Paraoxonase 1, 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 3 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 (<or=60 years) (5.3 [1.7-16]). No increase in risk was noted for parathion.


CONCLUSIONS
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.
Manthripragada
Angelika D
AD
Department of Epidemiology, UCLA School of Public Health, Los Angeles, CA 90095, USA.
Costello
Sadie
S
Cockburn
Myles G
MG
Bronstein
Jeff M
JM
Ritz
Beate
B
D000383:Agriculture; D043303:Aryldialkylphosphatase / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D002140:California; D004781:Environmental Exposure / Q000009:adverse effects*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010755:Organophosphates / Q000009:adverse effects*; D010300:Parkinson Disease / Q000209:etiology*; D011110:Polymorphism, Genetic; D018570:Risk Assessment
D010755:Organophosphates; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human