Genetic variation in nucleotide excision repair pathway genes, pesticide exposure and prostate cancer risk
Genetic variation in nucleotide excision repair pathway genes, pesticide exposure and prostate cancer risk
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DOI：
10.1093/carcin/bgr258
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发表时间：
2012-02-01
期刊：
影响因子：
4.7
通讯作者：
Berndt, Sonja I.
中科院分区：
文献类型：
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作者：
Barry, Kathryn Hughes;Koutros, Stella;Berndt, Sonja I.
以前的研究表明，农药施用者和农药制造工人患前列腺癌的风险增加。虽然根本机制尚不清楚，但人类生物监测研究表明，接触农药会增加遗传损害（如染色体畸变）。鉴于核苷酸切除修复（NER）途径修复广泛的DNA损伤，我们评估了农药暴露和324个单核苷酸多态性（SNPs）标记的27个NER基因之间的相互作用776例前列腺癌和1444名男性对照的嵌套病例对照研究的白色农业健康研究农药施用者。我们使用逻辑回归模型和三级农药变量（无/低/高）的似然比检验确定了相互作用P值，该变量基于使用寿命天数加权到强度评分。我们使用错误发现率（FDR）方法对多重比较进行了调整。在FDR < 0.2的17个相互作用中，3个显示前列腺癌风险随着一个基因型组暴露量的增加而单调增加，而在另一组中没有显著相关性。携带ERCC 1 rs 2298881变异A等位基因的男性在高剂量使用与不使用氟氯磷的情况下表现出前列腺癌风险增加[比值比（OR）2.98; 95%置信区间（CI）1.65-5.39; P-相互作用= 3.6 x 10（-4）; FDR校正P = 0.11]。在两个相关的CDK 7 SNPs rs 11744596和rs 2932778（r（2）= 1.0）上携带纯合野生型TT基因型的男性，在高剂量使用克百威与不使用克百威相比，风险增加（rs 11744596的OR 2.01; 95%CI 1.31-3.10; P-相互作用= 7.2 x 10（-4）; FDR校正P = 0.09）。相比之下，我们没有观察到男性与这些基因座的其他基因型之间的关联。虽然需要复制，但我们的研究结果表明NER遗传变异在农药相关前列腺癌风险中的作用。
Previous research demonstrates increased prostate cancer risk for pesticide applicators and pesticide manufacturing workers. Although underlying mechanisms are unknown, human biomonitoring studies indicate increased genetic damage (e.g. chromosomal aberrations) with pesticide exposure. Given that the nucleotide excision repair (NER) pathway repairs a broad range of DNA damage, we evaluated interactions between pesticide exposure and 324 single-nucleotide polymorphisms (SNPs) tagging 27 NER genes among 776 prostate cancer cases and 1444 male controls in a nested case-control study of white Agricultural Health Study pesticide applicators. We determined interaction P values using likelihood ratio tests from logistic regression models and three-level pesticide variables (none/low/high) based on lifetime days of use weighted to an intensity score. We adjusted for multiple comparisons using the false discovery rate (FDR) method. Of the 17 interactions that met FDR < 0.2, 3 displayed a monotonic increase in prostate cancer risk with increasing exposure in one genotype group and no significant association in the other group. Men carrying the variant A allele at ERCC1 rs2298881 exhibited increased prostate cancer risk with high versus no fonofos use [odds ratio (OR) 2.98; 95% confidence interval (CI) 1.65-5.39; P-interact = 3.6 x 10(-4); FDR-adjusted P = 0.11]. Men carrying the homozygous wild-type TT genotype at two correlated CDK7 SNPs, rs11744596 and rs2932778 (r(2) = 1.0), exhibited increased risk with high versus no carbofuran use (OR 2.01; 95% CI 1.31-3.10 for rs11744596; P-interact = 7.2 x 10(-4); FDR-adjusted P = 0.09). In contrast, we did not observe associations among men with other genotypes at these loci. While requiring replication, our findings suggest a role for NER genetic variation in pesticide-associated prostate cancer risk.