Abstract
Introduction. Cerebrovascular diseases are a heterogeneous group of conditions shaped by the interaction of polygenic susceptibility, rare monogenic variants, vascular remodeling, neuroinflammation, dysregulated hemostasis, and epigenetic reprogramming. Recent years have shifted the field from isolated candidate-gene studies toward multi-ancestry GWAS, transcriptomic and proteomic integration, single-cell approaches, and genetic risk scores, enabling a closer link between inherited predisposition and the biology of the neurovascular unit, cerebral small vessel disease, and intracranial aneurysms.
Objective: to assess the role of genetic factors and molecular mechanisms in the development of cerebrovascular diseases in terms of searching for new targets for diagnosis and therapy.
Material and methods. In the course of this study, a review and analysis of the most relevant domestic and foreign literary sources containing information on the problem of cerebrovascular diseases and their genetic aspects was conducted based on search engines in the MEDLINE, PUBMED databases and the scientific electronic libraries CyberLeninka and eLIBRARY.RU over the past 5 years.
Results. Modern research demonstrates that genetic predisposition to stroke and other cerebrovascular diseases is multilayered and complex. Dozens of polygenic loci associated with atherothrombotic mechanisms, cardioembolism, structural changes in the vascular wall, arterial hypertension, inflammatory processes, and endothelial dysfunction are significant for common forms of pathology. Meanwhile, monogenic variants, particularly in the NOTCH3, HTRA1, and COL4A1/COL4A2 genes, play a critical role for certain phenotypes. Furthermore, it has been established that ischemic brain injury is mediated not only by necrotic processes but also by a cascade mechanism of regulated cell death, mitochondrial dysfunction, excitotoxicity, disruption of the blood-brain barrier, cell-specific inflammatory responses, and epigenetic remodeling. In the context of intracranial aneurysms, the importance of genetic loci influencing the state of the endothelium, smooth muscle cells, extracellular matrix, and blood pressure regulation has been demonstrated.
Conclusion. Genetic determinants play a fundamental role in the pathogenesis of cerebrovascular diseases. Modern molecular genetic studies have identified polymorphic loci and mutations associated with an increased risk of developing these pathologies. Genetic predisposition, epigenetic modifications, and variability in regulatory pathways play a key role in the pathophysiological mechanisms of these diseases. Genetic heterogeneity significantly complicates the research process, influencing individual predisposition to cerebrovascular diseases. Pharmacogenetic and ethnogenetic factors also play a significant role in the context of etiology and pathogenesis. Further comprehensive research is needed to better understand all genetic risk factors, which will enable the development of personalized prevention and treatment strategies based on genetic profiling of patients.
Keywords
Authors and affiliations
https://elibrary.ru/ttrlcq
A.M. Morozov(1), T.V. Sorokovikova(1), A.D. Kuzmenko(2), K.S. Shablinskaya(3)
1-Federal State Budgetary Higher Educational Institution «Tver State Medical University» of the Ministry of Health of the Russian Federation, Sovetskaya Street, buil. 4, Tver, 170100, Russian Federation; 2-Pirogov Russian National Research Medical University, Ministry of Health
of the Russian Federation, Ostrovityanova St., 1, Bldg. 6, Moscow, 117513, Russian Federation; 3LLC Institute of Plastic Surgery,
Maly Sukharevsky Lane, 10, Bldg. 1, Moscow, 127051, Russian Federation
References
1. Steinmetz J.D. Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021. Lancet Neurol. 2024; 23 (4): 344–81.
2. Granata A., Harshfield E.L., Moxon J.V. Cerebrovascular disorders. BMC Cardiovascular Disorders. 2023; 23: 212. DOI: 10.1186/s12872-023-03225-8.
3. Dumitrescu A.-M., Anton Păduraru D., Hilițanu N.-L. et al. The implications of risk factors in the development of cerebrovascular disease in patients with anatomical variants in the Circle of Willis. Bulletin of Integrative Psychiatry. 2024; 103: 71–8. DOI: 10.36219/BPI.2024.4.07.
