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Authors: Bushueva O.Yu., Stetskaya T.A., Vyalykh E.K., Ivanov V.P., Polonikov A.V.

Pages: 176-184



Introduction. The renin-angiotensin system is a major regulator of blood pressure. The angiotensin II type 1 receptor (AGTR1) plays a key role in blood pressure control, and is implicated in the pathogenesis of cerebrovascular disease. Polymorphisms within the AGTR1 gene have been found to be associated with the risk cerebral stroke (CS) in some populations. However, the exact role of this gene polymorphism in genetic predisposition to cerebrovascular disease is unclear.


Purpose. The aim of thisstudy was to investigate the association of polymorphism A1166C (rs5186) of AGTR1 gene with the risk of cerebral stroke in hypertensive patients of Central Russia.


Materials and methods. The patients with CS and healthy controls were recruited at Kursk hospitals during periods 2007 and 2010, and also between 2012 and 2013. We studied DNA samples obtained from 830 subjects, including 454 CS patients and 276 sex- and age-matched healthy controls with normal blood pressure level. The diagnosis of CS in all cases was confirmed by magnetic resonance imaging investigation. The polymorphism A1166C of AGTR1 genewas genotyped by TaqMan allele discrimination assay.

Results and discussion. Comparative analysis showed a difference in allele and genotype frequencies of polymorphism A1166C of AGTR1 genebetween the case and control groups. The study suggests that the AGTR1 gene A1166C polymorphism is not associated with susceptibility to CS in population from Central Russian region. Analysis stratified by a gender did not reveal the associations of the AGTR1 gene A1166C polymorphism with the CS risk. Our results are in agreement with the studies performed in other Russian and African Americans populations regarding the polymorphismA1166C of the AGTR1 gene. It is not a susceptibility gene for cerebral stroke.

Key words: cerebral stroke, genetic predisposition, angiotensinogen gene, single nucleotide polymorphism, sexual dimorphism.

