorphisms (SNPs) in the critical androgen-regulating genes: 3-beta-hydroxysteroid dehydrogenase (HSD3B1) rs1047303, 5-alpha-reductase 2 (SRD5A2) rs523349, and solute carrier organic ion (SLCO2B1) rs1789693 and rs12422149. We tested the association of four androgen-regulating SNPs, individually and combined, with PC-specific mortality in the ARIC population-based prospective cohort. Men diagnosed with PC (N = 622; 79% White, 21% Black) were followed for death (N = 350) including PC death (N = 74). Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95%CI adjusting for center, age, stage, and grade at diagnosis using separate hazards for races. A priori genetic risk score (GRS) was created as the unweighted sum of risk alleles in the four pre-selected SNPs. The gain-of-function rs1047303C allele was associated PC-specific mortality among men with metastatic PC at diagnosis (HR = 4.89 per risk allele, p = 0.01). Higher GRS was associated with PC-specific mortality (per risk allele: HR = 1.26, p = 0.03). We confirmed that the gain-of-function allele in HSD3B1 rs1047303 is associated with greater PC mortality in men with metastatic disease. Additionally, our findings suggest a cumulative effect of androgen-regulating genes on PC-specific mortality; however, further validation is required.