4. Shehjar F., Mahajan R., Shahnaz S. et al. Genetic and epigenetic architectures of stroke: insights from GWAS to precision medicine. Neurochemistry International. 2025; 190: 106059. DOI: 10.1016/j.neuint.2025.106059.
5. Zhang K., Loong S.S.E., Yuen L.Z.H. et al. Genetics in ischemic stroke: current perspectives and future directions. J. Cardiovasc Dev Dis. 2023; 10 (12): 495. DOI: 10.3390/jcdd10120495
6. Yoshimoto T., Yamagami H., Matsumaru Y. et al. Recent advances in stroke genetics–unraveling the complexity of cerebral infarction: a brief review. Genes. 2025; 16: 59. DOI: 10.3390/genes16010059.
7. Granata A. Functional genomics in stroke: current and future applications of induced pluripotent stem cells and gene editing for risk variant functional analysis. BMC Cardiovascular Disorders. 2023; 23: 223. DOI: 10.1186/s12872-023-03227-6.
8. Jagodic A., Zivalj D., Krsek A., Baticic L. Genetic architecture of ischemic stroke: insights from genome-wide association studies and beyond. J. Cardiovasc Dev Dis. 2025; 12 (8): 281. DOI: 10.3390/jcdd12080281.
9. Сороковикова Т.В., Чичановская Л.В., Меньшикова Т.В. и др. Современные представления о гипоксически-ишемических поражениях ЦНС. Вестник неврологии, психиатрии и нейрохирургии. 2025; 18, 6 (185): 742–51. [Sorokovikova T.V., Chichanovskaya L.V., Menshikova T.V. et al. Modern concepts of hypoxic-ischemic lesions of the central nervous system. Bulletin of Neurology, Psychiatry and Neurosurgery. 2025; 18, 6 (185): 742–51. DOI: 10.33920/med-01-2506-04 (in Russian)].
10. Chandra Sekar P., Veerabathiran R. A genetic perspective on ischemic stroke: recent advances and future directions. Ann. Clin. Exp. Neurol. 2024; 18 (4): 55–67. DOI: 10.17816/ACEN.1064.
11. Сороковикова Т.В., Морозов А.М., Крюкова А.Н., Наумова С.А. Современный подход к диагностике мигрени. Вестник неврологии, психиатрии и нейрохирургии. 2023; 10: 841–51. [Sorokovikova T.V., Morozov A.M., Kryukova A.N., Naumova S.A. Modern approach to the diagnosis of migraine. Bulletin of Neurology, Psychiatry and Neurosurgery. 2023; 10: 841–51. DOI: 10.33920/med-01-2310-10 (in Russian)]
12. Чичановская Л.В., Сороковикова Т.В., Морозов А.М., Ковальчук Ю.И. Современный подход к диагностике мигрени. Неврология и нейрохирургия. Восточная Европа. 2024; 14 (1): 102–15. [Chichanovskaya L.V., Sorokovikova T.V., Morozov A.M., Kovalchuk Yu.I. Modern approach to the diagnosis of migraine. Neurology and neurosurgery. Eastern Europe. 2024; 14 (1): 102–15. DOI: 10.34883/PI.2024.14.1.049 (in Russian)]
13. Wang P., Wang T., Yu J. et al. Cerebrovascular phenotype analysis in Gucy1a3 loss-of-function mice: insights into moyamoya disease susceptibility. Front Neurol. 2026; 17: 1669177. DOI: 10.3389/fneur.2026.1669177.
14. Ghosh S. Angiotensin converting enzyme (ACE) gene polymorphism and arterial blood pressure among the Tawang Monpa of Eastern Himalayan Mountains: Is there a signature of natural selection? PLoS ONE. 2023; 18 (9): e0291810. DOI: 10.1371/journal.pone.0291810.