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  1. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, Cross M, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2095–128. doi: 10.1016/S0140-6736(12)61728-0
  2. Bevan S, Traylor M, Adib-Samii P, Malik R, Paul NL, Jackson C, Farrall M, Rothwell PM, Sudlow C, Dichgans M, Markus HS. Genetic heritability of ischemic stroke and the contribution of previously reported candidate gene and genomewide associations. Stroke. 2012;43(12):3161–3167. doi:10.1161/STROKEAHA.112.665760
  3. Hassan A, Markus HS. Genetics and ischaemic stroke. Brain. 2000;123(9):1784–1812.
  4. Dichgans M, Markus HS. Genetic association studies in stroke methodological issues and proposed standard criteria. Stroke. 2005;36(9):2027–2031.
  5. Wei JW, Arima H, Huang Y, Wang JG, Yang Q, Liu Z, Liu M, Lu C, Heeley EL, Anderson CS; ChinaQUEST Investigators. [Variation in the frequency of intracerebral haemorrhage and ischaemic stroke in China: a national, multicentre, hospital register study]. Cerebrovascular Diseases. 2010;29(4):321–327. doi: 10.1159/000278927
  6. Marcheselli S, Micieli G. Renin-angiotensin system and stroke. Neurological Sciences. 2008;29(2):277–278. doi:10.1007/s10072-008-0963-9
  7. Cronin S, Furie KL, Kelly PJ. Dose-related association of MTHFR 677T allele with risk of ischemic stroke Evidence from a cumulative meta-analysis. Stroke. 2005;36(7):1581–1587.
  8. Berger K, Stogbauer F, Stoll M, Wellmann J, Huge A, Cheng S, Kessler C, John U, Assmann G, Ringelstein EB, Funke H. 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. Human Genetics. 2007;121(2):169–178.
  9. Xu E, Li W, Zhan L, Guan G, Wang X, Chen S, Shi Y. Polymorphisms of the lipoprotein lipase gene are associated with atherosclerotic cerebral infarction in the Chinese. Neuroscience. 2008;155(2):403–408. doi: 10.1016/j.neuroscience.2008.06.007.
  10. Rubattu S, Di Angelantonio E, Stanzione R, Zanda B, Evangelista A, Pirisi A, De Paolis P, Cota L, Brunetti E, Volpe M. Gene polymorphisms of the renin-angiotensin-aldosterone system and the risk of ischemic stroke: a role of the A1166C/AT1 gene variant. Journal of Hypertension. 2004;22(11):2129–2134.
  11. Szolnoki Z, Havasi V, Talian G, Bene J, Komlosi K, Somogyvari F, Kondacs A, Szabo M, Fodor L, Bodor A, Melegh B. Angiotensin II type-1 receptor A1166C polymorphism is associated with increased risk of ischemic stroke in hypertensive smokers. Journal of Molecular Neuroscience. 2006;28(3):285–290.
  12. Timmermans PB, Wong PC, Chiu AT, Herblin WF, Benfield P, Carini DJ, Lee RJ, Wexler RR, Saye JA, Smith RD. Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacological Reviews. 1993;45(2):205–251.
  13. Brenner D, Labreuche J, Poirier O. Cambien F, Amarenco P. Renin–angiotensin–aldosterone system in brain infarction and vascular death. Annals of Neurology. 2005;58(1):131–138.
  14. Kim S, Iwao H. Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacological Reviews. 2000;52(1):11–34.
  15. Baudin B. Polymorphism in angiotensin II receptor genes and hypertension. Experimental Physiology. 2005;90(3):277–282.
  16. Henskens LH, Kroon AA, van Boxtel MP, Hofman PA, de Leeuw PW. Associations of the angiotensin II type 1 receptor A1166C and the endothelial NO synthase G894T gene polymorphisms with silent subcortical white matter lesions in essential hypertension. Stroke. 2005;36(9):1869–1873.
  17. Hindorff LA, Heckbert SR, Tracy R, Tang Z, Psaty BM, Edwards KL, Siscovick DS, Kronmal RA, Nazar-Stewart V. Angiotensin II type 1 receptor polymorphisms in the cardiovascular health study: relation to blood pressure, ethnicity, and cardiovascular events. American Journal of Hypertension. 2002;15(12):1050–1056.
  18. Usacheva MA, Nasedkina TV, Ikonnikova AYu, Kulikov AV, Chudinov AV, Lysov IuP, Bondarenko EV, Slominskii PA, Shamalov NA, Shetova IM, Limborskaia SA, Zasedatelev AS, Skvortsova VI. [Association study of renin-angiotensin system genes and hemostasis system genes with ischemic stroke among Russians of Central Russia]. Molekuliarnaia Bioogiia. (Mosk.). 2012;46(2):214–223.
  19. Zhang H, Sun M, Sun T, Zhang C, Meng X, Zhang Y, Yang J. Association between angiotensin II type 1 receptor gene polymorphisms and ischemic stroke: a meta-analysis. Cerebrovascular Diseases. 2011;32(5):431–438. doi: 10.1159/000330655
  20. Vialykh EK, Solidolova MA, Bushueva OIu, Bulgakova IV, Polonikov AV. [Catalase gene polymorphism is associated with increased risk of cerebral stroke in hypertensive patients]. Zhurnal nevrologii i psikhiatrii imeni S.. 2012;112(8, pt 2):3–7.
  21. Polonikov AV, Solodilova MA, Ivanov VP, Shestakov AM, Ushachev DV, Vialykh EK, Vasil'eva OV, Poliakova NV, Antsupov VV, Kabanina VA, Kupriianova IaS, Bulgakova IV, Kozhukhov MA, Tevs DS. [A protective effect of GLY272SER polymorphism of GNB3 gene in development of essential hypertension and its relations with environmental hypertension risk factors]. Terapevticheskiiarkhiv. 2011;83(4):55–60.
  22. Burnier M, Brunner HR. Angiotensin II receptor antagonists. Lancet. 2000;355(9204):637–645.
