Zeigler-Johnson Charnita, Friebel Tara, Walker Amy H, Wang Yiting, Spangler Elaine, Panossian Saarene, Patacsil Margerie, Aplenc Richard, Wein Alan J, Malkowicz S Bruce, Rebbeck Timothy R
Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6021, USA.
Cancer Res. 2004 Nov 15;64(22):8461-7. doi: 10.1158/0008-5472.CAN-04-1651.
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. CYP3A433 was associated with family history-positive prostate cancer (age- and race-adjusted odds ratio = 5.86, 95% confidence interval, 1.10-31.16). CYP3A41B 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 CYP3A41B and CYP3A433 may influence the probability of having prostate cancer and disease severity.
细胞色素P450 3A（CYP3A）基因位于7号染色体q21的一个多基因簇中。CYP3A4和CYP3A43的酶产物参与睾酮代谢。CYP3A4和CYP3A5先前已被认为与前列腺癌的发生和严重程度有关。为了全面研究这些基因对前列腺癌发生和严重程度的影响，我们研究了622例新发前列腺癌病例和396名对照。在两个种族中，CYP3A4和CYP3A5之间均观察到显著的种族特异性连锁不平衡，但其他基因座对之间未观察到。我们发现CYP3A5基因型与前列腺癌或疾病严重程度无关。CYP3A433与家族史阳性的前列腺癌相关（年龄和种族调整后的优势比=5.86，95%置信区间，1.10-31.16）。CYP3A41B与白种人患前列腺癌的概率呈负相关（年龄调整后的优势比=0.54，95%置信区间，0.32-0.94）。我们还观察到这些与前列腺癌发生和严重程度相关的基因座之间存在显著的相互作用。与对照组相比，在晚期病例中，涉及这三个基因的单倍型频率存在统计学显著差异（P<0.05）。CYP3A4和CYP3A43与前列腺癌相关、不处于连锁平衡状态且均参与睾酮代谢，这一观察结果表明，CYP3A41B和CYP3A433都可能影响患前列腺癌的概率和疾病严重程度。
