Abstract
Although the relationships between endothelial nitric oxide synthase (eNOS) gene polymorphisms (including G894T, VNTR and T786C) and risk of ischemic stroke (IS) have been extensively studied, controversial results have been reported. The aim of this study was to assess the relationships between them by using a meta-analysis. Literatures were retrieved through the following databases: Medline, Embase and Wangfang (updated to January 1st, 2013). Fixed- or random-effects model was used to calculate pooled odds ratio and 95 % confidence interval (OR and 95 % CI). A total of 31 case–control studies including 8,547 patients and 9,117 controls were included in this meta-analysis eventually. For eNOS G894T polymorphism, the results indicated that TT genotype was significantly associated with increased risk of IS incidence compared to G allele (OR and 95 % CI 1.25 (1.09–1.42) for TT vs. GT+GG, P < 0.001). When subgroup analysis was conducted according to ethnicities, T allele was significantly associated with risk of IS for Asians rather than for Caucasians. For eNOS VNTR polymorphism, 4aa genotype was significantly associated with risk of IS incidence compared to 4bb genotype (OR (95 % CI) 2.22 (1.66–2.97) for aa vs. bb, P < 0.001). Similarly, when subgroup analyses were conducted, 4aa was closely associated with increased risk of IS for Asians rather than for Caucasians. For eNOS T786C polymorphism, it was not associated with risk of IS incidence. In conclusion, this study indicated that eNOS 894T and VNTR 4a allele was significantly associated with risk of IS incidence for Asians. However, eNOS T786C polymorphism was not a likely risk factor for IS incidence.
Similar content being viewed by others
References
Thorvaldsen P, Asplund K, Kuulasmaa K, Rajakangas AM, Schroll M (1995) Stroke incidence, case fatality, and mortality in the WHO MONICA project. World Health Organization Monitoring Trends and Determinants in Cardiovascular Disease. Stroke 26:361–367
Weimar C, Kurth T, Kraywinkel K, Wagner M, Busse O, Haberl RL, Diener HC (2002) Assessment of functioning and disability after ischemic stroke. Stroke 33:2053–2059
Liu M, Wu B, Wang WZ, Lee LM, Zhang SH, Kong LZ (2007) Stroke in China: epidemiology, prevention, and management strategies. Lancet Neurol 6:456–464
Martin CO, Rymer MM (2011) Hemorrhagic stroke: aneurysmal subarachnoid hemorrhage. Mo Med 108:124–127
Bhat VM, Cole JW, Sorkin JD, Wozniak MA, Malarcher AM, Giles WH, Stern BJ, Kittner SJ (2008) Dose-response relationship between cigarette smoking and risk of ischemic stroke in young women. Stroke 39:2439–2443
Autenrieth CS, Evenson KR, Yatsuya H, Shahar E, Baggett C, Rosamond WD (2012) Association between physical activity and risk of stroke subtypes: the atherosclerosis risk in communities study. Neuroepidemiology 40:109–116
Saidi S, Mallat SG, Almawi WY, Mahjoub T (2010) Endothelial nitric oxide synthase Glu298Asp, 4b/a, and −786T>C gene polymorphisms and the risk of ischemic stroke. Acta Neurol Scand 121:114–119
Wang B, Guo Q, Peng Y, Lu J, Singh B, Hua B (2012) Association of AGT M235T and ACE I/D polymorphisms with the risk of ischemic stroke: meta-analysis in Han Chinese population. J Neurol Sci 320:79–84
Zhang Z, Xu G, Liu D, Fan X, Zhu W, Liu X (2012) Angiotensin-converting enzyme insertion/deletion polymorphism contributes to ischemic stroke risk: a meta-analysis of 50 case-control studies. PLoS ONE 7:e46495
Casas JP, Bautista LE, Humphries SE, Hingorani AD (2004) Endothelial nitric oxide synthase genotype and ischemic heart disease: meta-analysis of 26 studies involving 23028 subjects. Circulation 109:1359–1365
Chatterjee A, Black SM, Catravas JD (2008) Endothelial nitric oxide (NO) and its pathophysiologic regulation. Vasc Pharmacol 49:134–140
Tao HM, Chen GZ (2009) Endothelial NO synthase gene polymorphisms and risk of ischemic stroke: a meta-analysis. Neurosci Res 64:311–316
Iadecola C (1997) Bright and dark sides of nitric oxide in ischemic brain injury. Trends Neurosci 20:132–139
Di JH, Li C, Yu HM, Zheng JN, Zhang GY (2012) nNOS downregulation attenuates neuronal apoptosis by inhibiting nNOS–GluR6 interaction and GluR6 nitrosylation in cerebral ischemic reperfusion. Biochem Biophys Res Commun 420:594–599
Szentirmai O, Carter BS (2008) Genetic and cellular therapies for cerebral infarction. Neurosurgery 62:1465–1479
