Nitric oxide and nitric oxide synthase in Huntington's disease

Nitric oxide (NO) is a biologically active inorganic molecule produced when the semiessential amino acid l-arginine is converted to l-citrulline and NO via the enzyme nitric oxide synthase (NOS). NO is known to be involved in the regulation of many physiological processes, such as control of blood flow, platelet adhesion, endocrine function, neurotransmission, neuromodulation, and inflammation, to name only a few. During neuropathological conditions, the production of NO can be either protective or toxic, dependent on the stage of the disease, the isoforms of NOS involved, and the initial pathological event. This paper reviews the properties of NO and NOS and the pathophysiology of Huntington's disease (HD). It discusses ways in which NO and NOS may interact with the protein product of HD and reviews data implicating NOS in the neuropathology of HD. This is followed by a synthesis of current information regarding how NO/NOS may contribute to HD-related pathology and identification of areas for potential future research.     

Influence of endothelial nitric oxide synthase gene polymorphisms (-786T>C, 4a4b, 894G>T) in Korean patients with coronary artery disease

INTRODUCTION: Endothelium-derived nitric oxide (NO) is synthesized from l-arginine by endothelial nitric oxide synthase (eNOS) encoded by the eNOS3 gene on chromosome 7. The effects of the eNOS polymorphisms with the risk of coronary artery disease are conflicting. In this study, we investigated the association of the eNOS genotypes with coronary artery disease in Koreans. MATERIALS AND METHODS: A case-control study was performed to evaluate the association between the eNOS -786T>C, 4a4b, or 894G>T polymorphism and coronary artery disease. 147 consecutive patients with coronary artery disease and 222 healthy controls were recruited. The genotypes of eNOS -786T>C and 894G>T polymorphisms were determined by the polymerase chain reaction-restriction fragment length polymorphism analysis. The genotypes of a 27 bp insertion/deletion in intron 4 (eNOS 4a4b) were determined by the banding pattern on gel electrophoresis. RESULTS: The eNOS -786T>C (odds ratio [OR]; 1.61, 95% confidence interval [CI]; 0.97-2.69), 894G>T (OR; 1.12, 95% CI; 0.65-1.92) and 4a4b (OR; 1.44, 95% CI; 0.87-2.39) polymorphisms were not an independent predisposition factor to coronary artery disease. However, a subgroup analysis adjusted with various cardiovascular risk factors confirmed positive association of the -786T>C polymorphism in CAD patients with hypertension and a smoking history and also a significant association of the intron 4 genotypes with a smoking history, but no significance has been found in the eNOS polymorphisms of 894G>T upon any risk adjustment. In this study we also found that the distribution of heterozygotes (-786TC, 894GT, and 4a4b) and variant homozygotes for the -786C, 894T, and intron 4a alleles of eNOS in Koreans were significantly lower than in Caucasian populations. CONCLUSIONS: The present study demonstrates that polymorphisms of the eNOS -786T>C and 4a4b are associated with coronary artery disease with adjustments for cardiovascular risk factors in the Koreans.     

Association between Endothelial nitric oxide synthase G894T gene polymorphism and risk of ischemic stroke in North Indian population: a case-control study

Background and purpose: Stroke is a multi-factorial disease influenced by both genetic and environmental factors. The aim of this case-control study was to determine the association between Endothelial Nitric Oxide Synthase G894T (rs1799983) gene polymorphism and susceptibility to ischemic stroke (IS) in North Indian population.

Methods: In this present case-control study, genotyping was performed by using Polymerase chain reaction – Restriction fragment length polymorphism (PCR-RFLP) method for 250 IS patients and 250 age and sex matched controls. PCR results were confirmed by DNA sequencing. Frequency distribution of genotypes and alleles were compared between cases and controls using conditional logistic regression.

Results: Hypertension, Diabetes, Dyslipidemia, Low Socioeconomic Status and Family History of Stroke were found to be independent risk factors for IS. Mean age of cases and controls were 52.83 ± 12.59 and 50.97 ± 12.70 years. Multivariate logistic regression analysis showed a significant association between eNOS G894T (rs1799983) polymorphism and risk of IS [OR = 1.57; 95%CI 1.05–2.37; p = 0.028] under dominant model. Based on Trial of Org 10172 in Acute Stroke Treatment classification, an independent association of large vessel disease (LVD) was observed with the risk of IS under the dominant [OR = 2.09; 95% CI 1.17–3.75; p = 0.01] and recessive [4.09 95% CI 1.06–15.68; p = 0.04] models. All the observed genotype frequencies were in accordance with the Hardy–Weinberg equilibrium (HWE) in both cases and controls.

Conclusion: The findings of the present study suggest that polymorphism in G894T position of eNOS gene might be a risk factor for IS mainly for LVD stroke subtype in North Indian population. Further large prospective studies are required to confirm these findings.     

Lack of evidence for association between factor XIII-A Val34Leu polymorphism and ischemic stroke: A meta-analysis of 8,800 subjects

Introduction

Epidemiological studies have evaluated the association between factor XIII-A (FXIII-A) Val34Leu polymorphism and risk of ischemic stroke, but the results remain inconclusive. This meta-analysis was therefore designed to clarify these controversies.

Methods

Systematic searches of electronic databases Embase, PubMed and Web of Science, as well as hand searching of the references of identified articles and the meeting abstracts were performed. Study selection, data abstraction and study quality evaluation (using the Newcastle-Ottawa Scale, NOS) were independently conducted in duplicate. Statistical analyses were performed using software Review Manager (Version 5.1.2) and Stata (Version 11.0). The pooled odds ratios (ORs) with 95% confidence intervals (95%CIs) were performed. Fixed or random effects model was separately used depending on the heterogeneity between studies. Publication bias was tested by funnel plot, Egger's regression test and Begg's test. Sensitivity analysis was conducted by limiting the meta-analysis to the high quality studies (NOS score≥8).

Results

A total of 16 studies including 3,807 cases and 4,993 controls were combined showing no evidence of association between FXIII-A Val34Leu polymorphism and ischemic stroke (for Val/Leu vs. Val/Val : OR = 0.95, 95%CI = 0.77-1.16; for Leu/Leu vs. Val/Val: OR = 0.90, 95%CI = 0.73-1.11; for dominant model: OR = 0.97, 95%CI = 0.81-1.17; for recessive model: OR = 0.95, 95%CI = 0.77-1.17). In the subgroup analyses by study design, ethnicity and specific subtypes (small-vessel occlusive ischemic stroke and large-artery atherosclerotic ischemic stroke ), there was lack of evidence for the association.

Conclusions

This meta-analysis indicates that there is no evidence for association between factor XIII-A Val34Leu polymorphism and ischemic stroke.