Associations of genetic markers of the sympathoadrenal system and endothelial dysfunction with coronary heart disease on the example of a small Shoriya population

Aim. To establish associations of polymorphisms of candidate genes coding for the components of the endothelial (NOS3, MTHFR) and sympathoadrenal systems (ADRB1, ADRA2B) with coronary heart disease (CHD) in the cohort of the small population of Mountain Shoriya.

Material and methods. A clinical and epidemiological study was conducted in the areas of Mountain Shoriya (Orton, Ust-Kabyrza, Sheregesh, Tashtagol). Analysis of risk factors included recording the age, sex, body mass index, waist circumference, presence/absence of arterial hypertension (AH), smoking, and the presence of disorders of lipid and carbohydrate metabolism. CHD diagnosis was made by three epidemiological criteria: coding of the electrocardiogram according to the Minnesota code, Rose questionnaire, and a history of myocardial infarction. The patient underwent molecular genetic testing. DNA isolation from blood was carried out by the method of phenol-chloroform extraction. Statistical processing was carried out using the programs STATISTICA 6.1 (StatSoft Inc., USA) and SNPStats.

Results. The prevalence of CHD in the Shoriya cohort was 9,7%. The results of our study established the relationship of genetic markers of the sympathoadrenal and endothelial systems with coronary atherosclerosis in the indigenous population of Shoriya. The high risk of atherosclerotic heart disease was associated with the 4b/4a genotype of the NOS3 gene (OR 2,57 95% CI (1,12-5,86), p=0,026) according to the dominant mode of inheritance. The relationship of the T/T genotype of the MTHFR gene with CHD by recessive inheritance was established (OR 13,28; 95% CI (1,79-98,40), p=0,024).

Conclusion. Due to genetic research, there is a real opportunity not only to carry out accurate molecular diagnostics, but also to determine an underlying risk for a disease. Detection of genetic disposition to CHD can be carried out long before the onset of clinical symptoms, which can effectively prevent its development.

1. Shal'nova SA, Deev AD. Coronary heart disease in Russia: prevalence and treatment (according to clinical-epidemiological data). Therapeutic archive. 2011;1:7-12. (In Russ).

2. Popova LV, Nikolaev KYu, Nikolaeva AA, Voronina EN. The features of myocardial infarction clinical course at gene of endothelial NO-synthase polymorphisms. Klin. Med. (Mosk) 2008;86(4):32-5. (In Russ).

3. Kireeva VV, Koch NV, Lifshits GI, Apartsin KA. Endothelial dysfunction as cornerstone of cardiovascular events: molecular and pharmaceutic aspects. Russ J Cardiol. 2014;19(10):64-8. (In Russ). doi:10.15829/1560-4071-2014-10-64-68.

4. Parhomenko AN, Kozhuhov SN, Lutaj JaM, et al. The T-786C polymorphism of the endothelial nitric oxide gene: connection with the efficacy of thrombolysis in patients with acute myocardial infarction. Ukrainian medical journal. 2008;66(4):20-3. (In Russ).

5. Mjandina GI, Kasapova EN, Zotova TJu, et al. The polymorphism C677T of the gene MTHFR correlates with the complications of the coronary heart disease and arterial hypertension for the patients with dislipidaemia. RUDN bulletin, Medicine series. 2012;2:23-7. (In Russ).

6. Okorokov AN. Diagnosis of internal diseases: T. 8. Diagnosis of heart troubles and vessels: Myocardium diseases. Heart failure Moscow: Medical literature. 2004. 432 р. (In Russ). ISBN: 9785896770794.

7. Nikolaev KY, Urvantseva IA, Batueva KY, et al. Regional aspects of the gene polymorphism VEGFR2 with coronary atherosclerosis in acute coronary syndrome. Russian Journal of Cardiology. 2017;22(10):61-5. (In Russ). doi:10.15829/1560-4071-2017-10-61-65.

8. Romanova AN, Voevoda М!, Maksimov VN. Genetic markers of metabolic syndrome and coronary atherosclerosis in Yakutia inhabitants. Russian Journal of Cardiology. 2017;22(10):66-75. (In Russ). doi:10.15829/1560-4071-2017-10-66-75.

9. Maksimov VN, Orlov PS, Ivanova AA, et al. Complex evaluation of the significance of population genetic markers associated with a myocardial infarction and its risk factors. Russian Journal of Cardiology. 2017;22(10):33-41. (In Russ). doi:10.15829/1560-4071-2017-10-33-41.

10. Maniatis T, Fritsch E, Sembrook J. Methods of genetic engineering. Molecular cloning. M., Mir, 1984, 480 р. (In Russ).

11. Snapir A, Scheinin M, Groop LC, et al. The insertion/deletion variation in the a2B- 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;24(2):15. doi:10.1186/1475-2840-2-15.

