GENETIC ASPECTS OF MODIFIABLE RISK FACTORS ASSOCIATED WITH ARTERIAL HYPERTENSION BY THE EXAMPLE OF THE INDIGENOUS POPULATION OF MOUNTAIN SHORIYA

Aim. To study the associations of ACE, ADRA2B, ADRB1, MTHFR and e-NOS3 candidate genes of arterial hypertension with its risk factors among the indigenous and non-indigenous population of Mountain Shoriya.

Material and methods. Clinical epidemiological community-based study was conducted in hard-to-reach regions of Mountain Shoriya (villages Orton, Ust’-Kabyrza, Sheregesh in Kemerovo Region). 1178 inhabitants of the mentioned villages were examined by the continuous method, selection consisted of adult population (18 years old and above), 565 people were genotyped. All patients underwent clinical, laboratory and instrumental examination. Polymorphisms of genes ACE (I/D, rs 4340), ADRB1 (s.145A> G, Ser49Gly, rs1801252) ADRA2B (I/D, rs 28365031), MTHFR (c.677S>T, Ala222Val, rs1801133) and e-NOS3 (VNTR, 4a/4b) were tested by polymerase chain reaction.

Results. Maximum number of associations with risk factors was revealed in indigenous population for genotype D/D ACE gene, in non-indigenous representatives – for genotype D/D ADRA2B gene. In indigenous carriers of genotype D/D ACE gene, the odds ratio of hypercholesterolemia, hyper-betacholesterolemia, obesity and abdominal obesity were 11.20 (р=0.018); 4.65 (р=0.001); 2.31 (р=0.031) and 1.83 (р=0.059), respectively. In the cohort of non-indigenous ethnic group in those with genotype D/D gene ADRA2B the risk of hypercholesterolemia, hyperbetacholesterolemia, hypertriglyceridemia and carbohydrate metabolism disorders was higher in 5.11 (р=0.006), 5.41 (р=0.021), 2.73 (р=0.035) and 4.13 (р=0.005) times, respectively. In the indigenous group the genotype D/D of ACE gene was associated with obesity, hypercholesterolemia, hyperbetacholesterolemia; the genotype D/D of ADRA2B gene – with hypertriglyceridemia; the genotype 4а/4а of e-NOS3 gene – with abdominal obesity. In the group of non-indigenous ethnic group genotype D/D of АСЕ gene was associated with hypoalphacholesterolemia; genotype I/I of АСЕ gene – with carbohydrate metabolism disorders; genotype D/D of ADRA2B gene – with hypercholesterolemia, hyperbetacholesterolemia and hypertriglyceridemia, carbohydrate metabolism disorders; genotype Т/Т of MTHFR gene – with hypoalphacholesterolemia, genotype C/C of MTHFR gene – with abdominal obesity.

Conclusion. The determination of polymorphisms of candidate genes and the identification of associations with modifiable risk factors broadens the understanding of the genetic component of cardiovascular diseases and creates the prerequisites for the development of a more advanced and effective prevention program.

1. Shalnova S.A., Conradi A.O., Karpov Y.A., et al. Analysis of mortality from cardiovascular disease in 12 Russian regions participating in the study, "Epidemiology of cardiovascular diseases in different regions of Russia". Rossiyskiy Kardiologicheskiy Zhurnal. 2012;5(97):6-11. (In Russ.) (Шальнова С.А., Конради А.О., Карпов Ю.А. и др. Анализ смертности от сердечно-сосудистых заболеваний в 12 регионах Российской Федерации, участвующих в исследовании «Эпидемиология сердечно-сосудистых заболеваний в различных регионах России». Российский Кардиологический Журнал. 2012;5(97):6-11]

2. Ford E.S., Capewell S. Proportion of the decline in cardiovascular mortality disease due to prevention versus treatment: public health versus clinical care. Annu Rev Public Health. 2011;32:5-22.

3. Kapustina A.V., Evstifeeva S.E., Muromtseva G.A., et al. The study of the vital status and non-fatal cardiovascular events in the prospective cohort study stage, "Epidemiology of cardiovascular diseases and their risk factors in different regions of the Russian Federation. Profilakticheskaya Medicina. 2014;6:26-

4. (In Russ.) [Капустина А.В., Евстифеева С.Е., Муромцева Г.А., и соавт. Изучение витального статуса и нефатальных сердечно-сосудистых осложнений на проспективном этапе когортного исследования «Эпидемиология сердечно-сосудистых заболеваний и их факторов риска в различных регионах Российской Федерации (ЭССЕ-РФ)». Профилактическая Медицина. 2014;6:26-31]

5. Nayak P., Panda S., Thatoi P.K., et al. Evaluation of lipid profile and apolipoproteins in essential hypertensive patients. J Clin Diagn Res. 2016;10(10):BC01-BC04.

