Type 2 Diabetes-Related Variants Influence the Risk of Developing Prostate Cancer: A Population-Based Case-Control Study and Meta-Analysis

In this study, we have evaluated whether 57 genome-wide association studies (GWAS)-identified common variants for type 2 diabetes (T2D) influence the risk of developing prostate cancer (PCa) in a population of 304 Caucasian PCa patients and 686 controls. The association of selected single nucleotide polymorphisms (SNPs) with the risk of PCa was validated through meta-analysis of our data with those from the UKBiobank and FinnGen cohorts, but also previously published genetic studies. We also evaluated whether T2D SNPs associated with PCa risk could influence host immune responses by analysing their correlation with absolute numbers of 91 blood-derived cell populations and circulating levels of 103 immunological proteins and 7 steroid hormones. We also investigated the correlation of the most interesting SNPs with cytokine levels after in vitro stimulation of whole blood, peripheral mononuclear cells (PBMCs), and monocyte-derived macrophages with LPS, PHA, Pam3Cys, and Staphylococcus Aureus. The meta-analysis of our data with those from six large cohorts confirmed that each copy of the FTO_rs9939609A, HNF1B_rs7501939T, HNF1B_rs757210T, HNF1B_rs4430796G, and JAZF1_rs10486567A alleles significantly decreased risk of developing PCa (p = 3.70 × 10^-5, p = 9.39 × 10^-54, p = 5.04 × 10^-54, p = 1.19 × 10^-71, and p = 1.66 × 10^-18, respectively). Although it was not statistically significant after correction for multiple testing, we also found that the NOTCH2_rs10923931T and RBMS1_rs7593730 SNPs associated with the risk of developing PCa (p = 8.49 × 10^-4 and 0.004). Interestingly, we found that the protective effect attributed to the HFN1B locus could be mediated by the SULT1A1 protein (p = 0.00030), an arylsulfotransferase that catalyzes the sulfate conjugation of many hormones, neurotransmitters, drugs, and xenobiotic compounds. In addition to these results, eQTL analysis revealed that the HNF1B_rs7501939, HNF1B_rs757210, HNF1B_rs4430796, NOTCH2_rs10923931, and RBMS1_rs7593730 SNPs influence the risk of PCa through the modulation of mRNA levels of their respective genes in whole blood and/or liver. These results confirm that functional TD2-related variants influence the risk of developing PCa, but also highlight the need of additional experiments to validate our functional results in a tumoral tissue context.