GENETIC RISK FACTORS FOR THE DEVELOPMENT OF ARTERIAL HYPERTENSION

Authors

DOI:

https://doi.org/10.32782/2306-2436.15.1.2025.324

Keywords:

cardiometabolic risk factors, dyslipidemia, hypertension, epigenetics, pathogenesis

Abstract

Background. Hypertension, a multifaceted disorder influenced by genetic, epigenetic, and environmental factors, poses a significant risk of cardiovascular disease. Genetic components, namely, numerous genes, influence the phenotype of blood pressure through the allelic effects of individual genes and interactions between genes. The aim of the study was to identify the main genetic risk factors for the development of hypertension. Results. Despite the availability of a large number of medications, achieving effective blood pressure control remains a challenge in modern medicine. This is what motivates scientists to conduct research to determine the genetic components of the disease pathogenesis and the target of drug action. It has been proven that both genetic and environmental factors are involved in blood pressure homeostasis and the development of hypertension. Risk factors have been identified, namely obesity, unbalanced diet, smoking, alcohol consumption, sedentary lifestyle, excessive sodium and potassium intake. Modern genetic approaches help to understand the basic biology and identify the main links in the pathogenesis of hypertension. Scientists have found that genetic factors such as heredity, genetic mutations, factors affecting the phenotype, and epigenetic factors regulate blood pressure. Among the most important are genes related to the renin-angiotensin-aldosterone system (angiotensin II, renin, angiotensin-converting enzyme, aldosterone, etc.), genes responsible for water-salt balance and those that control vascular tone (epoxyecosatrienoic acid and 20-hydroxyecosatetraenoic acid, etc.), genes that regulate obesity (renin, aldosterone, glucocorticoid receptor, aldosterone synthase, kinase 1, and glucocorticoids). It has been determined that the study of hypertension and blood pressure using genetic methods improves the interpretation and identification of genetic risk factors, which increases clinical utility. Conclusions. It has been shown that the identification of genetic factors improves the prediction of the risk of hypertension, timely identification of groups of patients with factors and prevention and effective treatment.

References

1. Oparil S., Acelajado M.C., Bakris G.L., Berlowitz D.R., Cífková R., Dominiczak A.F., Grassi G., Jordan J., Poulter N.R., Rodgers A., Whelton P.K. Hypertension. Nature Reviews Disease Primers. 2018. Vol. 4. P. 18014. doi: 10.1038/nrdp.2018.14.

2. Feng L., Jehan I., de Silva H.A., Naheed A., Farazdaq H., Hirani S., et al. Prevalence and correlates of cardiometabolic multimorbidity among hypertensive individuals: a cross-sectional study in rural South Asia-Bangladesh, Pakistan and Sri Lanka. BMJ Open. 2019. Vol. 9. No. 9. P. e030584. doi: 10.1136/bmjopen-2019-030584.

3. Zhou B., Perel P., Mensah G.A., Ezzati M. Global epidemiology, health burden and effective interventions for elevated blood pressure and hypertension. Nature Reviews Cardiology. 2021. Vol. 18. No. 11. P. 785–802. doi: 10.1038/s41569-021-00559-8.

4. Carey R.M., Moran A.E., Whelton P.K. Treatment of Hypertension: A Review. JAMA. 2022. Vol. 328. No. 18. P. 1849–1861. doi: 10.1001/jama.2022.19590.

5. Dzau V.J., Balatbat C.A. Future of Hypertension. Hypertension. 2019. Vol. 74. No. 3. P. 450–457. doi: 10.1161/HYPERTENSIONAHA.119.13437.

6. Fava C., Ricci M., Melander O., Minuz P. Hypertension, cardiovascular risk and polymorphisms in genes controlling the cytochrome P450 pathway of arachidonic acid: A sex-specific relation? Prostaglandins & Other Lipid Mediators. 2012. Vol. 98. No. 3–4. P. 75–85. doi: 10.1016/j.prostaglandins.2011.11.007.

7. de Ruiter S.C., Schmidt A.F., Grobbee D.E., den Ruijter H.M., Peters S.A.E. Sex-specific Mendelian randomisation to assess the causality of sex differences in the effects of risk factors and treatment: spotlight on hypertension. Journal of Human Hypertension. 2023. Vol. 37. No. 8. P. 602–608. doi: 10.1038/s41371-023-00821-1. PMID: 37024639.

