Cell Biochemistry and Biophysics

, Volume 69, Issue 2, pp 237–246

Polymorphisms of ECE1 May Contribute to Susceptibility to Ischemic Stroke in Han Chinese of Northern China

Original Paper

Abstract

Endothelin (ET) converting enzyme 1 (ECE1) is well known for its critical role in the process of ET. Recent studies have demonstrated that two genetic variants of ECE1 gene, rs212528 and rs213045 (C338A), are associated with hypertension and atherosclerosis formation. To investigate the association between the ECE1 gene polymorphisms and ischemic stroke (IS) in Chinese population. With a candidate loci strategy, we conducted a case–control study involving 381 IS cases and 366 non-IS controls in Han population of the Northern China. Two single nucleotide polymorphisms of ECE1 were genotyped and assessed the association with the risk of IS. Furthermore, stratified analyses were also carried out to evaluate the association between the gender or two etiologic subtypes [small-artery occlusion (SAO) and large-artery atherosclerosis (LAA)] and IS. Compared with rs213045 G homozygote, rs213045 TG genotype and rs213045 TT/TG genotypes are in dominant model significantly increased the risk of IS [adjusted odds ratio (OR) = 1.47, 95 % confidence interval (CI) = 1.04–2.07, P = 0.03; adjusted OR = 1.43, 95 % CI = 1.04–1.99, P = 0.029, respectively]. However, we did not find the significant association between the ECE1 gene polymorphisms and SAO or LAA of IS in this study. Our results indicated that ECE1 gene polymorphisms may contribute to the susceptibility of IS in Han population of the Northern China.

