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Multicenter Study
. 2008 Oct;9(4):249-62.
doi: 10.1007/s10048-008-0137-1. Epub 2008 Jul 29.

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

Dana B Hancock  1 , Eden R Martin, Jeffery M Vance, William K Scott
Affiliations
Multicenter Study

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

Dana B Hancock et al. Neurogenetics. 2008 Oct.

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.

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Figures

Figure 1
Figure 1
LD patterns in 333 unrelated individuals with PD from families with sporadic PD. r2 values between (A) NOS1, (B) NOS2A, and (C) NOS3 SNPs are shown with shading becoming darker as the r2 value increases.
Figure 1
Figure 1
LD patterns in 333 unrelated individuals with PD from families with sporadic PD. r2 values between (A) NOS1, (B) NOS2A, and (C) NOS3 SNPs are shown with shading becoming darker as the r2 value increases.
Figure 1
Figure 1
LD patterns in 333 unrelated individuals with PD from families with sporadic PD. r2 values between (A) NOS1, (B) NOS2A, and (C) NOS3 SNPs are shown with shading becoming darker as the r2 value increases.
Figure 2
Figure 2
NOS1 allelic associations with PD using APL with varying AAO cutoffs in early-onset families with sporadic PD. –log10(APL p) are shown for each SNP.
Figure 3
Figure 3
NOS2A allelic associations with PD using APL with varying AAO cutoffs in early-onset families with sporadic PD. –log10(APL p) are shown for each SNP.
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