6. Kannel W.B. Risk stratification in hypertension: new insights from the Framingham Study.Am J Hypertens. 2000;13(1 Pt 2):3S-10S.

7. Evans A., Salomaa V., Kulathinal S., et al. MORGAM Project. MORGAM (an international pooling of cardiovascular cohorts). Int J Epidemiol. 2005;34(1):21-7.

8. Halperin R.O., Sesso H.D., Ma J., et al. Dyslipidemia and the risk of incident hypertension in men. Hypertension. 2006;47(1):45-50.

9. Davy K.P., Hall J.E. Obesity and hypertension: two epidemics or one? Amer. J. Physiol. Regul. Integr. Comp. Physiol. 2004;286:R803-R813.

10. Zhernakova Y.V., Sharipov G.H., Chazova I.E. Patients with arterial hypertension associated with metabolic disorders: characteristics and therapeutic approach. Sistemnye Gipertenzii. 2015;1(12):52-7. (In Russ.) [Жернакова Ю.В., Шарипова Г.Х., Чазова И.Е. Артериальная гипертония у больных с метаболическими нарушениями: особенности и тактика лечения. Системные Гипертензии. 2015;1(12):52-7].

11. Babin AG, Chechetkina EA, Koltunuv IE. Psychosomatic aspects of obesity as a risk factor of metabolic syndrome. Cardiovascular Therapy and Prevention 2010;7(9):71-8. Russian (Бабин А.Г., Чечеткина Е.А., Колтунов И.Е. Психосоматический аспект ожирения как фактор риска метаболического синдрома. Кардиоваскулярная терапия и профилактика 2010;7(9):71-8)

12. Kupchinskaya E.G., Voloshina O.A., Lizogub I.V. Hypertension in patients with obesity. Zdorov'e Ukrainy. Meditsinskaya Gazeta. 2010;3:36-38. in Russian (Купчинская Е.Г., Волошина О.А., Лизогуб И.В. Артериальная гипертензия у пациентов с ожирением. Здоровье Украины. Медицинская Газета. 2010;3:36-8].

13. Scbillaci G, Pirro M, Vaudo G et al. Prognostic value of the metabolic syndrome in essential hypertension. J Am Coll Cardiol. 2004;19:1817-22.

14. Cornier M.A., Després J.P., Davis N., et al. Assessing adiposity: a scientific statement from the American Heart Association. Circulation. 2011;124(18):1996-2019.

15. Fernández-Rhodes L., Hodonsky C.J., Graff M., et al. Comparison of 2 models for gene-environment interactions: an example of simulated gene-medication interactions on systolic blood pressure in family-based data. BMC Proc. 2016;10(Suppl 7):371-7.

16. Gorbunova V.N. Genetics and epigenetics syntropic diseases. Ekologicheskaya Genetika. 2010;4(8):39-43. (In Russ.) [Горбунова В.Н. Генетика и эпигенетика синтропных заболеваний. Экологическая Генетика. 2010;4(8):39-43].

17. Singh M., Singh A.K., Singh S., et al. Angiotensin-converting enzyme gene I/D polymorphism increases the susceptibility to hypertension and additive diseases: a study on North Indian patients. Clin Exp Hypertens. 2016;38(3):305-11.

18. You F.J., Shen D.M. Association between angiotensin-converting enzyme insertion/deletion polymorphisms and the risk of heart disease: an updated meta-analysis. Genet Mol Res. 2016;15(1):15017194.

19. Bahramali E., Rajabi M., Jamshidi J., et al. Association of ACE gene D polymorphism with left ventricular hypertrophy in patients with diastolic heart failure: a case-control study. BMJ Open. 2016;6(2):e010282.

20. Pan Y.H., Wang M., Huang Y.M., et al. ACE Gene I/D Polymorphism and Obesity in 1,574 Patients with Type 2 Diabetes Mellitus. Dis Markers. 2016;2016:7420540.

21. Kirstein S.L., Insel P.A. Autonomic nervous system pharmacogenomics: a progress report. Pharmacol Rev. 2004;56:31-52.

