已经发现了超过200个与前列腺癌风险独立相关的遗传变异。研究发现农民与特定有机磷（甲基对硫磷、磷溴乙烷、马拉松、介绍英文）和有机氯（奥尔津、哥乙烯）杀虫剂接触有关，也观察到前列腺癌风险增加。在农业卫生研究队列中，我们研究了农药、已知前列腺癌易感位点和前列腺癌风险的联合关系，其中包括1,162例前列腺癌患者（其中588例为侵袭性）和2,206例配对控制。根据256个已知前列腺癌风险变异生成的多基因风险评分（PRS），将终身农药使用史与之结合。逻辑回归模型估计了农药、PRS和256个单个遗传变异与总前列腺癌和侵袭性前列腺癌风险的联合关系。似然比检验评估了其是否为乘法交互作用。我们观察到氧化磷与PRS的永久使用与总前列腺癌和侵袭性前列腺癌风险的关系之间的相互作用。与参考组（从未使用，PRS低于中位数）相比，曾经使用氧化磷和PRS高于中位数的男性患上总前列腺癌（OR 1.35 [1.06-1.73]，p交互作用=0.03）和侵袭性前列腺癌（OR 1.49 [1.09-2.04]，p交互作用=0.19）的风险升高。还表明，在与DNA损伤响应（CDH3、EMSY基因）相关的区域和与改变雄激素受体驱动的转录程序与前列腺癌相关的变异中，存在农药和个体遗传变异之间的相互作用的迹象。我们的研究提供了证据，表明对于前列腺癌具有更高遗传易感性的男性，如果暴露于农药，可能面临更高的风险，并暗示了农药可能增加前列腺癌风险的潜在机制。版权所有©2023。由Elsevier Inc.出版。

More than 200 genetic variants have been independently associated with prostate cancer risk. Studies among farmers have also observed increased prostate cancer risk associated with exposure to specific organophosphate (fonofos, terbufos, malathion, dimethoate) and organochlorine (aldrin, chlordane) insecticides. We examined the joint associations between these pesticides, established prostate cancer loci, and prostate cancer risk among 1,162 cases (588 aggressive) and 2,206 frequency-matched controls nested in the Agricultural Health Study cohort. History of lifetime pesticide use was combined with a polygenic risk score (PRS) generated using 256 established prostate cancer risk variants. Logistic regression models estimated the joint associations of the pesticides, the PRS, and the 256 individual genetic variants with risk of total and aggressive prostate cancer. Likelihood ratio tests assessed multiplicative interaction. We observed interaction between ever use of fonofos and the PRS in relation to total and aggressive prostate cancer risk. Compared to the reference group (never use, PRS < median), men with ever use of fonofos and PRS > median had elevated risks of total (OR 1.35 [1.06-1.73], p-interaction = 0.03) and aggressive (OR 1.49 [1.09-2.04], p-interaction = 0.19) prostate cancer. There was also suggestion of interaction between pesticides and individual genetic variants occurring in regions associated with DNA damage response (CDH3, EMSY genes) and with variants related to altered androgen receptor-driven transcriptional programs critical for prostate cancer. Our study provides evidence that men with greater genetic susceptibility to prostate cancer may be at higher risk if they are also exposed to pesticides and suggests potential mechanisms by which pesticides may increase prostate cancer risk.Copyright © 2023. Published by Elsevier Inc.