8. Takase M., Hirata T., Nakaya N., et al. Associations of combined genetic and lifestyle risks with hypertension and home hypertension. Hypertension Research. 2024. Vol. 47. No. 8. P. 2064–2074. doi: 10.1038/s41440-024-01705-8.

9. Pratamawati T.M., Alwi I., Asmarinah. Summary of Known Genetic and Epigenetic Modification Contributed to Hypertension. International Journal of Hypertension. 2023. Vol. 2023. P. 5872362. doi: 10.1155/2023/5872362.

10. Olczak K.J., Taylor-Bateman V., Nicholls H.L., Traylor M., Cabrera C.P., Munroe P.B. Hypertension genetics past, present and future applications. Journal of Internal Medicine. 2021. Vol. 290. No. 6. P. 1130–1152. doi: 10.1111/joim.13352.

11. Filippou C., Tatakis F., Polyzos D., Manta E., Thomopoulos C., Nihoyannopoulos P., Tousoulis D., Tsioufis K. Overview of salt restriction in the Dietary Approaches to Stop Hypertension (DASH) and the Mediterranean diet for blood pressure reduction. Reviews in Cardiovascular Medicine. 2022. Vol. 23. No. 1. P. 36. doi: 10.31083/j.rcm2301036.

12. Xie H., Li J., Zhu X., Li J., Yin J., Ma T., Luo Y., He L., Bai Y., Zhang G., Cheng X., Li C. Association between healthy lifestyle and the occurrence of cardiometabolic multimorbidity in hypertensive patients: a prospective cohort study of UK Biobank. Cardiovasc Diabetol. 2022. Vol. 21. No. 1. P. 199. doi: 10.1186/s12933-022-01632-3.

13. Valenzuela P.L., Carrera-Bastos P., Galvez B.G., Ruiz-Hurtado G., Ordovas J.M., Ruilope L.M., et al. Lifestyle interventions for the prevention and treatment of hypertension. Nature Reviews Cardiology. 2021. No. 18 (4). P. 251–275. https://doi.org/10.1038/s41569-020-00437-9.

14. Unger T., Borghi C., Charchar F., Khan N.A., Poulter N.R., Prabhakaran D., et al. 2020 International Society of Hypertension global hypertension practice guidelines. Hypertension. 2020. No. 75 (6). P. 1334–1357. https://doi.org/10.1161/HYPERTENSIONAHA.120.15026.

15. Choi J.W., Park J.S., Lee C.H. Interactive effect of high sodium intake with increased serum triglycerides on hypertension. PLoS One. 2020. No. 15 (4). P. e0231707. https://doi.org/10.1371/journal.pone.0231707.

16. Gao Q., Lin Y., Xu R., Luo F., Chen R., Li P., Zhang Y., Liu J., Deng Z., Li Y., Su L., Nie S. Positive association of triglyceride-glucose index with new-onset hypertension among adults: a national cohort study in China. Cardiovasc Diabetol. 2023. No. 22 (1). P. 58. https://doi.org/10.1186/s12933-023-01795-7.

17. Wang S., Wang Q., Yan X. Association between triglyceride-glucose index and hypertension: a cohort study based on the China Health and Nutrition Survey (2009-2015). BMC Cardiovasc Disord. 2024. No. 24 (1). P. 168. https://doi.org/10.1186/s12872-024-03747-9.

18. Xu A.R., Jin Q., Shen Z., Zhang J., Fu Q. Association between the risk of hypertension and triglyceride glucose index in Chinese regions: a systematic review and dose-response meta-analysis of a regional update. Frontiers in Cardiovascular Medicine. 2023. No. 10. P. 1242035. https://doi.org/10.3389/fcvm.2023.1242035.

19. Yang C., Song Y., Wang P. Relationship between triglyceride-glucose index and new-onset hypertension in general population-a systemic review and meta-analysis of cohort studies. Clinical and Experimental Hypertension. 2024. No. 46 (1). P. 2341631. https://doi.org/10.1080/10641963.2024.2341631.

20. Liu Y., Shi M., Dolan J., He J. Sodium sensitivity of blood pressure in Chinese populations. Journal of Human Hypertension. 2020. No. 34 (2). P. 94–107. https://doi.org/10.1038/s41371-018-0152-0.

