CYP3A4 and CYP3A5 genotypes, haplotypes, and risk of prostate cancer.

Previous case-only studies have shown that men with the CYP3A41B promoter variant are at an increased risk of developing more aggressive forms of prostate cancer. However, no changes in CYP3A4 activity have been found in CYP3A41B carriers, suggesting that its association with disease may simply reflect linkage disequilibrium with another functional variant. CYP3A5 is located within 200 kb of CYP3A4, and a variant in CYP3A5 (1/3) correlates with function of the CYP3A5 enzyme. In this study, the potential effect of CYP3A41B and CYP3A51 on prostate cancer risk and aggressiveness were evaluated in a family-based case-control population. The CYP3A41B variant was positively associated with prostate cancer among Caucasians with more aggressive disease [odds ratio (OR), 1.91; 95% confidence interval (CI), 1.02-3.57; P=0.04], and inversely associated with risk among Caucasians with less aggressive disease (OR, 0.08; 95% CI, 0.01-0.49; P=0.006) and men with an age of diagnosis <63 (OR, 0.51; 95% CI, 0.26-1.00; P=0.05). The CYP3A51 variant was inversely associated with prostate cancer, especially among Caucasians with less aggressive disease (OR, 0.42; 95% CI, 0.22-0.78; P=0.006). As expected based on these genotype-level results, the CYP3A41B/CYP3A53 haplotype was positively associated with disease (OR, 2.91; 95% CI, 1.36-6.23; P=0.006), and the CYP3A41B/CYP3A51 haplotype was inversely associated with risk among Caucasians with less aggressive disease (OR, 0.07; 95% CI, 0.01-0.51; P=0.009). These findings suggest that the CYP3A4 and CYP3A5 variants, or other alleles on the haplotypes they help distinguish, are associated with prostate cancer risk and aggressiveness.