Radomski MW, Palmer RM, Moncada S (1987) Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium. Lancet 2:1057–1058
Ponnuswamy P, Schrottle A, Ostermeier E, Gruner S, Huang PL, Ertl G, Hoffmann U, Nieswandt B, Kuhlencordt PJ (2012) eNOS protects from atherosclerosis despite relevant superoxide production by the enzyme in apoE mice. PLoS ONE 7:e30193
Berger K, Stogbauer F, Stoll M, Wellmann J, Huge A, Cheng S, Kessler C, John U, Assmann G, Ringelstein EB, Funke H (2007) The glu298asp polymorphism in the nitric oxide synthase 3 gene is associated with the risk of ischemic stroke in two large independent case-control studies. Hum Genet 121:169–178
Yan JT, Zhang L, Xu YJ, Wang XJ, Wang CY, Wang DW (2011) Polymorphisms of genes in nitric oxide-forming pathway associated with ischemic stroke in Chinese Han population. Acta Pharmacol Sin 32:1357–1363
Wang ZW, Li Y, Huang LY, Guan QK, da Xu W, Zhou WK, Zhang XZ (2012) Helicobacter pylori infection contributes to high risk of ischemic stroke: evidence from a meta-analysis. J Neurol 259:2527–2537
Liu F, Liu L, Li B, Wei YG, Yan LN, Wen TF, Xu MQ, Wang WT, Yang JY (2011) p73 G4C14-A4T14 polymorphism and cancer risk: a meta-analysis based on 27 case-control studies. Mutagenesis 26:573–581
Attia J, Thakkinstian A, D’Este C (2003) Meta-analyses of molecular association studies: methodologic lessons for genetic epidemiology. J Clin Epidemiol 56:297–303
Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560
DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188
Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22:719–748
Markus HS, Ruigrok Y, Ali N, Powell JF (1998) Endothelial nitric oxide synthase exon 7 polymorphism, ischemic cerebrovascular disease, and carotid atheroma. Stroke 29:1908–1911
Yahashi Y, Kario K, Shimada K, Matsuo M (1998) The 27-bp repeat polymorphism in intron 4 of the endothelial cell nitric oxide synthase gene and ischemic stroke in a Japanese population. Blood Coagul Fibrinolysis 9:405–409
MacLeod MJ, Dahiyat MT, Cumming A, Meiklejohn D, Shaw D, St Clair D (1999) No association between Glu/Asp polymorphism of NOS3 gene and ischemic stroke. Neurology 53:418–420
Elbaz A, Poirier O, Moulin T, Chedru F, Cambien F, Amarenco P (2000) Association between the Glu298Asp polymorphism in the endothelial constitutive nitric oxide synthase gene and brain infarction. The GENIC Investigators. Stroke 31:1634–1639
Hou L, Osei-Hyiaman D, Yu H, Ren Z, Zhang Z, Wang B, Harada S (2001) Association of a 27-bp repeat polymorphism in ecNOS gene with ischemic stroke in Chinese patients. Neurology 56:490–496
Ge R, Chen F, Tian D, Yang C, Zhang C (2004) Association between variable number of tendem repeat polymorphism of endothelial nitric oxide synthase gene and cerebral infarction. J Clin Neurol 17:86–88
Hassan A, Gormley K, O’Sullivan M, Knight J, Sham P, Vallance P, Bamford J, Markus H (2004) Endothelial nitric oxide gene haplotypes and risk of cerebral small-vessel disease. Stroke 35:654–659
Howard TD, Giles WH, Xu J, Wozniak MA, Malarcher AM, Lange LA, Macko RF, Basehore MJ, Meyers DA, Cole JW, Kittner SJ (2005) Promoter polymorphisms in the nitric oxide synthase 3 gene are associated with ischemic stroke susceptibility in young black women. Stroke 36:1848–1851
Szolnoki Z, Havasi V, Bene J, Komlosi K, Szoke D, Somogyvari F, Kondacs A, Szabo M, Fodor L, Bodor A, Gati I, Wittman I, Melegh B (2005) Endothelial nitric oxide synthase gene interactions and the risk of ischaemic stroke. Acta Neurol Scand 111:29–33
Cui J, Yang G, Su X, Shao Y, Liu D (2007) Correlations between AGT, ACE and eNOS genetic polymorphisms and risk of cerebral infarction. Zhong Guo Lao Nian Xue Za Zhi 11:2197–2199
Lv J, Qu F, Wang J, Cao D (2007) Correlation between eNOS gene polymorphism and risk of cerebral infarction. Hei Long Jiang Yi Yao Ke Xue 30:58–59
Cheng J, Liu J, Li X, Yu L, Peng J, Zhang R, Geng Y, Nie S (2008) Effect of polymorphisms of endothelial nitric oxide synthase on ischemic stroke: a case-control study in a Chinese population. Clin Chim Acta 392:46–51
Moe KT, Woon FP, De Silva DA, Wong P, Koh TH, Kingwell B, Chin-Dusting J, Wong MC (2008) Association of acute ischemic stroke with the MTHFR C677T polymorphism but not with NOS3 gene polymorphisms in a Singapore population. Eur J Neurol 15:1309–1314
