The relationship of gene polymorphism with the heart failure risk in patients with hypertension and high adherence to treatment

Aim. To determine the heart failure (HF) risk in patients with hypertension (HTN) and high adherence to treatment, depending on the blood concentration of the N-terminal pro-brain natriuretic peptide (NT-proBNP) and gene polymorphism.

Material and methods. The study included 232 patients with HTN without a verified diagnosis of HF. The mean age was 46,13±8,21 years. Patients were evaluated for genotypes by following markers: AGT Thr174Met rs4762, GNB3 C825T rs5443, MTHFR C677T rs1801133, MTRR Ile22Met rs1801394, ApoE Cys130Arg rs 429358, PPARα G/C rs425377. We also assessed ejection fraction, diastolic function and left ventricular mass index by echocardiography and determined NT-proBNP blood levels. Patients were divided into two groups depending on the NT-proBNP concentration. The group 1 consisted of 64 (27,6%) patients with NT-proBNP >125 pg/ml, the group 2 — 168 (72,4%) patients with NT-proBNP <125 pg/ml.

Results. Among patients with NT-proBNP >125 pg/ml, the most significant was the C/T genotype of MTHFR C677T polymorphism (rs1801133), 95% confidence interval (CI) for the odds ratio (OR) and relative risk (RR) of HF was 4,82 and 3,29, respectively (95% CI for OR=2,24-10,60; for OR=1,80-6,39). The A/G and G/G genotypes of the MTRR Ile22Met polymorphism (rs1801394) were statistically significant. The probability of HF with the A/G genotype of the MTRR gene increased by more than 2 times (OR=2,32, 95% CI=1,15-4,64), and the OR of its development was 1,77 (95% CI=1,11-2,69). The probability of HF with the G/G genotype increased more than 3 times (OR=3,65, 95% CI=1,37-9,76), and the OR of its development was 2,20 (95% CI=1,25-3,27). Correlation analysis revealed a direct relationship between the NTproBNP levels and polymorphism of the MTHFR (r=0,47; p<0,005) and MTRR (r=0,33; p<0,05) genes.

Conclusion. In patients with HTN and high adherence to treatment, the HF risk with an Nt-proBNP >125 pg/ml depends on genetic determinism. Candidate genes for the HF in HTN patients with high adherence to treatment are the genotypes C/T of MTHFR C677T polymorphism (rs1801133), and A/G and G/G of MTRR Ile22Met polymorphism (rs1801394).

gene polymorphism, hypertension, natriuretic peptides

1. Mareev VY, Fomin IV, Ageev FT, et al. Clinical guidelines OSSN-RSC-RNMOT. Heart failure: chronic (CHF) and acute decompensated (ODSN). Diagnosis, preveNTion and treatmeNT. Cardiology. 2018;58(S6):8-164. (In Russ.) doi:10.18087/cardio.2475.

2. Ponikowski Р, Voors АА, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatmeNT of acute and chronic heart failure: The Task Force for the diagnosis and treatmeNT of acute and chronic heart failure of the European Society of Cardiology (ESC). European Heart Journal. 2016;37(27):2129-200. doi:10.1093/eurheartj/ehw128.

3. Ndumele CE, Matsushita K, Sang Y, et al. N-Terminal Pro-Brain Natriuretic Peptide and Heart Failure Risk Among Individuals With and Without Obesity: The Atherosclerosis Risk in Communities (ARIC) Study. Circulation. 2016;133(7):631-8. doi:10.1161/CIRCULATIONAHA.115.017298.

4. Obrezan AG, Kulikov NV. Neuro-humoral disbalance in chronic heart failure: classic and modern perspectives. Russ J Cardiol. 2017;(9):83-92. (In Russ.) doi:10.15829/1560-4071-2017-9-83-92.

5. Kryukov NN, Gubareva IV. The relationship between Nterminal pro Btype natriuretic peptide and indicators of daily monitoring of blood pressure in middle-aged hypertensive men with chronic heart failure. Arterial Hypertension. 2013;22(3):263-73. (In Russ.) doi:10.18705/1607-419X-2016-22-3-263-273.

6. Guo M, Guo G, Ji X. Genetic polymorphisms associated with heart failure: A literature review. J INT Med Res. 2016;44(1):15-29. doi:10.1177/0300060515604755.

7. Chernyavina AI, Surovtseva MV. Impact of polymorphism of cardiovascular risk genes on arterial remodelling developmeNT depending on presence of systemic hypertension. Russ J Cardiol. 2018;(1):43-50. (In Russ.) doi:10.15829/1560-40712018-1-43-50.

8. Kolovou V, Lagou E, Mihas C, еt al. Angiotensinogen (AGT) M235T, AGT T174M and Angiotensin-1-Converting Enzyme (ACE) I/D Gene Polymorphisms in EsseNTial Hypertension: Effects on Ramipril Efficacy. Cardiovasc Med J. 2015;29(9):118-26. doi:10.2174/1874192401509010118.

9. Wang WZ. Association between T174M polymorphism in the angiotensinogen gene and risk of coronary artery disease: a meta-analysis. J Geriatr Cardiol. 2013;10(1):59-65. doi:10.3969/j.issn.1671-5411.2013.01.010.

10. Chang SN, Lin JW, Juang JM, et al. Association between Genetic Polymorphisms in the Renin-Angiotensin System and Systolic Heart Failure Revised by a Propensity ScoreBased Analysis. Cardiology. 2010;116:279-85. doi:10.1159/000321123.

11. Semplicini А, Grandi Т, Sandona С, et al. G-Protein b3-Subunit Gene C825T Polymorphism and Cardiovascular Risk: An Updated Review. High Blood Press & Cardiovasc Prev. 2015;22(3):225-32. doi:10.1007/s40292-015-0093-4.

12. Li WX, Dai SX, Zheng JJ, et al. Homocysteine Metabolism Gene Polymorphisms (MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) JoiNTly Elevate the Risk of Folate Deficiency. NutrieNTs. 2015;7(8):6670-87. doi:10.3390/nu7085303.

13. 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):601. doi:10.3390/ijerph13060601.

14. Wu S, Hsu LA, Teng MS, et al. INTeractive effects of C-reactive protein levels on the association between APOE variaNTs and triglyceride levels in a Taiwanese population. Lipids Health Dis. 2016;15:94. doi:10.1186/s12944-016-0262-z.

15. Fan W, Shen C, Wu M, et al. Association and iNTeraction of PPARα, δ, and γ gene polymorphisms with low-density lipoprotein-cholesterol in a Chinese Han population. Genet Test Mol Biomarkers. 2015;19(7):379-86. doi:10.1089/gtmb.2015.0002.