22. Rankinen T., Zuberi A., Chagnon Y.C., et al. The human obesity gene map: the 2005 update. Obesity (Silver Spring). 2006;14(4):529-644.

23. Iwamoto Y., Ohishi M., Yuan M., et al. β-Adrenergic receptor gene polymorphism is a genetic risk factor for cardiovascular disease: a cohort study with hypertensive patients. Hypertens Res 2011;34(5):573-77.

24. Snapir A., Heinonen P., Tuomainen T.P., et al. An insertion/deletion polymorphism in the alpha2B-adrenergic receptor gene is a novel genetic risk factor for acute coronary events. J Am Coll Cardiol. 2001;37(6):1516-22.

25. Vasudevan R., Ismail P., Stanslas J. Association of Insertion/Deletion Polymorphism of Alpha-Adrenoceptor Gene in Essential Hypertension with or without Type 2 Diabetes Mellitus in Malaysian Subjects. Int J BiolSci. 2008;4(6):362-67.

26. Heinonen P., Koulu M., Pesonen U., et al. Identification of a three-amino acid deletion in the alpha2B-adrenergic receptor that is associated with reduced basal metabolic rate in obese subjects. J Clin Endocrinol Metab. 1999;84(7):2429-33.

27. Ghogomu S.M., Ngolle N.E., Mouliom R.N., et al. Association between the MTHFR C677T gene polymorphism and essential hypertension in South West Cameroon. Genet Mol Res. 2016;15(1):28.

28. Nassereddine S., Kassogue Y., Korchi F., et al. Association of methylenetetrahydrofolate reductase gene (C677T) with the risk of hypertension in Morocco. BMC Res Notes. 2015;8(1):775.

29. Wotherspoon F., Laight D., Shaw K., et al. Homocysteine, endothelial dysfunction and oxidativestress in type 1 diabetes mellitus. Br J Diabetes Vasc Dis. 2003;3(5):334-40.

30. Napoli C., Paolisso G., Casamassimi A. Effects of nitric oxide on cell proliferation: novel insights. J. Am. Coll. Cardiol. 2013;62(9):89-95.

31. Seidlerovа J., Filipovsky J., Mayer O.Jr., et al. Association between endothelial NO synthase polymorphisms and arterial properties in the general population. Nitric Oxide. 2015;44:47-51.

32. Snapir A., Scheinin M., Groop L.C., et al. The insertion/deletion variation in the α2B-adrenoceptor does not seem to modify the risk for acute myocardial infarction, but may modify the risk for hypertension in sib-pairs from families with type 2 diabetes. Cardiovasc Diabetol. 2003;2:15.

33. Lima J.J., Feng H., Duckworth L., et al. Association analyses of adrenergic receptor polymorphisms with obesity and metabolic alterations. Metabolism. 2007;56(6):757-65.

34. Salimi S., Firoozrai M., Nourmohammadi I., et al. Endothelial nitric oxide synthase gene intron4 VNTR polymorphism in patients with coronary artery disease in Iran. Indian J Med Res. 2006;124(6):683-88.

35. Kondo H., Ninomiya T., Hata J., et al. Angiotensin I-converting enzyme gene polymorphism enhances the effect of hypercholesterolemia on the risk of coronary heart disease in a general Japanese population: the hisayama study. J Atheroscler Thromb. 2015;22(4):390-403.

36. Mittal G., Gupta V., Haque S.F., Khan A.S. Effect of angiotensin converting enzyme gene I/D polymorphism in patients with metabolic syndrome in North Indian population. Chin Med J (Engl). 2011;124(1):45-48.

37. Shunmugam V., Say Y.H. Evaluation of Association of ADRA2A rs553668 and ACE I/D Gene Polymorphisms with Obesity Traits in the Setapak Population, Malaysia. Iran Red Crescent Med J. 2016;18(2):e22452.

38. Mao S., Huang S. A meta-analysis of the association between angiotensin-converting enzyme insertion/ deletion gene polymorphism and the risk of overweight/obesity. J Renin Angiotensin Aldosterone Syst. 2015;16(3):687-94.

39. Vallejo M., Martínez-Palomino G., Ines-Real S., et al. Relationship between the angiotensin I-converting enzyme insertion/deletion (I/D) polymorphism and cardiovascular risk factors in healthy young Mexican women. Genet Test Mol Biomarkers. 2009;13(2):237-242.

