Abstract
Aim:
To investigate the association of polymorphisms in four critical genes implicated in the NO-forming pathway with ischemic stroke (IS) in a Chinese Han population.
Methods:
DNA samples of 558 IS patients and 557 healthy controls from Chinese Han population were genotyped using the TaqmanTM 7900HT Sequence Detection System. Six SNPs (rs841, rs1049255, rs2297518, rs1799983, rs2020744, rs4673) of the 4 related genes (eNOS, iNOS, GCH1, and CYBA) in the NO forming pathway were analyzed using the SPSS 13.0 software package for Windows.
Results:
One SNP located in the intron of GCH1 (rs841) was associated with IS independent of the traditional cardiovascular risk factors in co-dominant and dominant models (P=0.003, q=0.027; P=0.00006, q=0.0108; respectively). Moreover, the combination of rs1049255 CC+CT and rs841 GA+AA genotypes was associated with significantly higher risk for IS after adjustments (OR=1.73, 95% CI: 1.27–2.35, P<0.0001, q<0.0001).
Conclusion:
The data suggest that genetic variants within the NO-forming pathway alter susceptibility to IS in Chinese Han population. Replication of the present results in other independent cohorts is warranted.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Jia Q, Liu LP, Wang YJ . Stroke in China. Clin Exp Pharmacol Physiol 2010; 37: 259–64.
Meschia JF, Brott TG, Brown RD Jr, Crook RJ, Frankel M, Hardy J, et al. The ischemic stroke genetics study (ISGS) protocol. BMC Neurol 2003; 3: 4.
Iadecola C, Pelligrino DA, Moskowitz MA, Lassen NA . Nitric oxide synthase inhibition and cerebrovascular regulation. J Cereb Blood Flow Metab 1994; 14: 175–92.
Faraci FM, Brian JE Jr . Nitric oxide and the cerebral circulation. Stroke 1994; 25: 692–703.
Forman LJ, Liu P, Nagele RG, Yin K, Wong PY . Augmentation of nitric oxide, superoxide, and peroxynitrite production during cerebral ischemia and reperfusion in the rat. Neurochem Res 1998; 23: 141–8.
Yogo K, Shimokawa H, Funakoshi H, Kandabashi T, Miyata K, Okamoto S, et al. Different vasculoprotective roles of NO synthase isoforms in vascular lesion formation in mice. Arterioscler Thromb Vasc Biol 2000; 20: E96–E100.
Wang SS, Davis S, Cerhan JR, Hartge P, Severson RK, Cozen W, et al. Polymorphisms in oxidative stress genes and risk for non-Hodgkin lymphoma. Carcinogenesis 2006; 27: 1828–34.
Alvarez R, Gonzalez P, Batalla A, Reguero JR, Iglesias-Cubero G, Hevia S, et al. Association between the NOS3 (-786 T/C) and the ACE (I/D) DNA genotypes and early coronary artery disease. Nitric Oxide 2001; 5: 343–8.
Shimasaki Y, Yasue H, Yoshimura M, Nakayama M, Kugiyama K, Ogawa H, et al. Association of the missense Glu298Asp variant of the endothelial nitric oxide synthase gene with myocardial infarction. J Am Coll Cardiol 1998; 31: 1506–10.
Hingorani AD, Liang CF, Fatibene J, Lyon A, Monteith S, Parsons A, et al. A common variant of the endothelial nitric oxide synthase (Glu298→Asp) is a major risk factor for coronary artery disease in the UK. Circulation 1999; 100: 1515–20.
Cai H, Wilcken DE, Wang XL . The Glu-298→Asp (894G→T) mutation at exon 7 of the endothelial nitric oxide synthase gene and coronary artery disease. J Mol Med 1999; 77: 511–4.
Nakayama M, Yasue H, Yoshimura M, Shimasaki Y, Kugiyama K, Ogawa H, et al. T-786→C mutation in the 5′-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm. Circulation 1999; 99: 2864–70.
Guzik TJ, West NE, Black E, McDonald D, Ratnatunga C, Pillai R, et al. Functional effect of the C242T polymorphism in the NAD(P)H oxidase p22phox gene on vascular superoxide production in atherosclerosis. Circulation 2000; 102: 1744–7.
Inoue N, Kawashima S, Kanazawa K, Yamada S, Akita H, Yokoyama M . Polymorphism of the NADH/NADPH oxidase p22 phox gene in patients with coronary artery disease. Circulation 1998; 97: 135–7.
Li A, Prasad A, Mincemoyer R, Satorius C, Epstein N, Finkel T, et al. Relationship of the C242T p22phox gene polymorphism to angiographic coronary artery disease and endothelial function. Am J Med Genet 1999; 86: 57–61.
