Functional paraoxonase 1 variants modify the risk of Parkinson's disease due to organophosphate exposure

Background: We previously demonstrated that carriers of the "slower metabolizer" MM genotype of paraoxonase (PON1) who were also exposed to ambient organophosphate (OP) pesticides at their residences were at increased risk of developing Parkinson's disease (PD). Here, with a larger sample size, we extend our previous investigation to consider additional sources of ambient exposure and examined two additional functional PON1 variants. Methods: From 2001 to 2011, we enrolled incident cases of idiopathic PD and population controls living in central California. We genotyped three well-known functional PON1 SNPs: two exonic polymorphisms (PON1_L55M and PON1_Q192R) and the promoter region variant (PON1_C-108T). Ambient exposures to diazinon, chlorpyrifos, and parathion at residential and workplace addresses were assessed using a validated geographic information system-based model incorporating records of agricultural pesticide applications in California. Results: The odds ratio (OR) for Caucasians exposed to OPs at either residential or workplace addresses varied by PON1 genotype; for exposed carriers of the "faster" metabolizer genotypes, ML or LL, we estimated lower odds ratios (range, 1.20-1.39) than for exposed carriers of the "slower" metabolizer genotype MM (range, 1.78-2.45) relative to unexposed carriers of the faster genotypes. We observed similarly increased ORs for exposure across PON1_Q192R genotypes, but no differences across PON1_C-108T genotypes. The largest ORs were estimated for exposed carriers of both PON1_192QQ and PON1_55MM (OR range, 2.84-3.57). Conclusions: Several functional PON1 variants may act together to modify PD risk for ambient OP exposures. While either PON1_L55M or PON1_Q192R may be sufficient to identify increased susceptibility, carriers of both slow metabolizer variants seem most susceptible to OP exposures.