Common genetic variation of the calcium-sensing receptor and lethal prostate cancer risk

Abstract

Background: Bony metastases cause substantial morbidity and mortality from prostate cancer (PCa). The calcium-sensing receptor (CaSR) is expressed on prostate tumors and may participate in bone metastases development. We assessed whether (i) common genetic variation in CaSR was associated with PCa risk and (ii) these associations varied by calcium intake or plasma 25-hydroxyvitamin D [25(OH)D] levels. Methods: We included 1,193 PCa cases and 1,244 controls nested in the prospective Health Professionals Follow-up Study (1993-2004). We genotyped 18 CaSR single-nucleotide polymorphism (SNPs) to capture common variation. The main outcome was risk of lethal PCa (n = 113); secondary outcomes were overall (n = 1,193) and high-grade PCa (n = 225). We used the kernel machine approach to conduct a gene-level multi-marker analysis and unconditional logistic regression to compute per-allele ORs and 95% confidence intervals (CI) for individual SNPs. Results: The joint association of SNPs in CaSR was significant for lethal PCa (P = 0.04); this association was stronger in those with low 25(OH)D (P = 0.009).Noindividual SNPs were associated after considering multiple testing; three SNPs were nominally associated (P < 0.05) with lethal PCa with ORs (95% CI) of 0.65(0.42-0.99): rs6438705; 0.65(0.47-0.89): rs13083990; and 1.55(1.09-2.20): rs2270916. The three nonsynonymous SNPs (rs1801725, rs1042636, and rs1801726) were not significantly associated; however, the association for rs1801725 was stronger in men with low 25(OH)D [OR(95%CI): 0.54(0.31-0.95)]. There were no significant associations with overall or high-grade PCa. Conclusions: Our findings indicate that CaSR may be involved in PCa progression. Impact: Further studies investigating potential mechanisms for CaSR and PCa, including bone remodeling and metastases are warranted. ©2012 AACR.