title: Genetic modification of the association of paraquat and Parkinson's disease.
abstract: Paraquat is one of the most widely used herbicides worldwide. It produces a Parkinson's disease (PD) model in rodents through redox cycling and oxidative stress (OS) and is associated with PD risk in humans. Glutathione transferases provide cellular protection against OS and could potentially modulate paraquat toxicity. We investigated PD risk associated with paraquat use in individuals with homozygous deletions of the genes encoding glutathione S-transferase M1 (GSTM1) or T1 (GSTT1). Eighty-seven PD subjects and 343 matched controls were recruited from the Agricultural Health Study, a study of licensed pesticide applicators and spouses in Iowa and North Carolina. PD was confirmed by in-person examination. Paraquat use and covariates were determined by interview. We genotyped subjects for homozygous deletions of GSTM1 (GSTM1*0) and GSTT1 (GSTT1*0) and tested interaction between paraquat use and genotype using logistic regression. Two hundred and twenty-three (52%) subjects had GSTM1*0, 95 (22%) had GSTT1*0, and 73 (17%; all men) used paraquat. After adjustment for potential confounders, there was no interaction with GSTM1. In contrast, GSTT1 genotype significantly modified the association between paraquat and PD. In men with functional GSTT1, the odds ratio (OR) for association of PD with paraquat use was 1.5 (95% confidence interval [CI]: 0.6-3.6); in men with GSTT1*0, the OR was 11.1 (95% CI: 3.0-44.6; P interaction: 0.027). Although replication is needed, our results suggest that PD risk from paraquat exposure might be particularly high in individuals lacking GSTT1. GSTT1*0 is common and could potentially identify a large subpopulation at high risk of PD from oxidative stressors such as paraquat.
authors.affiliation: The Parkinson's Institute, Sunnyvale, California 94085, USA. sgoldman@thepi.org
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Goldman
authors.forename: Freya
authors.initials: F
authors.lastname: Kamel
authors.forename: G Webster
authors.initials: GW
authors.lastname: Ross
authors.forename: Grace S
authors.initials: GS
authors.lastname: Bhudhikanok
authors.forename: Jane A
authors.initials: JA
authors.lastname: Hoppin
authors.forename: Monica
authors.initials: M
authors.lastname: Korell
authors.forename: Connie
authors.initials: C
authors.lastname: Marras
authors.forename: Cheryl
authors.initials: C
authors.lastname: Meng
authors.forename: David M
authors.initials: DM
authors.lastname: Umbach
authors.forename: Meike
authors.initials: M
authors.lastname: Kasten
authors.forename: Anabel R
authors.initials: AR
authors.lastname: Chade
authors.forename: Kathleen
authors.initials: K
authors.lastname: Comyns
authors.forename: Marie B
authors.initials: MB
authors.lastname: Richards
authors.forename: Dale P
authors.initials: DP
authors.lastname: Sandler
authors.forename: Aaron
authors.initials: A
authors.lastname: Blair
authors.forename: J William
authors.initials: JW
authors.lastname: Langston
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Tanner
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D015331:Cohort Studies; D003936:Diagnosis, Computer-Assisted; D004198:Disease Susceptibility / Q000139:chemically induced* / Q000453:epidemiology*; D005260:Female; D017353:Gene Deletion; D056726:Genetic Association Studies; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics; D006540:Herbicides / Q000633:toxicity*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016273:Occupational Exposure; D010269:Paraquat / Q000633:toxicity*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000453:epidemiology / Q000235:genetics; D012307:Risk Factors; D011795:Surveys and Questionnaires
chemical_list: D005982:Glutathione Transferase; D006540:Herbicides; D010269:Paraquat; C413545:glutathione S-transferase T1