15. MiriMoghaddam S., Vafaeie F., Bizhaem S.K. et al. Angiotensin-converting enzyme insertion/deletion genotype (rs4646994) association with increased risk of stroke: a case-control study in Eastern Iran. BMC Neurol. 2025; 25: 478. DOI: 10.1186/s12883-025-04503-y.
16. Maslat A.O., Al‑Mahmood O.M., Al Khawaja N.M. et al. Association of genetic polymorphisms of EDN1 gene and endothelin‑1 level in patients with type 2 diabetes mellitus in the Jordanian population. Heliyon. 2024; 10 (1). DOI: 10.1016/j.heliyon.2023.e23676.
17. Iacobucci M., Risitano A., Amisano P. et al. Role of endothelin-1 and nitric oxide in acute ischemic stroke leptomeningeal collateral activation. Int. J. Mol. Sci. 2025; 26: 3205. DOI: 10.3390/ijms26073205.
18. Selvarajan I., Kiema M., Huang R.T. et al. Coronary artery disease risk variant dampens the expression of CALCRL by reducing HSF binding to shear stress responsive enhancer in endothelial cells in vitro. Arterioscler Thromb Vasc Biol. 2024; 44 (6): 1330–45. DOI: 10.1161/ATVBAHA.123.318964.
19. Hald E., Løchen M., Mathiesen E. et al. Joint effects of atrial fibrillation and prothrombotic genotypes on the risk of ischemic stroke. J. Thromb Haemost. 2025; 23: 1401–6.
20. Mishra A., Malik R., Hachiya T. et al. Stroke genetics informs drug discovery and risk prediction across ancestries. Nature. 2022; 611: 115–23. DOI: 10.1038/s41586-022-05165-3.
21. Zhong Y., Lin M., Zhou X. et al. ABO exon polymorphisms are related to ischemic stroke in a Chinese Han population. BMC Med Genomics. 2025; 18 (1): 102. DOI: 10.1186/s12920-025-02170-z.
22. Klajmon A., Ząbczyk M., Undas A. et al. SERPINE1 and MTHFR genetic variants in patients with embolic stroke of undetermined source: links with fibrin clot properties. Neurol Neurochir Pol. 2024; 58 (4): 405–12. DOI: 10.5603/pjnns.99352.
23. Shaikh S.B., Balaya R.D.A., Dagamajalu S. et al. Signaling pathway map of plasminogen activator inhibitor‑1 (PAI‑1/SERPINE‑1): a review of an innovative frontier in molecular aging and cellular senescence. Cell Communication and Signaling. 2024; 22 (1): 544. DOI: 10.1186/s12964-024-01910-5.
24. Ko E.J., Ahn E.H., Park H.W. et al. Genetic associations of ITGB3, FGG, GP1BA, PECAM1, and PEAR1 polymorphisms and the platelet activation pathway with recurrent pregnancy loss in the Korean population. Int. J. Mol. Sci. 2025; 26: 7505. DOI: 10.3390/ijms26157505.
25. Etuze T., Triniac H., Zheng Z. et al. Apolipoproteins in ischemic stroke progression and recovery: key molecular mechanisms and therapeutic potential. Neurobiol Dis. 2025; 209: 106896. DOI: 10.1016/j.nbd.2025.106896.
26. Yuan H., Li P., Li B. Genetic polymorphisms of apolipoprotein E and their impact on ischemic stroke severity and recovery. Neurol Clin Neurosci. 2025; 13: 305–15. DOI: 10.1111/ncn3.70025.
27. Kosmas C.E., Bousvarou M.D., Papakonstantinou E.J. et al. Lipoprotein (a) and cerebrovascular disease. J. Int. Med. Res. 2024; 52 (7): 3000605241264182. DOI: 10.1177/03000605241264182.
