Association of eNOS and Cav-1 gene polymorphisms with susceptibility risk of large artery atherosclerotic stroke.

Hann-Yeh Shyu,Chun-Wen Cheng,Ming-Hua Chen,Yi-Hsien Hsieh,Jia-Ching Shieh,Hsiao-Wei Wang,Ling-Rong Yen,Carlos Zaragoza

doi:10.1371/journal.pone.0174110

Abstract

Endothelial nitric oxide synthase (eNOS) is localized in caveole and has important effects on caveolar coordination through its interaction with caveolin-1 (Cav-1), which supports normal functioning of vascular endothelial cells. However, the relationship between genotypic polymorphisms of e-NOS and Cav-1 genes and ischemic stroke (IS) remains lesser reported. This hospital-based case-control study aimed to determine the genetic polymorphisms of the eNOS (Glu298Asp) and Cav-1 (G14713A and T29107A) genes in association with susceptibility risk in patients who had suffered from a large artery atherosclerotic (LAA) stroke. Genotyping determination for these variant alleles was performed using the TaqMan assay. The distributions of observed allelic and genotypic frequencies for the polymorphisms were in Hardy-Weinberg equilibrium in healthy controls. The risk for an LAA stroke in the Asp298 variant was 1.72 (95% CI = 1.09–2.75) versus Glu298 of the eNOS. In the GA/AA (rs3807987) variant, it was 1.79 (95% CI = 1.16–2.74) versus GG and in TA/AA (rs7804372) was 1.61 (95% CI = 1.06–2.43) versus TT of the Cav-1, respectively. A tendency toward an increased LAA stroke risk was significant in carriers with the eNOS Glu298Asp variant in conjunction with the G14713 A and T29107A polymorphisms of the Cav-1 (aOR = 2.03, P-trend = 0.002). A synergistic effect between eNOS and Cav-1 polymorphisms on IS risk elevation was significantly influenced by alcohol drinking, heavy cigarette smoking (P-trend<0.01), and hypercholesterolemia (P-trend < 0.001). In conclusion, genotypic polymorphisms of the eNOS Glu298Asp and Cav-1 14713A/29107A polymorphisms are associated with the elevated risk of LAA stroke among Han Chinese in Taiwan.

Highlights

Despite the growing optimism due to recent advances in stroke therapy, strokes remain a major leading cause of disability and the third-leading cause of death among ethnic Chinese in Taiwan
An increased large artery atherosclerotic (LAA) stroke risk was associated with risk factors, including hypertension, diabetes, hypercholesterolemia using multiple logistic regression analysis after adjusting for age and sex
The frequencies of observed alleles and genotypes for these polymorphisms were in Hardy-Weinberg proportions in the controls

Summary

Introduction

Despite the growing optimism due to recent advances in stroke therapy, strokes remain a major leading cause of disability and the third-leading cause of death among ethnic Chinese in Taiwan. Recent progress in the understanding of the mechanism underlying the pathogenesis of cardiomyopathy has led to the discovery of therapeutic targets of nitric oxide (NO) with hopeful optimism [5]. Vascular endothelial NO synthesis is produced by the action of endothelial NO synthase (eNOS), whose encoded gene is located on chromosome 7q35. ENOS has been reported to occur in the subdomain within caveolin-1, encoded by the Cav-1 gene, which assembles as a coat and scaffolding protein in caveolae and is responsible for the multiple phenotypes in vascular endothelial cells. Binding affinity of eNOS/Cav-1 has multifunctional signaling in NO release which may account for the modified effect of Cav-1 in association with eNOS activity on vasodilation [12]

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Results

Conclusion