21. He F.J., Tan M., Ma Y., MacGregor G.A. Salt Reduction to Prevent Hypertension and Cardiovascular Disease: JACC State-of-the-Art Review. Journal of the American College of Cardiology. 2020. No. 75 (6). P. 632–647. https://doi.org/10.1016/j.jacc.2019.11.055.

22. Zucker R., Kovalerchik M., Linial M. Gene-based association study reveals a distinct female genetic signal in primary hypertension. Human Genetics. 2023. No. 142 (7). P. 863–878. https://doi.org/10.1007/s00439-023-02567-9.

23. Mueller F.B. AI (Artificial Intelligence) and Hypertension Research. Current Hypertension Reports. 2020. No. 22 (9). P. 70. https://doi.org/10.1007/s11906-020-01068-8.

24. Colafella K.M.M., Denton K.M. Sex-specific differences in hypertension and associated cardiovascular disease. Nature Reviews Nephrology. 2018. No. 14 (3). P. 185–201. https://doi.org/10.1038/nrneph.2017.189.

25. Karabaeva R.Z., Vochshenkova T.A., Mussin N.M., Albayev R.K., Kaliyev A.A., Tamadon A. Epigenetics of hypertension as a risk factor for the development of coronary artery disease in type 2 diabetes mellitus. Front Endocrinol (Lausanne). 2024. No. 15. P. 1365738. https://doi.org/10.3389/fendo.2024.1365738.

26. Wei L.K., Au A., Teh L.K., Lye H.S. Recent Advances in the Genetics of Hypertension. Advances in Experimental Medicine and Biology. 2017. No. 956. P. 561–581. https://doi.org/10.1007/5584_2016_75.

27. Zhang D., Tang X., Shen P., Si Y., Liu X., Xu Z., et al. Multimorbidity of cardiometabolic diseases: prevalence and risk for mortality from one million Chinese adults in a longitudinal cohort study. BMJ Open. 2019. No. 9 (3). P. e024476. https://doi.org/10.1136/bmjopen-2018-024476.

28. Vaura F., Kauko A., Suvila K., Havulinna A.S., Mars N., Salomaa V., FinnGen, Cheng S., Niiranen T. Polygenic Risk Scores Predict Hypertension Onset and Cardiovascular Risk. Hypertension. 2021. No. 77 (4). P. 1119–1127. https://doi.org/10.1161/HYPERTENSIONAHA.120.16471. PMID: 33611940.

29. Ambatiello L.G. [Stress-induced arterial hypertension]. Ter Arkh. 2022. No. 94 (7). P. 908-913. https://doi.org/10.26442/00403660.2022.07.201733.

30. Padmanabhan S., Dominiczak A.F. Genomics of hypertension: the road to precision medicine. Nature Reviews Cardiology. 2021. No. 18 (4). P. 235–250. https://doi.org/10.1038/s41569-020-00466-4.

31. Giri A., Hellwege J.N., Keaton J.M., et al. Trans-ethnic association study of blood pressure determinants in over 750,000 individuals. Nature Genetics. 2019. No. 51 (1). P. 51–62. https://doi.org/10.1038/s41588-018-0303-9.

32. Evangelou E., Warren H.R., Mosen-Ansorena D. Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits Nature Genetics. 2018. No. 50 (10). P. 1412–1425. https://doi.org/10.1038/s41588-018-0205-x.

33. Gurdasani D., Barroso I., Zeggini E., Sandhu M.S. Genomics of disease risk in globally diverse populations. Nature Reviews Genetics. 2019. No. 20 (9). P. 520–535. https://doi.org/10.1038/s41576-019-0144-0.

34. Huang S., Wang J., Liu N., Li P., Wu S., Qi L., Xia L. A cross-tissue transcriptome association study identifies key genes in essential hypertension. Frontiers in Genetics. 2023. No. 14. P. 1114174. https://doi.org/10.3389/fgene.2023.1114174.

35. Liang J., Fu Z., Liu Q., Shen Y., Zhang X., Weng Z., Xu J., Li W., Xu C., Zhou Y., Gu A. Interactions among maternal smoking, breastfeeding, and offspring genetic factors on the risk of adult-onset hypertension. BMC Medicine. 2022. No. 20 (1). P. 454. https://doi.org/10.1186/s12916-022-02648-y.

36. Singh V., Van Why S.K. Monogenic Etiology of Hypertension. Medical Clinics of North America. 2024. No. 108 (1). P. 157–172. https://doi.org/10.1016/j.mcna.2023.06.005.

