NOS2A and the modulating effect of cigarette smoking in Parkinson's disease.
OBJECTIVE
Inducible nitric oxide synthase, a protein product of NOS2A, generates nitric oxide as a defense mechanism, but excessive levels threaten cellular survival. NOS2A is a candidate gene for Parkinson's disease (PD) that potentially interacts with cigarette smoking. We examined NOS2A for association with PD risk and age at onset (AAO) and for interaction with smoking.


METHODS
We genotyped 13 NOS2A single nucleotide polymorphisms (SNPs) in 466 singleton families and in a validation set of 286 multiplex families. We tested allelic and haplotypic association using the association in the presence of linkage test, genotypic associations using the genotype pedigree disequilibrium test, AAO effects using the quantitative transmission disequilibrium test, and interactions using generalized estimating equations.


RESULTS
Among the pooled earliest onset families, rs2255929 and rs1060826 generated significant allelic (p = 0.000059 and 0.0062, respectively) and genotypic (p = 0.0039 and 0.0014, respectively) associations with risk and AAO (p = 0.00070 and 0.0073, respectively); the two-SNP haplotype generated even stronger association with PD (p = 0.000013). Significant interactions with smoking (p = 0.0015 for rs 2255929 and p < 0.0001 for rs 1060826) were detected in a subset of the families; smoking was inversely associated with PD among risk allele noncarriers, but significance diminished among carriers.


CONCLUSIONS
Our findings support NOS2A as a genetic risk factor in PD, potentially by influencing AAO and by modifying the inverse association between PD and smoking.
Hancock
Dana B
DB
Center for Human Genetics, Duke University Medical Center, Durham, NC 27710, USA. bill.scott@duke.edu
Martin
Eden R
ER
Fujiwara
Kenichiro
K
Stacy
Mark A
MA
Scott
Burton L
BL
Stajich
Jeffrey M
JM
Jewett
Rita
R
Li
Yi-Ju
YJ
Hauser
Michael A
MA
Vance
Jeffery M
JM
Scott
William K
WK
D000328:Adult; D000367:Age Factors; D017668:Age of Onset; D000368:Aged; D000483:Alleles; D016001:Confidence Intervals; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D010300:Parkinson Disease / Q000145:classification / Q000235:genetics* / Q000523:psychology*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012907:Smoking / Q000235:genetics* / Q000503:physiopathology
C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II