Keywords

ECE1 IS Polymorphism Susceptibility Risk 

References

  1. 1.
    Liu, L., Wang, D., Wong, K. S., et al. (2011). Stroke and stroke care in China: Huge burden, significant workload, and a national priority. Stroke, 42(12), 3651–3654.PubMedCrossRefGoogle Scholar
  2. 2.
    Traylor, M., Farrall, M., Holliday, E. G., et al. (2012). Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): A meta-analysis of genome-wide association studies. The Lancet Neurology, 11(11), 951–962.CrossRefGoogle Scholar
  3. 3.
    Markus, H. S. (2011). Stroke genetics. Human Molecular Genetics, 20(R2), R124–R131.PubMedCrossRefGoogle Scholar
  4. 4.
    Brainin, M., Teuschl, Y., & Kalra, L. (2007). Acute treatment and long-term management of stroke in developing countries. The Lancet Neurology, 6(6), 553–561.CrossRefGoogle Scholar
  5. 5.
    Liu, M., Wu, B., Wang, W.-Z., et al. (2007). Stroke in China: Epidemiology, prevention, and management strategies. The Lancet Neurology, 6(5), 456–464.CrossRefGoogle Scholar
  6. 6.
    Adams, H. P., Jr., Bendixen, B. H., Kappelle, L. J., et al. (1993). Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke, 24(1), 35–41.PubMedCrossRefGoogle Scholar
  7. 7.
    Schulz, U. G., Flossmann, E., & Rothwell, P. M. (2004). Heritability of ischemic stroke in relation to age, vascular risk factors, and subtypes of incident stroke in population-based studies. Stroke, 35(4), 819–824.PubMedCrossRefGoogle Scholar
  8. 8.
    Kuruppu, S., & Smith, A. I. (2012). Endothelin Converting Enzyme-1 phosphorylation and trafficking. FEBS Letters, 586(16), 2212–2217.PubMedCrossRefGoogle Scholar
  9. 9.
    Hamilton, G., Harris, S. E., Davies, G., et al. (2012). The role of ECE1 variants in cognitive ability in old age and Alzheimer’s disease risk. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 159B(6), 696–709.CrossRefGoogle Scholar
  10. 10.
    Iglarz, M., & Clozel, M. (2007). Mechanisms of ET-1-induced endothelial dysfunction. Journal of Cardiovascular Pharmacology, 50(6), 621–628.PubMedCrossRefGoogle Scholar
  11. 11.
    Penna, C., Rastaldo, R., Mancardi, D., et al. (2006). Effect of endothelins on the cardiovascular system. Journal of Cardiovascular Medicine (Hagerstown), 7(9), 645–652.CrossRefGoogle Scholar
  12. 12.
    Russell, F. D., Skepper, J. N., & Davenport, A. P. (1998). Human endothelial cell storage granules: A novel intracellular site for isoforms of the endothelin-converting enzyme. Circulation Research, 83(3), 314–321.PubMedCrossRefGoogle Scholar
  13. 13.
    Lowenstein, C. J., Morrell, C. N., & Yamakuchi, M. (2005). Regulation of Weibel–Palade body exocytosis. Trends in Cardiovascular Medicine, 15(8), 302–308.PubMedCrossRefGoogle Scholar
  14. 14.
    Luscher, T. F., & Barton, M. (2000). Endothelins and endothelin receptor antagonists: Therapeutic considerations for a novel class of cardiovascular drugs. Circulation, 102(19), 2434–2440.PubMedCrossRefGoogle Scholar
  15. 15.
    Hoang, M. V., Sansom, C. E., & Turner, A. J. (1997). Mutagenesis of Glu403 to Cys in rabbit neutral endopeptidase-24.11 (neprilysin) creates a disulphide-linked homodimer: Analogy with endothelin-converting enzyme. Biochemical Journal, 327(Pt 3), 925–929.PubMedCentralPubMedGoogle Scholar
  16. 16.
    Turner, A. J., & Murphy, L. J. (1996). Molecular pharmacology of endothelin converting enzymes. Biochemical Pharmacology, 51(2), 91–102.PubMedCrossRefGoogle Scholar
  17. 17.
    Smollich, M., & Wulfing, P. (2008). Targeting the endothelin system: Novel therapeutic options in gynecological, urological and breast cancers. Expert Review of Anticancer Therapy, 8(9), 1481–1493.PubMedCrossRefGoogle Scholar
  18. 18.
    Jeng, A. Y. (2003). Utility of endothelin-converting enzyme inhibitors for the treatment of cardiovascular diseases. Current Opinion in Investigational Drugs, 4(9), 1076–1081.PubMedGoogle Scholar
  19. 19.
    Martinez-Miguel, P., Raoch, V., Zaragoza, C., et al. (2009). Endothelin-converting enzyme-1 increases in atherosclerotic mice: Potential role of oxidized low density lipoproteins. Journal of Lipid Research, 50(3), 364–375.PubMedCrossRefGoogle Scholar
  20. 20.
    Funalot, B., Ouimet, T., Claperon, A., et al. (2004). Endothelin-converting enzyme-1 is expressed in human cerebral cortex and protects against Alzheimer’s disease. Molecular Psychiatry, 9(12), 1122–1128, 1059.Google Scholar
  21. 21.
    Minamino, T., Kurihara, H., Takahashi, M., et al. (1997). Endothelin-converting enzyme expression in the rat vascular injury model and human coronary atherosclerosis. Circulation, 95(1), 221–230.PubMedCrossRefGoogle Scholar
  22. 22.
    Shirai, N., Naruko, T., Ohsawa, M., et al. (2006). Expression of endothelin-converting enzyme, endothelin-1 and endothelin receptors at the site of percutaneous coronary intervention in humans. Journal of Hypertension, 24(4), 711–721.PubMedCrossRefGoogle Scholar
  23. 23.
    Wang, Y., Liu, Y., Peng, W., et al. (2012). ECE1 polymorphisms may contribute to the susceptibility of sporadic congenital heart disease in a Chinese population. DNA and Cell Biology, 31(8), 1425–1430.PubMedCrossRefGoogle Scholar
  24. 24.