Shi C, Kang X, Wang Y, Zhou Y (2008) The coagulation factor V Leiden, MTHFRC677T variant and eNOS 4ab polymorphism in young Chinese population with ischemic stroke. Clin Chim Acta 396:7–9
Song Y, Zhang C, Zou H (2008) Study of a 27-bp variable number of tandem repeat polymorphism of the endothelial nitric oxide synthase gene in patients with transient ischemic attack of brain. Zhong Hua Lao Nian Yi Xue Za Zhi 24:809–811
Zhao S, Hu Y, Niu G, Zhang C, Wang Z, Jiang M, Hu R (2008) Relationship between eNOS gene G894T polymorphism and essential hypertension complicating stroke in Mongolian patients. Zhong Guo Nao Xue Guan Bing Za Zhi 5:167–171
Chen G (2009) The correlation between stroke and eNOS gene polymorphism and prevention strategy. Zhong Guo She Qu Yi Shi 6:19–20
Guldiken B, Sipahi T, Guldiken S, Ustundag S, Budak M, Turgut N, Ozkan H (2009) Glu298Asp polymorphism of the endothelial nitric oxide synthase gene in Turkish patients with ischemic stroke. Mol Biol Rep 36:1539–1543
Yemisci M, Sinici I, Ozkara HA, Hayran M, Ay H, Celtikci B, Onder E, Buyukserbetci G, Kaya EB, Tokgozoglu L, Dalkara T (2009) Protective role of 27 bp repeat polymorphism in intron 4 of eNOS gene in lacunar infarction. Free Radic Res 43:272–279
Zhou X, Du Y (2009) The relationships between eNOS gene polymorphisms and risk of ischemic brain vascular disease in Ling Xing Han peoples. Ling Xia Yi Ke Da Xue Xue Bao 31:306–307
Han H, Gao H (2010) The distribution of eNOS VNTR polymorphism in older patients with ischemic stroke. Zhong Guo Lao Nian Xue Za Zhi 30:1352–1354
Kim OJ, Kim UK, Oh SH, Cho YW, Oh KI, Oh D, Park YS, Kim NK (2010) Association of endothelial nitric oxide synthase polymorphisms and haplotypes with ischemic stroke in Korean individuals with or without diabetes mellitus. Mol Med Rep 3:509–513
Majumdar V, Nagaraja D, Karthik N, Christopher R (2010) Association of endothelial nitric oxide synthase gene polymorphisms with early-onset ischemic stroke in South Indians. J Atheroscler Thromb 17:45–53
Munshi A, Rajeshwar K, Kaul S, Chandana E, Shafi G, Anila AN, Balakrishna N, Alladi S, Jyothy A (2010) VNTR polymorphism in intron 4 of the eNOS gene and the risk of ischemic stroke in a South Indian population. Brain Res Bull 82:247–250
Song J, Kim OJ, Kim HS, Bae SJ, Hong SP, Oh D, Kim NK (2010) Endothelial nitric oxide synthase gene polymorphisms and the risk of silent brain infarction. Int J Mol Med 25:819–823
Fang L, Wang L, Lin M, Murong S (2011) Association of endothelial nitric oxide synthase gene intron 4 polymorphisms with cerebrovascular disease in Han population of Fujian. Zhong Guo Jing Shen Ji Bing Za Zhi 37:687–690
Harbord RM, Higgins JPT (2008) Meta–regression in stata. Stata J 8:493–519
Yetik-Anacak G, Catravas JD (2006) Nitric oxide and the endothelium: history and impact on cardiovascular disease. Vascul Pharmacol 45:268–276
Atochin DN, Huang PL (2011) Role of endothelial nitric oxide in cerebrovascular regulation. Curr Pharm Biotechnol 12:1334–1342
Tesauro M, Thompson WC, Rogliani P, Qi L, Chaudhary PP, Moss J (2000) Intracellular processing of endothelial nitric oxide synthase isoforms associated with differences in severity of cardiopulmonary diseases: cleavage of proteins with aspartate vs. glutamate at position 298. Proc Natl Acad Sci USA 97:2832–2835
Senthil D, Raveendran M, Shen YH, Utama B, Dudley D, Wang J, Wang XL (2005) Genotype-dependent expression of endothelial nitric oxide synthase (eNOS) and its regulatory proteins in cultured endothelial cells. DNA Cell Biol 24:218–224
Saini V, Bhatnagar MK, Bhattacharjee J (2011) Association of endothelial dysfunction with endothelin, nitric oxide and eNOS Glu298Asp gene polymorphism in coronary artery disease. Dis Markers 31:215–222
He Y, Fan Z, Zhang J, Zhang Q, Zheng M, Li Y, Zhang D, Gu S, Yang H (2011) Polymorphisms of eNOS gene are associated with diabetic nephropathy: a meta-analysis. Mutagenesis 26:339–349
Stern JM, Simes RJ (1997) Publication bias: evidence of delayed publication in a cohort study of clinical research projects. BMJ 315:640–645
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Guo, X. Endothelial nitric oxide (eNOS) gene G894T and VNTR polymorphisms are closely associated with the risk of ischemic stroke development for Asians: meta-analysis of epidemiological studies. Mol Biol Rep 41, 2571–2583 (2014). https://doi.org/10.1007/s11033-014-3115-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11033-014-3115-8