28. Dai Z., Wang Y., Li P. et al. The association between polymorphism of LDL-R gene and ischemic stroke risk in Chinese population: a meta-analysis. Heliyon. 2024; 10 (4): e26314. DOI: 10.1016/j.heliyon.2024.e26314.
29. Xie Y., Liu S., Wang X. et al. Lipids, apolipoproteins, lipid-lowering drugs, and the risk of cerebral small vessel disease: a Mendelian randomization study. J. Am. Heart Assoc. 2024; 13 (16): e032409. DOI: 10.1161/JAHA.123.032409.
30. Guan Y.Y., Liu X., Yang Z. et al. PCSK9 promotes LDLR degradation by preventing SNX17‑mediated LDLR recycling. Circulation. 2025; 151 (21): 1512–26. DOI: 10.1161/CIRCULATIONAHA.124.072336.
31. Wang J., Li S., Ren Y. et al. The impact of PCSK9 gene polymorphisms on ischemic stroke: a systematic review and meta-analysis. J. Integr Neurosci. 2024; 23 (3): 62. DOI: 10.31083/j.jin2303062.
32. Grejtakova D., Boronova I., Bernasovska J. et al. PCSK9 and lipid metabolism: genetic variants, current therapies, and cardiovascular outcomes. Cardiovasc Drugs Ther. 2025; 39 (6): 1439–51. DOI: 10.1007/s10557-024-07599-5.
33. Perera S.D., Hegelé R.A. Genetic variability of apolipoprotein B in hypertriglyceridemia. Current Opinion in Lipidology. 2024; 35 (2): 66–77. DOI: 10.1097/MOL.0000000000000916.
34. Urbano-Cano A.L., Álvarez-Rosero R.E., Liscano Y. Association of CETP, APOA5, IL6, and PON1 gene variants with dyslipidemia and cardiovascular risk in a population from Cauca Department, Colombia. Genes. 2025; 16: 545. DOI: 10.3390/genes16050545.
35. Сороковикова Т.В., Морозов А.М., Анисимова В.В. [и др.] Особенности этиопатогенеза инсульта в молодом возрасте. Врач. 2025; 36 (9): 22–7. [Sorokovikova T.V., Morozov A.M., Anisimova V.V. et al. Features of the etiopathogenesis of stroke in young people. Doctor. 2025; 36 (9): 22–27. DOI 10.29296/25877305-2025-09-04 (in Russian)]
36. Majumder D. Ischemic Stroke: Pathophysiology and Evolving Treatment Approaches. Neurosci Insights. 2024; 19: 26331055241292600. DOI: 10.1177/26331055241292600
37. Allinson K.S.J. Deaths related to stroke and cerebrovascular disease. Diagnostic Histopathology. 2025; 31 (1): 22–31. DOI: 10.1016/j.mpdhp.2024.10.005.
38. Рачин А.П., Чутко Л.С., Карпов С.М. и др. Хроническая ишемия мозга: современный взгляд на проблему и нейрометаболическая терапия. Обзор. Коморбидная неврология. 2025; 2 (4): 52–62. [Rachin A.P., Chutko L.S., Karpov S.M. et al. Chronic cerebral ischemia: a modern view on the problem and neurometabolic therapy. Review. Comorbid Neurology. 2025; 2 (4): 52–62. DOI:10.62505/3034-185x-2025-2-4-52-62 (in Russian)]
39. Salaudeen M.A., Bello N., Danraka R.N. et al. Understanding the Pathophysiology of Ischemic Stroke: The Basis of Current Therapies and Opportunity for New Ones. Biomolecules. 2024; 14 (3): 305. DOI: 10.3390/biom14030305.