Cahilly C, Ballantyne CM, Lim DS, Gotto A, Marian AJ . A variant of p22(phox), involved in generation of reactive oxygen species in the vessel wall, is associated with progression of coronary atherosclerosis. Circ Res 2000; 86: 391–5.
Zhang L, Rao F, Zhang K, Khandrika S, Das M, Vaingankar SM, et al. Discovery of common human genetic variants of GTP cyclohydrolase 1 (GCH1) governing nitric oxide, autonomic activity, and cardiovascular risk. J Clin Invest 2007; 117: 2658–71.
Wang Q, Ding H, Tang JR, Zhang L, Xu YJ, Yan JT, et al. C-reactive protein polymorphisms and genetic susceptibility to ischemic stroke and hemorrhagic stroke in the Chinese Han population. Acta Pharmacol Sin 2009; 30: 291–8.
Storey JD, Tibshirani R . Statistical significance for genomewide studies. Proc Natl Acad Sci U S A 2003; 100: 9440–5.
QUANTO 1.1: A computer program for power and sample size calculations for genetic-epidemiology studies, http://hydra.usc.edu/gxe; 2006.
Hassan A, Gormley K, O'Sullivan M, Knight J, Sham P, Vallance P, et al. Endothelial nitric oxide gene haplotypes and risk of cerebral small-vessel disease. Stroke 2004; 35: 654–9.
Szolnoki Z, Havasi V, Bene J, Komlosi K, Szoke D, Somogyvari F, et al. Endothelial nitric oxide synthase gene interactions and the risk of ischaemic stroke. Acta Neurol Scand 2005; 111: 29–33.
Markus HS, Ruigrok Y, Ali N, Powell JF . Endothelial nitric oxide synthase exon 7 polymorphism, ischemic cerebrovascular disease, and carotid atheroma. Stroke 1998; 29: 1908–11.
Moens AL, Kass DA . Tetrahydrobiopterin and cardiovascular disease. Arterioscler Thromb Vasc Biol 2006; 26: 2439–44.
Vasquez-Vivar J, Kalyanaraman B, Martasek P, Hogg N, Masters BS, Karoui H, et al. Superoxide generation by endothelial nitric oxide synthase: the influence of cofactors. Proc Natl Acad Sci U S A 1998; 95: 9220–5.
Auerbach G, Nar H . The pathway from GTP to tetrahydrobiopterin: three dimensional structures of GTP cyclohydrolase I and 6-pyruvoyl tetrahydropterin synthase. Biol Chem 1997; 378: 185–92.
Khoo JP, Nicoli T, Alp NJ, Fullerton J, Flint J, Channon KM . Congenic mapping and genotyping of the tetrahydrobiopterin-deficient hph-1 mouse. Mol Genet Metab 2004; 82: 251–4.
Khoo JP, Zhao L, Alp NJ, Bendall JK, Nicoli T, Rockett K, et al. Pivotal role for endothelial tetrahydrobiopterin in pulmonary hypertension. Circulation 2005; 111: 2126–33.
Hyland K, Gunasekara RS, Munk-Martin TL, Arnold LA, Engle T . The hph-1 mouse: a model for dominantly inherited GTP-cyclohydrolase deficiency. Ann Neurol 2003; 54: S46–8.
San Jose G, Fortuno A, Beloqui O, Diez J, Zalba G . NADPH oxidase CYBA polymorphisms, oxidative stress and cardiovascular diseases. Clin Sci (Lond) 2008; 114: 173–82.
Mueller CF, Laude K, McNally JS, Harrison DG . ATVB in focus: redox mechanisms in blood vessels. Arterioscler Thromb Vasc Biol 2005; 25: 274–8.
Acknowledgements
This study was supported by China 973 program (No 2007CB512004), and 863 program (No 2006AA02A406).
Author information
Authors and Affiliations
Corresponding author
Additional information
Supplementary tables are available at Acta Pharmacologica Sinica website of NPG.
Supplementary information
Supplementary Table 1
Distribution of Genotypes in three models in Atherothrombosis of Ischemic Stroke
Supplementary Table 2
Distribution of Genotypes in three models in Lacunar Infarction of Ischemic Stroke
Rights and permissions
About this article
Cite this article
Yan, Jt., Zhang, L., Xu, Yj. et al. Polymorphisms of genes in nitric oxide-forming pathway associated with ischemic stroke in Chinese Han population. Acta Pharmacol Sin 32, 1357–1363 (2011). https://doi.org/10.1038/aps.2011.114
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/aps.2011.114
Keywords
This article is cited by
-
GCH1 (rs841) polymorphism in the nitric oxide-forming pathway has protective effects on obstructive sleep apnea
Scientific Reports (2019)
-
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
Molecular Biology Reports (2014)