Paraoxonase 1 (PON1), agricultural organophosphate exposure, and Parkinson disease

Background—Human, animal and cell models support a role for pesticides in the etiology of Parkinson disease. Susceptibility to pesticides may be modified by genetic variants of xenobiotic enzymes, such as paraoxonase, that play a role in metabolizing some organophosphates. Methods—We examined associations between Parkinson disease and the organophosphates diazinon, chlorpyrifos, and parathion, and the influence of a functional polymorphism at position 55 in the coding region of the PON1 gene (PON1-55). From 1 January 2001 through 1 January 2008, we recruited 351 incident cases and 363 controls from three rural California counties in a population-based case-control study. Participants provided a DNA sample, and residential exposure to organophosphates was determined from pesticide usage reports and a geographic information system (GIS) approach. We assessed the main effects of both genes and pesticides in unconditional logistic regression analyses, and evaluated the effect of carrying a PON1-55 MM variant on estimates of effects for diazinon, chlorpyrifos, and parathion exposures. Results—Carriers of the variant MM PON1-55 genotype exposed to organophosphates exhibited a greater than 2-fold increase in Parkinson disease risk compared with persons who had the wildtype or heterozygous genotype and no exposure (for diazinon, odds ratio = 2.2 [95% confidence interval = 1.1–4.5]; for chlorpyrifos, 2.6 [1.3–5.4]). The effect estimate for chlorpyrifos, was more pronounced in younger-onset cases and controls (≤60 years) (5.3 [1.7– 16]). No increase in risk was noted for parathion. Conclusion—The increase in risk we observed among PON1-55 variant carriers for specific organophosphates metabolized by PON1 underscores the importance of considering susceptibility factors when studying environmental exposures in Parkinson disease. The etiology of Parkinson disease, as with many complex diseases, is widely believed to be multi-factorial, i.e., involving environmental and genetic risk factors. One notable and widely acknowledged environmental risk factor of etiologic importance for Parkinson disease is exposure to pesticides.1 Organophosphates, a group of pesticides commonly used Address for correspondence: Beate Ritz, UCLA, Epidemiology, Box 951772, Los Angeles, CA 90095, Telephone: 310-206-7438, Fax: 310-206-6039, [email protected]. SDCSupplemental digital content is available through direct URL citations in the HTML and PDF versions of this article (www.epidem.com). NIH Public Access Author Manuscript Epidemiology. Author manuscript; available in PMC 2011 June 17. Published in final edited form as: Epidemiology. 2010 January ; 21(1): 87–94. doi:10.1097/EDE.0b013e3181c15ec6. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript in agriculture, are recognized neurotoxins and have been implicated in some studies of Parkinson disease.2,3 It has also been suggested that susceptibility to the adverse effects of neurotoxins might be modified by genes encoding for possible functional variants of xenobiotic metabolizing enzymes. Paraoxonase, the product of the PON1 gene, has been shown to determine an individual’s susceptibility to organophosphates, especially the insecticides diazinon and chlorpyrifos, such that individuals with low PON1 activity might be at higher risk for adverse health effects from organophosphate exposure.4 Studies report that the oxygen analogs of chlorpyrifos and diazinon (but not parathion) are efficiently degraded in vivo by paraoxonase.5,6 While these studies provide evidence that paraoxon, the oxygen analogue of the parathion responsible for the enzyme’s name, may in fact not be efficiently degraded by PON1, we nevertheless include this organophosphate to further investigate these novel findings. We conducted a case-control study of Parkinson disease in a rural population of California’s Central Valley among people living close to areas with extensive agricultural pesticide application, especially organophosphate applications. We developed a novel method of estimating pesticide exposure using a geographic information system (GIS) tool and data from California Pesticide Use Reports, land-use maps, and geocoded residential historical locations to assess residential exposures to agricultural organophosphate applications. Here we examine associations between Parkinson disease and environmental exposure to the organophosphates diazinon, chlorpyrifos, and parathion, and we investigate whether a functional polymorphism at position 55 in the coding region of the PON1 gene (PON1-55) modifies these associations.