40. Шишкова В.Н., Адашева Т.В. Хроническая ишемия головного мозга и головная боль у пациентов в практике терапевта. Неврология, нейропсихиатрия, психосоматика. 2021; 13 (1): 131–7. [Shishkova V.N., Adasheva T.V. Chronic cerebral ischemia and headache in patients in general practice. Neurology, Neuropsychiatry, Psychosomatics. 2021; 13 (1): 131–7. DOI: 10.14412/2074-2711-2021-1-131-137 (in Russian)]
41. Чуканова А.С., Чуканова Е.И., Надарейшвили Г.Г. и др. Патогенетические аспекты формирования острой фокальной ишемии головного мозга. Журнал неврологии и психиатрии им. С.С. Корсакова. Спецвыпуски. 2017; 117 (12 2): 4–10. [Chukanova A.S., Chukanova E.I., Nadareyshvili G.G. et al. Pathogenetic aspects of the development of acute focal cerebral ischemia S.S. Korsakov J. of Neurology and Psychiatry. Special Issues. 2017; 117 (12 2): 4–10. DOI: 10.17116/jnevro20171171224-10 (in Russian)]
42. Majumder D. Ischemic stroke: pathophysiology and emerging treatment approaches. Neuroscience Insights. 2024; 19. DOI: 10.1177/26331055241292600.
43. Mahajan R., Shekhjar F., Qureshi A.I. et al. Hyperchloremia and hypernatremia reduce microglia and neuron survival during oxygen‑glucose deprivation/reperfusion. Biomedicines. 2024; 12: 551. DOI: 10.3390/biomedicines12030551. (https://www.nature.com/articles/s41401-025-01576-w)
44. Sello G., Ballerini L. Interaction between synaptic glutamate release and excitotoxicity: neuronal damage and protection provided by graphene based materials. Life. 2025; 15: 1776. DOI: 10.3390/life15111776.
45. Jiang Y., Wang G., Jiang S. et al. Molecular mechanisms and strategies for targeted intervention in calcium overload during ischemic stroke. Int. J. Mol. Sci. 2026; 27: 2279. DOI: 10.3390/ijms27052279.
46. Шиленко Л.А., Карпов А.А., Веретенникова Е.И. и др. Патогенетические сценарии развития ишемии головного мозга и основные элементы ишемического каскада. Трансляционная медицина. 2024; 11 (1): 87–102. [Shilenko L.A., Karpov A.A., Veretennikova E.I. et al. Pathogenetic scenarios of cerebral ischemia development and key elements of the ischemic cascade. Translational Medicine. 2024; 11 (1). DOI: 10.18705/2311-4495-2024-11-1-87-102 (in Russian)]
47. Dash U.C., Bhol N.K., Swain S.K. et al. Oxidative stress and inflammation in the pathogenesis of neurological disorders: mechanisms and implications. Acta Pharm Sin B. 2025; 15 (1): 15–34. DOI: 10.1016/j.apsb.2024.10.004.
48. Rehman S., Nadim A., Akram U. et al. Molecular mechanisms of ischemic stroke: a review integrating clinical imaging and therapeutic perspectives. Biomedicines. 2024; 12: 812. DOI: 10.3390/biomedicines12040812.
49. Sasannia S., Leigh R., Bastani P.B. et al. Blood‑brain barrier breakdown in brain ischemia: insights from MRI perfusion imaging. Neurotherapeutics. 2025; 22 (1): e00516. DOI: 10.1016/j.neurot.2024.e00516.
50. Lan X., Xie X., Deng C. Targeting epigenetics in ischemic stroke: from mechanisms to therapeutics. Curr Neuropharmacol. 2026. DOI: 10.2174/011570159X462267260120104242.
51. Guo Y., Li J., Liu X. et al. Potential therapeutic targets for ischemic stroke in pre-clinical studies: epigenetic-modifying enzymes DNMT/TET and HAT/HDAC. Front Pharmacol. 2025; 16: 1571276. DOI: 10.3389/fphar.2025.1571276.
52. Majdi A., Yaraghi S., Moharrami A. et al. Role of histone deacetylases and sirtuins in the ischaemic stroke: a systematic review and meta-analysis of animal studies Stroke Vasc Neurol. 2026; 11 (1): 6–20. DOI: 10.1136/svn-2025-004159.