40. Pacholczyk M., Ferenc T., Kowalski J., et al. Association of angiotensin-converting enzyme and angiotensin II type I receptor gene polymorphisms with extreme obesity in Polish individuals. DNA Cell Biol. 2013;32(8):435-442.

41. Alharbi K.K., Kashour T.S., Al-Hussaini W., et al. Association of angiotensin converting enzyme gene insertion/deletion polymorphism and familial hypercholesterolemia in the Saudi population. Lipids Health Dis 2013;12:177.

42. Das M., Pal S., Ghosh A. Synergistic effects of ACE (I/D) and Apo E (Hha I) gene polymorphisms on obesity, fat mass, and blood glucose level among the adult Asian Indians:A population-based study from Calcutta, India. Indian J Endocrinol Metab. 2013;17(1):101-4.

43. Ukkola O., Rankinen T., Weisnagel S.J. et al. Interactions among the alpha2, beta2, and beta3 adrenergic receptor genes and obesity related phenotypes in the Quebec family study. Metabolism. 2000;49:1063-70.

44. Papanas N., Papatheodorou K., Papazoglou D., et al. An insertion/deletion polymorphism in the alpha2B adrenoceptor gene is associated with peripheral neuropathy in patients with type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes. 2007;115(5):327-30.44. Zhang H., Li X, Huang J., et al. Thijs L. Cardiovascular and metabolic phenotypes in relation to the ADRA2B insertion/deletion polymorphism in a Chinese population. J Hypertens. 2005;23(12):2201-7.

45. Sykiotis G.P., Polyzogopoulou E., Georgopoulos N.A., et al. The alpha2B adrenergic receptor deletion/insertion polymorphism in morbid obesity. Clin Auton Res. 2003;13(3):203-7.

46. Wang Y., Xu X., Huo Y., et al. Predicting hyperhomocysteinemia by Methylenetetrahydrofolate Reductase C677T polymorphism in Chinese patients with hypertension. Clin Appl Thromb Hemost. 2015;21(7):661-6.

47. Huang L., Song X.M., Zhu W.L., et al. Plasma homocysteine and gene polymorphisms associated with the risk of hyperlipidemia in northern Chinese subjects. Biomed Environ Sci. 2008;21(6):514-20.

48. Yang B., Fan S., Zhi X., et al. Associations of MTHFR C677T and MTRR A66G gene polymorphisms with metabolic syndrome: a case-control study in Northern China. Int J Mol Sci. 2014;15(12):21687-702.

49. Fan S., Yang B., Zhi X., et al. Interactions of Methylenetetrahydrofolate Reductase C677T Polymorphism with Environmental Factors on Hypertension Susceptibility. Int J Environ Res Public Health. 2016;13(6):E601.

50. Kucukhuseyin O., Kurnaz O., Akadam-Teker A.B., et al. The association of MTHFR C677T gene variants and lipid profiles or body mass index in patients with diabetic and nondiabetic coronary heart disease. J Clin Lab Anal. 2013;27(6):427-34.

51. Souza-Costa D.C., Belo V.A., Silva P.S., et al. eNOS haplotype associated with hypertension in obese children and adolescents. Int J Obes (London). 2011;35(3):387-392.

52. Li J.Y., Tao F., Wu X.X., et al. Polymorphic variations in manganese superoxide dismutase (MnSOD) and endothelial nitric oxide synthase (eNOS) genes contribute to the development of type 2 diabetes mellitus in the Chinese Han population. Genet Mol Res. 2015;14(4):12993-13002.

53. Jia Z., Zhang X., Kang S., et al. Association of endothelial nitric oxide synthase gene polymorphisms with type 2 diabetes mellitus: a meta-analysis. Endocr J. 2013;60(7):893-901.

54. Alkharfy K.M., Al-Daghri N.M., Al-Attas O.S., et al. Variants of endothelial nitric oxide synthase gene are associated with components of metabolic syndrome in an Arab population. Endocr J. 2012;59(3):253-63.

55. Hoffmann I.S., Tavares-Mordwinkin R., Castejon A.M., et al. Endothelial nitric oxide synthase polymorphism, nitric oxide production, salt sensitivity and cardiovascular risk factors in Hispanics. J Hum Hypertens. 2005;19(3):233-40.

56. Miranda J.A., Belo V.A., Souza-Costa D.C., et al. eNOS polymorphism associated with metabolic syndrome in children and adolescents. Mol Cell Biochem. 2013;372(1-2):155-60.