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Nitric oxide synthase genes and their interactions with environmental factors in Parkinson's disease.

ABSTRACT: Nitric oxide synthase (NOS) genes (NOS1, NOS2A, and NOS3) may create excess nitric oxide that contributes to neurodegeneration in Parkinson's disease (PD). NOS genes might also interact with one another or with environmental factors in PD. Coding and tagging single nucleotide polymorphisms (SNPs) (27 NOS1, 18 NOS2A, and five NOS3 SNPs) were genotyped in families with PD (1,065 cases and 1,180 relative and other controls) and were tested for allelic associations with PD using the association in the presence of linkage test and the pedigree disequilibrium test (PDT), allelic associations with age-at-onset (AAO) using the quantitative transmission disequilibrium test, and interactions using the multifactor dimensionality reduction-PDT. Gene-environment interactions involving cigarette smoking, caffeine, nonsteroidal anti-inflammatory drugs, and pesticides were examined using generalized estimating equations in participants with environmental data available. Significant associations with PD were detected for the NOS1 SNPs rs3782218, rs11068447, rs7295972, rs2293052, rs12829185, rs1047735, rs3741475, and rs2682826 (range of p = 0.00083-0.046) and the NOS2A SNPs rs2072324, rs944725, rs12944039, rs2248814, rs2297516, rs1060826, and rs2255929 (range of p = 0.0000040-0.047) in earlier-onset families with sporadic PD, and some SNPs were also associated with earlier AAO. There was no compelling statistical evidence for gene-gene interactions. However, of the significantly associated SNPs, interactions were found between pesticides and the NOS1 SNPs rs12829185, rs1047735, and rs2682826 (range of p = 0.012-0.034) and between smoking and the NOS2A SNPs rs2248814 (p = 0.021) and rs1060826 (p = 0.013). These data implicate NOS1 and NOS2A as genetic risk factors for PD and demonstrate that their interactions with established environmental factors may modulate the environmental effects.

SUBMITTER: Hancock DB

PROVIDER: S-EPMC2630458 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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Nitric oxide synthase genes and their interactions with environmental factors in Parkinson's disease.

Hancock Dana B DB Martin Eden R ER Vance Jeffery M JM Scott William K WK

Neurogenetics 20080729 4

Nitric oxide synthase (NOS) genes (NOS1, NOS2A, and NOS3) may create excess nitric oxide that contributes to neurodegeneration in Parkinson's disease (PD). NOS genes might also interact with one another or with environmental factors in PD. Coding and tagging single nucleotide polymorphisms (SNPs) (27 NOS1, 18 NOS2A, and five NOS3 SNPs) were genotyped in families with PD (1,065 cases and 1,180 relative and other controls) and were tested for allelic associations with PD using the association in t ...[more]

PMID: 18663495

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Project description: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.

Project description:Nitric oxide synthase (NOS), a flavo-hemoprotein, tightly regulates nitric oxide (NO) synthesis and thereby its dual biological activities as a key signaling molecule for vasodilatation and neurotransmission at low concentrations, and also as a defensive cytotoxin at higher concentrations. Three NOS isoforms, iNOS, eNOS and nNOS (inducible, endothelial, and neuronal NOS), achieve their key biological functions by tight regulation of interdomain electron transfer (IET) process via interdomain interactions. In particular, the FMN-heme IET is essential in coupling electron transfer in the reductase domain with NO synthesis in the heme domain by delivery of electrons required for O(2) activation at the catalytic heme site. Compelling evidence indicates that calmodulin (CaM) activates NO synthesis in eNOS and nNOS through a conformational change of the FMN domain from its shielded electron-accepting (input) state to a new electron-donating (output) state, and that CaM is also required for proper alignment of the domains. Another exciting recent development in NOS enzymology is the discovery of importance of the the FMN domain motions in modulating reactivity and structure of the catalytic heme active site (in addition to the primary role of controlling the IET processes). In the absence of a structure of full-length NOS, an integrated approach of spectroscopic (e.g. pulsed EPR, MCD, resonance Raman), rapid kinetics (laser flash photolysis and stopped flow) and mutagenesis methods is critical to unravel the molecular details of the interdomain FMN/heme interactions. This is to investigate the roles of dynamic conformational changes of the FMN domain and the docking between the primary functional FMN and heme domains in regulating NOS activity. The recent developments in understanding of mechanisms of the NOS regulation that are driven by the combined approach are the focuses of this review. An improved understanding of the role of interdomain FMN/heme interaction and CaM binding may serve as the basis for the design of new selective inhibitors of NOS isoforms.

Dataset Information

Nitric oxide synthase genes and their interactions with environmental factors in Parkinson's disease.

Publications

Nitric oxide synthase genes and their interactions with environmental factors in Parkinson's disease.

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