37. Rodriguez-Iturbe B., Johnson R.J. Genetic Polymorphisms in Hypertension: Are We Missing the Immune Connection? American Journal of Hypertension. 2019. No. 32 (2). P. 113–122. https://doi.org/10.1093/ajh/hpy168.

38. Ismail N., Abdullah N., Abdul Murad N.A., Jamal R., Sulaiman S.A. Long Non-Coding RNAs (lncRNAs) in Cardiovascular Disease Complication of Type 2 Diabetes. Diagnostics (Basel). 2021. No. 11 (1). P. 145. https://doi.org/10.3390/diagnostics11010145. PMID: 33478141.

39. Wang Y., Hu H., Yin J., Shi Y., Tan J., Zheng L., Wang C., Li X., Xue M., Liu J., Wang Y., Li Y., Li X., Liu F., Liu Q., Yan S. TLR4 participates in sympathetic hyperactivity Post-MI in the PVN by regulating NF-κB pathway and ROS production. Redox Biology. 2019. No. 24. P. 101186. https://doi.org/10.1016/j.redox.2019.101186.

40. Sekar D. Circular RNA: a new biomarker for different types of hypertension. Hypertension Research. 2019. No. 42 (11). P. 1824–1825. https://doi.org/10.1038/s41440-019-0302-y.

41. Kara S.P., Ozkan G., Yılmaz A., Bayrakçı N., Güzel S., Geyik E. MicroRNA 21 and microRNA 155 levels in resistant hypertension, and their relationships with aldosterone. Renal Failure. 2021. No. 43 (1). P. 676–683. https://doi.org/10.1080/0886022X.2021.1915800.

42. Souza L.A.C., Worker C.J., Li W., Trebak F., Watkins T., Gayban A.J.B., Yamasaki E., Cooper S.G., Drumm B.T., Feng Y. (Pro)renin receptor knockdown in the paraventricular nucleus of the hypothalamus attenuates hypertension development and AT1 receptor-mediated calcium events. American Journal of Physiology Heart and Circulatory Physiology. 2019. No. 316 (6). P. H1389-H1405. https://doi.org/10.1152/ajpheart.00780.2018.

43. Mohsin M., Souza L.A.C., Aliabadi S., Worker C.J., Cooper S.G., Afrin S., Murata Y., Xiong Z., Feng Earley Y. Increased (Pro)renin Receptor Expression in the Hypertensive Human Brain. Frontiers in Physiology. 2020. No. 11. P. 606811. https://doi.org/10.3389/fphys.2020.606811.

44. Sekar D., Shilpa B.R., Das A.J. Relevance of microRNA 21 in Different Types of Hypertension. Current Hypertension Reports. 2017. No. 19 (7). P. 57. https://doi.org/10.1007/s11906-017-0752-z.

45. Ray A., Stelloh C., Liu Y., Meyer A., Geurts A.M., Cowley A.W. Jr., Greene A.S., Liang M., Rao S. Histone Modifications and Their Contributions to Hypertension. Hypertension. 2024. No. 81 (2). P. 229–239. https://doi.org/10.1161/HYPERTENSIONAHA.123.21755.

46. Levy E., Spahis S., Bigras J.L., Delvin E., Borys J.M. The Epigenetic Machinery in Vascular Dysfunction and Hypertension. Current Hypertension Reports. 2017. No. 19 (6). P. 52. https://doi.org/10.1007/s11906-017-0745-y.

47. Sekar D. Comment on the potential role of microRNAs in hypertension. Journal of Human Hypertension. 2018. No. 32 (10). P. 639–640. https://doi.org/10.1038/s41371-018-0104-8.

48. Larsson S.C., Butterworth A.S., Burgess S. Mendelian randomization for cardiovascular diseases: principles and applications. European Heart Journal. 2023. No. 44 (47). P. 4913–4924. https://doi.org/10.1093/eurheartj/ehad736.

49. Benn M., Nordestgaard B.G. From genome-wide association studies to Mendelian randomization: novel opportunities for understanding cardiovascular disease causality, pathogenesis, prevention, and treatment. Cardiovascular Research. 2018. No. 114 (9). P. 1192–1208. https://doi.org/10.1093/cvr/cvy045.

