Association between Parkinson's disease and polymorphisms in the nNOS and iNOS genes in a community-based case-control study

Abstract

Excess of nitric oxide (NO) has been shown to exert neurotoxic impacts in the brain. Moreover, inhibition of two NO-synthesizing enzymes, neuronal NOS (nNOS) and inducible NOS (iNOS), displays neuroprotective effects in the MPTP model of Parkinson's disease (PD). These data suggest a possible involvement of NOS as factors controlling the resistance of the nigral dopaminergic neurons to environmental insults. Therefore, we investigated whether polymorphisms present in these genes could contribute to the risk of developing PD. We carried out a community-based case-control study among subjects enrolled in the Mutualité Sociale Agricole, the French health insurance organization for workers connected to agriculture. Two-hundred and nine PD patients and 488 controls of European (mostly French) ancestry and matched for age, sex and region of residency were included in this study. Associations were observed with polymorphisms present in exon 22 of iNOS (OR for AA carriers=0.50, 95% CI=0.29-0.86, P=0.01) and in exon 29 of nNOS (OR for carriers of the T allele=1.53, 95% CI=1.08-2.16, P=0.02); no association was observed with a polymorphism in exon 18 of nNOS (OR for carriers of the T allele=1.20, 95% CI=0.85-1.69, P=0.30). Moreover, a significant interaction of the nNOS polymorphisms with current and ever cigarette smoking was found (nNOS 18, P=0.05; nNOS 29, P=0.04). All together, these data favour an involvement of these two genes as new modifier genes in PD.

Achalasia Is Associated With eNOS4a4a, iNOS22GA, and nNOS29TT Genotypes: A Case-control Study

“…The functional role of iNOS22 G/A polymorphism is not clearly known. 23 As the results of our study suggest that it might be associated with achalasia, it is possible that that these genes are in linkage disequilibrium with other genes, which might be associated with degeneration of inhibitory neurons. 41 In contrast to our study, previous studies by Mearin et al 11 and Vigo et al 24 showed that iNOS22 G/A polymorphism was comparable between patients with achalasia and HS.…”

“…A few studies showed these polymorphisms to be associated with Parkinson's disease, migraines and cardiovascular disease. 22,23,38 In different studies, it has been shown that in patients with achalasia, the LES has less NOS as compared to controls. 9 Studies in animals have…”

“…Sample size for iNOS gene G/A-37498 polymorphism was calculated keeping all the above-mentioned parameters same and variant "A" allele frequency of 41% among controls as reported from France. 23 The sample size was estimated to be 145 patients and 290 controls. Similarly, the sample size for nNOS gene C/T polymorphism was calculated according to the above parameters and variant "T" allele frequency of 26% among control population as reported from Spain.…”

“…16 The allelic variant of nNOS C/T in exon 29 is located in an untranslated region of the gene and may influence the rate of expression and stability of nNOS mRNA. 23 Studies on the association between NOS gene isoform polymorphisms and achalasia, however, are scanty. In a study from Spain, a trend toward a higher prevalence of genotypes iNOS22AA and eNOS4a4a was found among patients with achalasia.…”

Genetic variation in nitric oxide synthase 2A (NOS2A) and risk for multiple sclerosis

“…Moreover, its putative involvement in complex genetic disorders may go beyond autoimmune demyelination. Linkage in a subset of type I diabetes pedigrees (HLA-DR3/4 positives) 12 and genetic associations with diabetic renopathy, 13 dementia with Lewy bodies, 14 coronary artery disease, 15 malaria 16,17 and Parkinson's disease 18,19 have been reported. We previously reported a NOS2A exon 10 single-nucleotide polymorphism (SNP, C/T, D346D) being associated with disease susceptibility in two independent MS datasets.…”