53. Chen N.H., Ren J.X., Li G.J. et al. MicroRNAs as potential biomarkers and therapeutic targets in ischemic stroke from the perspective of inflammation. Curr Neuropharmacol. 2026; 24 (3): 348–63. DOI: 10.2174/011570159X380644250707075513.
54. Opare-Addo P.A., Sarfo F.S., Aikins M. et al. Epigenetics as a target to mitigate excess stroke risk in people of African ancestry: a scoping review. J. Stroke Cerebrovasc Dis. 2024; 33 (5): 107585. DOI: 10.1016/j.jstrokecerebrovasdis.2024.107585.
55. Jubair H. Epigenetics and environmental exposures in early neurodevelopment: implications for pediatric neurological disorders. Sage Open Pediatr. 2025; 12: 30502225251380331. DOI: 10.1177/30502225251380331.
56. Lisek M., Bochenska N., Tomczak J. et al. Epigenetic regulation in ischemic neuroprotection: the dual role of HDACs and HATs in neuroinflammation and recovery. Antioxidants. 2025; 14: 1015. DOI: 10.3390/antiox14081015.
57. Ding B., Wang Y., Li J. et al. Epigenetic mechanisms linking atherosclerosis to ischemic stroke: insights from DNA methylation and transcriptome integration. Front Genet. 2025; 16: 1567951. DOI: 10.3389/fgene.2025.1567951.
58. Chandra Sekar P., Veerabathiran R. A Genetic perspective on ischemic stroke: recent advances and future directions. Annals of Clinical and Experimental Neurology. 2024; 18 (4): 55–67. DOI: 10.17816/ACEN.1064.
59. Ciaccio A.M., Tuttolomondo A. Epigenetics of cerebrovascular diseases: an update review of clinical studies. Epigenomics. 2024; 16 (14): 1043–55. DOI: 10.1080/17501911.2024.2377947.
60. Opare Addo P.A., Sarfo F.S., Ovbiagele B. Role of nutritional epigenetics for cerebrovascular health in low and middle income countries. J. Am. Heart Assoc. 2025; 14 (2): e035984. DOI: 10.1161/JAHA.124.035984.
61. Oyovwi M.O., Ben‑Azu B., Jeroh E. et al. The role of genetics in stroke risk and outcome: a review of current evidence. Brain and Behavior (Brain Behav). 2025; 15 (10). DOI: 10.1002/brb3.70820.
62. Lopez J., Mark J., Duarte G.J. et al. Role of genetic polymorphisms in clopidogrel response variability: a systematic review. Open Heart. 2023; 10 (2): e002436. DOI: 10.1136/openhrt-2023-002436.
63. Lee K. J., Kang M., Lee E. J. et al. Clinical application of pharmacogenomics in stroke management: current evidence and future directions. J. Stroke. 2026; 28 (1): 58–75. DOI: 10.5853/jos.2025.04595.
64. Ross S., Krebs K., Paré G. et al. Pharmacogenomics in stroke and cardiovascular disease: state of the art. Stroke. 2023; 54 (1): 270–8. DOI: 10.1161/STROKEAHA.122.037717.
65. Rohini AmruthaSri N., Sailaja N., Kondumahanti Venkata Naga Lakshmi D. Genetics basis of cerebrovascular disease. International J. of Pharmaceutical Research and Applications. 2026; 11 (1): 1431–8. DOI: 10.35629/4494-110114311438.
66. Сороковикова Т.В., Морозов А.М., Анисимова В.В., Кондратьева Е.А., Фисюк Е.А. Особенности этиопатогенеза инсульта в молодом возрасте. Врач. 2025 (9): 22–27. [Sorokovikova T.V., Morozov A.M., Anisimova V.V., Kondratieva E.A., Fisyuk E.A. Features of the etiopathogenesis of stroke at a young age. Vrach. 2025 (9): 22–27 (in Russian)].