50. Raina R., Krishnappa V., Das A., Amin H., Radhakrishnan Y., Nair N.R., Kusumi K. Overview of Monogenic or Mendelian Forms of Hypertension. Frontiers in Pediatrics. 2019. No. 7. P. 263. https://doi.org/10.3389/fped.2019.00263.

51. Jia H., Bao P., Yao S., Zhang X., Mu J.J., Hu G.L., Du M.F., Chu C., Zhang X.Y., Wang L., et al. Associations of SGLT2 genetic polymorphisms with salt sensitivity, blood pressure changes and hypertension incidence in Chinese adults. Hypertension Research. 2023. No. 46 (7). P. 1795–1803. https://doi.org/10.1038/s41440-023-01301-2.

52. Niu Z.J., Yao S., Zhang X., Mu J.J., Du M.F., Zou T., Chu C., Liao Y.Y., Hu G.L., Chen C., et al. Associations of genetic variations in NEDD4L with salt sensitivity, blood pressure changes and hypertension incidence in Chinese adults. J Clin Hypertens (Greenwich). 2022. No. 24 (10). P. 1381–1389. https://doi.org/10.1111/jch.14566.

53. Ishigami T., Kino T., Minegishi S., Araki N., Umemura M., Ushio H., Saigoh S., Sugiyama M. Regulators of Epithelial Sodium Channels in Aldosterone-Sensitive Distal Nephrons (ASDN): Critical Roles of Nedd4L/Nedd4-2 and Salt-Sensitive Hypertension. International Journal of Molecular Sciences. 2020. No. 21 (11). P. 3871. https://doi.org/10.3390/ijms21113871.

54. Wang Y., Jia H., Gao W.H., Zou T., Yao S., Du M.F., Zhang X.Y., Chu C., Liao Y.Y., Chen C., et al. Associations of plasma PAPP-A2 and genetic variations with salt sensitivity, blood pressure changes and hypertension incidence in Chinese adults. Journal of Hypertension. 2021. No. 39 (9). P. 1817–1825. https://doi.org/10.1097/HJH.0000000000002846.

55. Sookaromdee P., Wiwanitkit V. Plasma PAPP-A2 and genetic variations with hypertension. Journal of Hypertension. 2022. No. 40 (4). P. 837. https://doi.org/10.1097/HJH.0000000000003082.

56. Wang Y., Zhou Q., Gao W.H., Yan Y., Chu C., Chen C., Yuan Y., Wang K.K., Ma Q., Gao K., et al. Association of plasma cyclooxygenase-2 levels and genetic polymorphisms with salt sensitivity, blood pressure changes and hypertension incidence in Chinese adults. Journal of Hypertension. 2020. No. 38 (9). P. 1745–1754. https://doi.org/10.1097/HJH.0000000000002473.

57. Drozdz D., Alvarez-Pitti J., Wójcik M., Borghi C., Gabbianelli R., Mazur A., Herceg-Čavrak V., Lopez-Valcarcel B.G., Brzeziński M., Lurbe E., Wühl E. Obesity and Cardiometabolic Risk Factors: From Childhood to Adulthood. Nutrients. 2021. No. 13 (11). P. 4176. https://doi.org/10.3390/nu13114176.

58. Pan S., Souza L.A.C., Worker C.J., Reyes Mendez M.E., Gayban A.J.B., Cooper S.G., Sanchez Solano A., Bergman R.N., Stefanovski D., Morton G.J., et al. (Pro)renin receptor signaling in hypothalamic tyrosine hydroxylase neurons is required for obesity-associated glucose metabolic impairment. JCI Insight. 2024. No. 9 (6). P. e174294. https://doi.org/10.1172/jci.insight.174294.

59. Souza L.A.C., Earley Y.F. (Pro)renin receptor and blood pressure regulation: a focus on the central nervous system. Current Hypertension Reviews. 2022. No. 18 (2). P. 101–116. https://doi.org/10.2174/1570162X20666220127105655.

60. Pan S., Souza L.A.C., Worker C.J., Reyes Mendez M.E., Gayban A.J.B., Cooper S.G., Sanchez Solano A., Bergman R.N., Stefanovski D., Morton G.J., et al. (Pro)renin receptor signaling in hypothalamic tyrosine hydroxylase neurons is required for obesity-associated glucose metabolic impairment. JCI Insight. 2024. No. 9 (6). P. e174294. https://doi.org/10.1172/jci.insight.174294.

Published

2025-05-15