12. Lima JJ, Feng H, Duckworth L, et al. Association analyses of adrenergic receptor polymorphisms with obesity and metabolic alterations. Metabolism. 2007;56(6):757-65. doi:10.1016/j.metabol.2007.01.007.

13. 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):683-8.

14. Mulerova TA, Yankin AYu, Kuzmina AA, et al. Polymorphism of a gene of ADRA2B and its association in population of aboriginals of Mountain Shoria. Complex problems of cardiovascular diseases. 2014;3:64. (In Russ).

15. Barbarash OL, Voevoda MI, Artamonova GV, et al. Genetic determinants of arterial hypertension in two national cohorts of Mountain Shoria. Therapeutic archive. 2017;89(9):68-77. (In Russ). doi:10.17116/terarkh201789968-77.

16. Ahmineeva AH, Polunina OS, Voronina LP, Sevost'janova IV. Clinical-diagnostic value of a research of markers of endothelial dysfunction at coronary heart disease. Kuban Medical Gazette. 2014;1(1):29-31. (In Russ).

17. Kumar GR, Spurthi KM, Kumar GK, et al. Genetic polymorphisms of eNOS (-786T/C, Intron 4b/4a & 894G/T) and its association with asymptomatic first degree relatives of coronary heart disease patients. Nitric Oxide. 2016;30(60):40-9. doi:10.1016/j.niox.2016.09.001.

18. Yang Y, Du K, Liu Z, Lu X. Endothelial nitric oxide synthase (eNOS) 4b/a gene polymorphisms and coronary artery disease: evidence from a meta-analysis. International Journal of Molecular Sciences. 2014;15(5):7987-8003. doi:10.3390/ijms15057987.

19. Granath B, Taylor RR, van Bockxmeer FM, Mamotte Granath CD. Lack of evidence for association between endothelial nitric oxide synthase gene polymorphisms and coronary artery disease in the Australian Caucasian population. J Cardiovasc Risc. 2001;8:235-41.

20. Lewis S, Ebrahim S, Davey S. Meta-analysis of MTHFR 677C->T polymorphism and coronary heart disease: does totality of evidence support causal role for homocysteine and preventive potential of folate? BMJ 2005;331 (7524):1053. doi: 10.1136/bmj.38611.658947.55.

21. Lakshmi S, Naushad S, Rupasree Y, et al. Interactions of 5'-UTR thymidylate synthase polymorphism with 677C -> T methylene tetrahydrofolate reductase and 66A ->G methyltetrahydrofolate homocysteine methyl-transferase reductase polymorphisms determine susceptibility to coronary artery disease. J Atheroscler Thromb. 2011;18(1):56-64.

22. Mehlig K, Leander K, de Faire U, et al. The association between plasma homocysteine and coronary heart disease is modified by the MTHFR 677C>T polymorphism. Heart. 2013;99(23):1761-5. doi:10.1136/heartjnl-2013-304460.

23. Ramkaran P, Phulukdaree A, Khan S, et al. Methylenetetrahydrofolate reductase C677T polymorphism is associated with increased risk of coronary artery disease in young South African Indians. Gene. 2015;571(1):28-32. doi:10.1016/j.gene.2015.06.044.

24. Chen W, Hua K, Gu H, et al. Methylenetetrahydrofolate reductase C667T polymorphism is associated with increased risk of coronary artery disease in a Chinese population. Scandinavian journal of immunology. 2014;80(5):346-53. doi:10.1111/sji.12215.

25. Sadewa AH, Sutomo R, Hayashi C, et al. The C677T mutation in the methylenetetrahydrofolate reductase gene among the Indonesian Javanese population. Kobe Journal of Medical Sciences. 2002;48(5/6):137-44.

26. Bushueva OYu, Dolzhenkova EM, Baryshev AS, et al. The relationship between polymorphism C667T of the MTHFR gene and ischemic heart disease risk in Russian population of Central Russia. Kursk Scientific and Practical Bulletin. Man and His Health 2015;4:76-80. (In Russ).

27. Anderson JL, King GJ, Thomson MJ, et al. A mutation in the methylenetetrahydrofolate reductase gene is not associated with increased risk for coronary artery disease or myocardial infarction. Journal of the American College of Cardiology. 1997;30(5):1206-11.

28. Hickey S, Curry C, Toriello H. ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genet Med. 2013;15(2):153-6. doi:10.1038/gim.2012.165.

29. Laukkanen JA, Makikallio TH, Kauhanen J, Kurl S. Insertion/deletion polymorphism in alpha2-adrenergic receptor gene is a genetic risk factor for sudden cardiac death. Am Heart J. 2009;158(4):615-21. doi:10.1016/j.ahj.2009.07.023.