| The biologic activity of vitamin D, mediated by the vitamin D receptor (VDR), may affect risk of prostate cancer (PCa) onset and progression. This genetic association study looked at relationships between PCa and VDR gene polymorphisms and haplotypes in a multi-ethnic cohort [non-Hispanic White (NHW), Hispanic White (HW), and African American (AA)]. Seven polymorphisms (CDX2, FokI, BsmI, Tru9I, ApaI, TaqI, a Poly-A repeat) were genotyped in 482 cases and 1,005 controls (60% NHW, 26% HW, 14% AA) from south Texas. Cases had biopsy-confirmed PCa; controls had normal screening exams (PSA < 2.5 ng/ml). Associations were found between PCa and BsmI, ApaI, and TaqI, but only in HW men heterozygous for the risk allele. HW men, however, with the CDX2 GG genotype had more than twice the risk for higher Gleason scores (vs. AG/AA, OR = 2.33, 1.23, 4.42). Common haplotypes were determined using standard linkage disequilibrium techniques. Risk haplotypes were estimated at the individual level using men homozygous for each of the haplotype alleles. The 3' end BsmI, Tru9I, ApaI, Taq I, and Poly-A (HA1) haplotype was inversely associated with PCa among HW men (OR = 0.49, 95%CI: 0.27, 0.89). The HB1 haplotype, that adds CDX2 to HA1, was inversely associated with cancer in NEW men (OR = 0.57, 0.38, 0.86). Gleason score is an important predictor of PCa progression. In NHW men, both haplotypes were inversely associated with higher Gleason scores (OR = 0.68, 0.47, 0.99; OR = 0.53, 0.34, 0.83, for H A1 and HB1, respectively). Interactions were found with FokI and the V89L polymorphism in the SRD5A2, a gene involved with testosterone metabolism. FokI alone was not associated with PCa. When stratified by V89L VV genotype, Fok I (TT/CT vs. CC) was associated with almost twice the risk for PCa (OR = 1.91, 1.21, 3.01). The inverse association of the H B1 haplotype was further strengthened in the V89L LL/LV genotypes. This thesis demonstrated that characterizing VDR haplotypes may add substantially to the approach of assessing genetic polymorphisms in the investigation of genetic risk for PCa, cancer progression, and interactions with other genes. The association of VDR polymorphisms with PCa may be better understood when examined together with genes along related risk pathways. |
