Pleiotropy between genetic markers of obesity and risk of prostate cancer.

BACKGROUND To address inconsistent findings of obesity and prostate cancer risk, we analyzed the association between prostate cancer and genetic markers of obesity and metabolism. METHODS Analyses included 176,520 single-nucleotide polymorphisms (SNP) associated with 23 metabolic traits. We examined the association between SNPs and prostate cancer in 871 cases and 906 controls, including 427 high-grade cases with Gleason ≥ 7. Genetic risk scores (GRS) for body mass index (BMI) and waist-to-hip ratio (WHR) were also created by summing alleles associated with increasing BMI or WHR. RESULTS Prostate cancer was associated with five loci, including cyclin M2, with P values less than 1 × 10(-4). In addition, the WHR GRS was associated with high-grade prostate cancer versus controls [OR, 1.05; 95% confidence interval (CI), 1.00-1.11; P = 0.048] and high-grade prostate cancer versus low-grade prostate cancer (OR, 1.07; 95% CI, 1.01-1.13; P = 0.03). None of these findings exceeds the threshold for significance after correction for multiple testing. CONCLUSIONS Variants in genes known to be associated with metabolism and obesity may be associated with prostate cancer. We show evidence for pleiotropy between WHR GRS and prostate cancer grade. This finding is consistent with the function of several WHR genes and previously described relationships with cancer traits. IMPACT Limitations in standard obesity measures suggest alternative characterizations of obesity may be needed to understand the role of metabolic dysregulation in prostate cancer. The underlying genetics of WHR or other Metabochip SNPs, while not statistically significant beyond multiple testing thresholds within our sample size, support the metabolic hypothesis of prostate carcinogenesis and warrant further investigation in independent samples.