title: CYP3A4, CYP3A5, and CYP3A43 genotypes and haplotypes in the etiology and severity of prostate cancer.
abstract: The CYP3A genes reside on chromosome 7q21 in a multigene cluster. The enzyme products of CYP3A4 and CYP3A43 are involved in testosterone metabolism. CYP3A4 and CYP3A5 have been associated previously with prostate cancer occurrence and severity. To comprehensively examine the effects of these genes on prostate cancer occurrence and severity, we studied 622 incident prostate cancer cases and 396 controls. Substantial and race-specific linkage disequilibrium was observed between CYP3A4 and CYP3A5 in both races but not between other pairs of loci. We found no association of CYP3A5 genotypes with prostate cancer or disease severity. CYP3A43*3 was associated with family history-positive prostate cancer (age- and race-adjusted odds ratio = 5.86, 95% confidence interval, 1.10-31.16). CYP3A4*1B was associated inversely with the probability of having prostate cancer in Caucasians (age-adjusted odds ratio = 0.54, 95% confidence interval, 0.32-0.94). We also observed significant interactions among these loci associated with prostate cancer occurrence and severity. There were statistically significant differences in haplotype frequencies involving these three genes in high-stage cases (P < 0.05) compared with controls. The observation that CYP3A4 and CYP3A43 were associated with prostate cancer, are not in linkage equilibrium, and are both involved in testosterone metabolism, suggest that both CYP3A4*1B and CYP3A43*3 may influence the probability of having prostate cancer and disease severity.
authors.affiliation: Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6021, USA. czeigler@cceb.med.upenn.edu
authors.forename: Charnita
authors.initials: C
authors.lastname: Zeigler-Johnson
authors.forename: Tara
authors.initials: T
authors.lastname: Friebel
authors.forename: Amy H
authors.initials: AH
authors.lastname: Walker
authors.forename: Yiting
authors.initials: Y
authors.lastname: Wang
authors.forename: Elaine
authors.initials: E
authors.lastname: Spangler
authors.forename: Saarene
authors.initials: S
authors.lastname: Panossian
authors.forename: Margerie
authors.initials: M
authors.lastname: Patacsil
authors.forename: Richard
authors.initials: R
authors.lastname: Aplenc
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Wein
authors.forename: S Bruce
authors.initials: SB
authors.lastname: Malkowicz
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Rebbeck
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001483:Base Sequence; D016022:Case-Control Studies; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D017931:DNA Primers; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D012720:Severity of Illness Index
chemical_list: D017931:DNA Primers; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C104464:CYP3A protein, human; C422408:CYP3A43 protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human