    Wang, L. S., Tang, N. P., Zhu, H. J., et al. (2007). Endothelin-converting enzyme-1b C-338A polymorphism is associated with the increased risk of coronary artery disease in Chinese population. Clinica Chimica Acta, 384(1–2), 75–79.CrossRefGoogle Scholar
  25. 25.
    Banno, M., Hanada, H., Kamide, K., et al. (2007). Association of genetic polymorphisms of endothelin-converting enzyme-1 gene with hypertension in a Japanese population and rare missense mutation in preproendothelin-1 in Japanese hypertensives. Hypertension Research, 30(6), 513–520.PubMedCrossRefGoogle Scholar
  26. 26.
    Whisnant, J. P. (1996). Effectiveness versus efficacy of treatment of hypertension for stroke prevention. Neurology, 46(2), 301–307.PubMedCrossRefGoogle Scholar
  27. 27.
    Collins, R., Peto, R., MacMahon, S., et al. (1990). Blood pressure, stroke, and coronary heart disease. Part 2, short-term reductions in blood pressure: Overview of randomised drug trials in their epidemiological context. Lancet, 335(8693), 827–838.PubMedCrossRefGoogle Scholar
  28. 28.
    Shinton, R., & Beevers, G. (1989). Meta-analysis of relation between cigarette smoking and stroke. British Medical Journal, 298(6676), 789–794.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Wannamethee, S. G., Shaper, A. G., Whincup, P. H., et al. (1995). Smoking cessation and the risk of stroke in middle-aged men. Journal of American Medical Association, 274(2), 155–160.CrossRefGoogle Scholar
  30. 30.
    (1995). Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 450,000 people in 45 prospective cohorts. Prospective studies collaboration. Lancet, 346(8991–8992), 1647–1653.Google Scholar
  31. 31.
    Iso, H., Jacobs, D. R., Jr., Wentworth, D., et al. (1989). Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial. The New England Journal of Medicine, 320(14), 904–910.PubMedCrossRefGoogle Scholar
  32. 32.
    Psaty, B. M., Lumley, T., Furberg, C. D., et al. (2003). Health outcomes associated with various antihypertensive therapies used as first-line agents: A network meta-analysis. Journal of American Medical Association, 289(19), 2534–2544.CrossRefGoogle Scholar
  33. 33.
    Matthan, N. R., Zhu, L., Pencina, M., et al. (2013). Sex-specific differences in the predictive value of cholesterol homeostasis markers and 10-year cardiovascular disease event rate in Framingham offspring study participants. Journal of American Heart Association, 2(1), e005066.CrossRefGoogle Scholar
  34. 34.
    He, C., Gu, M., Jiang, R., et al. (2013). Noninvasive assessment of the carotid and cerebrovascular atherosclerotic plaques by multidetector CT in type-2 diabetes mellitus patients with transient ischemic attack or stroke. Diabetology and Metabolic Syndrome, 5(1), 9.PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Dormandy, J. A., Charbonnel, B., Eckland, D. J., et al. (2005). Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): A randomised controlled trial. Lancet, 366(9493), 1279–1289.PubMedCrossRefGoogle Scholar
  36. 36.
    Scacchi, R., Gambina, G., Broggio, E., et al. (2008). C-338A polymorphism of the endothelin-converting enzyme (ECE-1) gene and the susceptibility to sporadic late-onset Alzheimer’s disease and coronary artery disease. Disease Markers, 24(3), 175–179.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Jin, Z., Luxiang, C., Huadong, Z., et al. (2009). Endothelin-converting enzyme-1 promoter polymorphisms and susceptibility to sporadic late-onset Alzheimer’s disease in a Chinese population. Disease Markers, 27(5), 211–215.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Funalot, B., Courbon, D., Brousseau, T., et al. (2004). Genes encoding endothelin-converting enzyme-1 and endothelin-1 interact to influence blood pressure in women: The EVA study. Journal of Hypertension, 22(4), 739–743.PubMedCrossRefGoogle Scholar
  39. 39.
    Jin, Z., Luxiang, C., Huadong, Z., et al. (2009). C-338A polymorphism of the endothelin-converting enzyme-1 gene and the susceptibility to carotid atherosclerosis. Microvascular Research, 78(1), 128–131.PubMedCrossRefGoogle Scholar
  40. 40.
    Funke-Kaiser, H., Reichenberger, F., Kopke, K., et al. (2003). Differential binding of transcription factor E2F-2 to the endothelin-converting enzyme-1b promoter affects blood pressure regulation. Human Molecular Genetics, 12(4), 423–433.PubMedCrossRefGoogle Scholar
  41. 41.
    von Websky, K., Heiden, S., Pfab, T., et al. (2009). Pathophysiology of the endothelin system—Lessons from genetically manipulated animal models. European Journal of Medical Research, 14(1), 1–6.Google Scholar
  42. 42.
    Levy, N., Gordin, M., Mamluk, R., et al. (2001). Distinct cellular localization and regulation of endothelin-1 and endothelin-converting enzyme-1 expression in the bovine corpus luteum: Implications for luteolysis. Endocrinology, 142(12), 5254–5260.PubMedCrossRefGoogle Scholar
  43. 43.
    Polderman, K. H., Stehouwer, C. D., van Kamp, G. J., et al. (1993). Influence of sex hormones on plasma endothelin levels. Annals of Internal Medicine, 118(6), 429–432.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Neurologythe First Affiliated Hospital of China Medical UniversityShenyangChina

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