title: Organophosphate Pesticide Exposures, Nitric Oxide Synthase Gene Variants, and Gene-Pesticide Interactions in a Case-Control Study of Parkinson's Disease, California (USA).
abstract: Nitric oxide synthase (NOS) genes are candidates for Parkinson's disease (PD) because NOS enzymes produce nitric oxide (NO), a pro-oxidant that can damage neurons. Widely used organophosphate (OP) pesticides can induce oxidative stress and are reported to increase PD risk. Additionally, two single nucleotide polymorphisms (SNPs) from the PON1 (paraoxonase 1) gene influence the ability to metabolize OPs.
  
  
  
  Here, we investigated contributions of NOS genes and OP pesticides to PD risk, controlling for PON1 status.
  
  
  
  In 357 incident PD cases and 495 population controls, we investigated eight NOS SNPs and interactions with both household and ambient agricultural OP exposures assessed with geographic information system (GIS).
  
  
  
  In comparing PD in homozygous variant carriers of NOS2A rs1060826 versus homozygous wild-type or heterozygotes, we estimate an adjusted odds ratio (OR) of 1.51 (95% CI: 0.95, 2.41). When considering interactions between NOS1 rs2682826 and OP exposure from household use, the OR for frequent OP use alone was 1.30 (95% CI: 0.72, 2.34) and for the CT+TT genotype alone was 0.89 (95% CI: 0.58, 1.39), and for frequent OP use combined with the CT+TT genotype the OR was 2.84 (95% CI: 1.49, 5.40) (interaction p-value 0.04). Similar results were seen for ambient OP exposure. Interactions between OP exposure and three other NOS1 SNPs and a genetic risk score combining all NOS1 SNPs reached statistical significance.
  
  
  
  We found that OP pesticides were more strongly associated with PD among participants with variant genotypes in NOS1, consistent with the importance of oxidative stress-inducing mechanisms. Our data provide evidence for NOS1 modifying PD risk in OP exposed populations.
  
  
  
  Paul KC, Sinsheimer JS, Rhodes SL, Cockburn M, Bronstein J, Ritz B. 2016. Organophosphate pesticide exposures, nitric oxide synthase gene variants, and gene-pesticide interactions in a case-control study of Parkinson's disease, California (USA). Environ Health Perspect 124:570-577; http://dx.doi.org/10.1289/ehp.1408976.
authors.affiliation: Department of Epidemiology, Fielding School of Public Health, University of California at Los Angeles (UCLA), Los Angeles, California, USA.
authors.forename: Kimberly C
authors.initials: KC
authors.lastname: Paul
authors.forename: Janet S
authors.initials: JS
authors.lastname: Sinsheimer
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Rhodes
authors.forename: Myles
authors.initials: M
authors.lastname: Cockburn
authors.forename: Jeff
authors.initials: J
authors.lastname: Bronstein
authors.forename: Beate
authors.initials: B
authors.lastname: Ritz
mesh_terms: D043303:Aryldialkylphosphatase / Q000235:genetics; D002140:California / Q000453:epidemiology; D016022:Case-Control Studies; D004781:Environmental Exposure / Q000706:statistics & numerical data*; D004785:Environmental Pollutants / Q000633:toxicity*; D006801:Humans; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D009943:Organophosphorus Compounds / Q000633:toxicity*; D010300:Parkinson Disease / Q000453:epidemiology*; D010575:Pesticides; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D004785:Environmental Pollutants; D009943:Organophosphorus Compounds; D010575:Pesticides; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D043303:Aryldialkylphosphatase