Pesticide exposure, genetic susceptibility, and prostate cancer risk in the Agricultural Health Study

Abstract

Background and aim: Specific pesticides have been associated with risk of prostate cancer, but interactions with genetic susceptibility loci have rarely been studied. We examined the joint associations of pesticides and genetic variants with prostate cancer risk. Methods: We studied 1,162 cases (588 aggressive) and 2,206 frequency-matched controls nested in the Agricultural Health Study cohort. History of pesticide use was self-reported at enrollment. Genotyping was conducted using the OncoArray-500K BeadChip (Illumina Inc). Logistic regression models estimated the joint associations of pesticides previously linked to prostate cancer (fonofos, terbufos, malathion, aldrin, linuron, and dimethoate) and 256 individual genetic variants and an aggregated polygenic risk score (PRS) with risk of total and aggressive prostate cancer. Likelihood ratio tests assessed multiplicative interaction. Results: We observed multiplicative interaction between fonofos and the PRS in relation to risk of total and aggressive prostate cancer. Compared to the reference group (non-exposed, PRS scores <median), those with fonofos exposure and PRS scores >median had elevated risks of total (OR 1.35, 95% CI 1.06-1.73, p-int=0.03) and aggressive (OR 1.49, 95% CI 1.09-2.04, p-int=0.19) prostate cancer. There was also evidence of interaction between the six pesticides and individual genetic variants occurring in genomic regions associated with 1) cancer signaling pathways, 2) hormonal perturbations relevant for prostate cancer, 3) DNA damage response and 4) neurological traits; many of the examined pesticides have known neurologic mechanisms. Conclusion: Joint exposure to the organophosphate insecticide fonofos and genetic susceptibility may further elevate the risk for total and aggressive prostate cancer, above the independent effects of each. These results, as well as those observed for individual genetic markers, suggest potential mechanisms by which these pesticides may increase prostate cancer risk. Keyword: Prostate Cancer, Pesticides, Occupational exposure, Genetic susceptibility