  23. Unger T. The role of the renin-angiotensin system in the development of cardiovascular disease. The American Journal of Cardiology. 2002;89(2):3–9.
  24. Stankovic A, Zivkovic M, Glisic S, Alavantic D. Angiotensin II type 1 receptor gene polymorphism and essential hypertension in Serbian population. Clinica Chimica Acta. 2003;327(1):181–185.
  25. Ferrario CM. Role of angiotensin II in cardiovascular disease therapeutic implications of more than a century of research. Journal of the Renin-angiotensin-aldosterone System. 2006;7(1):3–14.
  26. Weir MR. Providing endorgan protection with renin–angiotensin system inhibition: the evidence so far. The Journal of Clinical Hypertension. 2006;8(2):99–107.
  27. Benetos A, Gautier S, Ricard S, Topouchian J, Asmar R, Poirier O, Larosa E, Guize L, Safar M, Soubrier F, Cambien F. Influence of angio-tensin-converting enzyme and angiotensin II type 1 receptor gene polymorphisms on aortic stiffness in normotensive and hypertensive patients. Circulation. 1996;94:698–703.
  28. Zhao Y, Ma LY, Liu YC, Wang XY, Liu LS, Klaus L. Relationship between AT R21 gene A1166C polymorphism and ischemic stroke. Journal of Geriatric CardiovascularandCerebrovascular Diseases. 2001;4:247–249.
  29. Hulyam K, Aysegul B, Veysi GH, Demet O, Irfan D, Ertugrul C, Didem CT, Banu B, Miris D. Frequency of angiotensin II type 1 receptor gene polymorphism in Turkish acute stroke patients. Journal of Cellular and Molecular Medicine. 2013;17(4):475–81. doi: 10.1111/jcmm.12017
  30. Curnow KM, Pascoe L, White PC. Genetic analysis of the human type-1 angiotensin II receptor. Molecular Endocrinology (Baltimore, Md.). 1992;6(7):1113–1118.
  31. de Gasparo M, Catt KJ, Inagami T, Wright JW, Unger TH. International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacological Reviews. 2000;52(3):415–472.
  32. Zhu S, Meng QH. Association of angiotensin II type 1 receptor gene polymorphism with carotid atherosclerosis. Clinical Chemistry and Laboratory Medicine. 2006;44(3):282–284.
  33. Alvarez R, Reguero JR, Batalla A, Iglesias-Cubero G, Cortina A, Alvarez V, Coto E. Angiotensin-converting enzyme and angiotensin II receptor 1 polymorphisms: association with early coronary disease. Cardiovascular Research. 1998;40(2):375–379.
  34. Mottl AK, Shoham DA, North KE. Angiotensin II type 1 receptor polymorphisms and susceptibility to hypertension: a HuGE review. Genetics in Medicine. 2008;10(8):560–574. doi: 10.1097GIM.0b013e3181809613
  35. Xu M, Sham P, Ye Z, Lindpaintner K, He L. A1166C genetic variation of the angiotensin II type I receptor gene and susceptibility to coronary heart disease: collaborative of 53 studies with 20,435 cases and 23,674 controls. Atherosclerosis. 2010;213(1):191–199. doi: 10.1016/j.atherosclerosis.2010.07.046
  36. Bonnardeaux A, Davies E, Jeunemaitre X, Fery I, Charru A, Clauser E, Tiret L, Cambien F, Corvol P, Soubrier F. Angiotensin II type 1 receptor gene polymorphisms in human essential hypertension. Hypertension. 1994;24(1):63–69.
  37. Lehtonen J, Paukku K, Daviet L, Kontula K. Angiotensin II type 1 receptor 1166 polymorphism A to C Increases mRNA stability and steady-state levels. Circulation. 2006;114(II):190.
  38. Abdollahi MR, Lewis RM, Gaunt TR, Cumming DV, Rodriguez S, Rose-Zerilli M, Collins AR, Syddall HE, Howell WM, Cooper C, Godfrey KM, Cameron IT, Day IN. Quantitated transcript haplotypes (QTH) of AGTR1, reduced abundance of mRNA haplotypes containing 1166C (rs5186:A>C), and relevance to metabolic syndrome traits. Human Mutation. 2007;28:365–373.
  39. Sethupathy P, Borel C, Gagnebin M, Grant GR, Deutsch S, Elton TS, Hatzigeorgiou AG, Antonarakis SE. Human microRNA-155 on chromosome 21 differentially interacts with its polymorphic target in the AGTR1 3′ untranslated region: a mechanism for functional single-nucleotide polymorphisms related to phenotypes. The American Journal of Human Genetics. 2007;81(2):405–413.
  40. Ceolotto G, Papparella I, Bortoluzzi A, Strapazzon G, Raqazzo F, Bratti P, Fabricio AS, Squaraina E, Gion M, Palatini P, Semplicini A. Interplay between miR-155, AT1R A1166C polymorphism, and AT1R expression in young untreated hypertensives. American Journal of Hypertension. 2011;24:241–246. doi: 10.1038/ajh.2010.211
  41. Geisterfer AA, Peach MJ, Owens GK. Angiotensin II induces hypertrophy, not hyperplasia, of cultured rat aortic smooth muscle cells. Circulation Research. 1988;62(4):749–756.
  42. Paquet JL, Baudouin-Legros M, Brunelle G, Meyer P. Angiotensin ll-induced proliferation of aortic myocytes in spontaneously hypertensive rats. Journal of Hypertension. 1990;8(6):565–572.
  43. Stoll M, Steckelings UM, Paul M, Bottari SP, Metzger R, Unger T.[The angiotensin AT2-receptor mediates inhibition of cell proliferation in coronary endothelial cells. Journal of Clinical Investigation. 1995;95(2):651.
  44. Lucius R, Gallinat S, Busche S, Rosenstiel P, Unger T. Beyond blood pressure: new roles for angiotensin II. Cellular and Molecular Life Sciences. 1999;56(11–12):1008–1019.
  45. Berry C, Brosnan MJ, Fennell J, Hamilton CA, Dominiczak AF. Oxidative stress and vascular damage in hypertension. Current Opinion in Nephrology and Hypertension. 2001;10(2):247–255.