phgenomicsФармакогенетика и фармакогеномикаPharmacogenetics and Pharmacogenomics2588-05272686-8849LLC "Izdatelstvo OKI"10.37489/2588-0527-2024-2-13-18TMVQUDphgenomics-288Research ArticleАКТУАЛЬНЫЕ ОБЗОРЫCURRENT REVIEWКашель, ассоциированный с приёмом ингибиторов ангиотензинпревращающего фермента: роль фармакогенетикиCough associated with angiotensin-converting enzyme inhibitors: the role of pharmacogeneticshttps://orcid.org/0000-0001-8228-1114ЛеоноваМ. В.LeonovaM. V.

Марина Васильевна Леонова — д. м. н., профессор, членкорр. РАЕН, клинический фармаколог, Член Московского регионального отделения организации  

Москва

Marina V. Leonova — Dr. Sci. (Med.), Professor, Corresponding Member of the Russian Academy of Natural Sciences, Member the Interregional Public Organization

Moscow 

anti23@mail.ruМОО «Ассоциация клинических фармакологов»РоссияAssociation of Clinical PharmacologistsRussian Federation202431122024021318Copyright © Леонова М.В., 20242024Леонова М.В.Leonova M.V.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.pharmacogenetics-pharmacogenomics.ru/jour/article/view/288

Кашель — частый побочный эффект ингибиторов ангиотензинпревращающего фермента (иАПФ), требующий прекращения приёма препаратов. Частота сухого кашля у пациентов, получавших иАПФ, составляет примерно 1,5–11 %, по некоторым данным 35 %. Точный механизм кашля, вызванного иАПФ, остаётся неясным, брадикининовый путь является наиболее широко распространённой теорией. Роль генетического полиморфизма белков ферментов и переносчиков иАПФ в последние годы активно обсуждается медицинской общественностью. Так, первые исследования по оценке роли генетических факторов были направлены на полиморфизм гена АПФ (I/D) и разных локусов гена рецепторов брадикинина B2 (BDKRB2). В последующем в ряде метаанализов исследований была подтверждена связь между полиморфизмом гена АПФ I/D (rs4646994) и гена рецепторов брадикинина B2 58T/C (rs1799722). Другие гены потенциального риска развития кашля, вызванного иАПФ, могут кодировать белки-транспортеры, которые влияют на концентрацию иАПФ в плазме или белки мембранного транспорта, такие как ABO и SCLO1B1 (OATP1B1), полиморфизм которых имеет связь с кашлем. В полногеномных ассоциативных исследованиях (GWAS) проводился поиск новых генов-кандидатов, ответственных за развитие кашля, вызванного приёмом иАПФ, и были получены связи с полиморфизмом генов CLASP1, KCNIP4, PREP, NTSR1, L3MBTL4, SRBT1, PNPT1 и PCGF3, среди которых многие гены ответственны за нейробиологические механизмы развития кашля. Результаты исследований фармакогеномики расширяют понимание патофизиологических процессов, лежащих в основе кашля, связанного с иАПФ. По результатам исследований GWAS возможен полигенный прогноз риска развития кашля и прекращения приёма иАПФ, что в будущем может идентифицировать пациентов с риском развития кашля, связанного с иАПФ.

Cough is a common side effect of angiotensin-converting enzyme (ACE) inhibitors, requiring the discontinuation of these medications. The frequency of dry cough in patients treated with ace inhibitors was approximately 1.5–11%, according to a previous study of 35%. The exact mechanism underlying cough caused by ACE inhibitors remains unclear, with the bradykinin pathway being the most widely accepted theory. The roles of genetic polymorphisms in enzyme proteins and ACE inhibitors have been actively discussed by the medical community. Thus, the first studies to assess the role of genetic factors focused on the polymorphism of the ACE (I/D) gene and different loci of the bradykinin B2 (BDKRB2) receptor gene. Subsequently, several meta-analyses of studies confirmed the relationship between the polymorphism of the ACE I/D gene (rs4646994) and the bradykinin B2 58T/C receptor gene (rs1799722). Other genes at potential risk of developing ACE inhibitors may encode transporter proteins that affect plasma ACE inhibitors or membrane transport proteins such as ABO and SCLO1B1 (OATP1B1), whose polymorphism is associated with cough. Genome-wide association studies (GWAS) searched for new candidate genes responsible for the development of cough caused by ACE inhibitors, and links were found with gene polymorphisms CLASP1, KCNIP4, PREP, NTSR1, L3MBTL4, SRBT1, PNPT1, and PCGF3, among which many genes are responsible for the neurobiological mechanisms of cough development. The results of pharmacogenomics studies have expanded the understanding of the pathophysiological processes underlying ACE-associated cough. According to the results of the GWAS studies, a polygenic prognosis of the risk of developing cough and discontinuation of ace inhibitors is possible, which in the future may identify patients at risk of developing ace-associated cough.

ингибиторы АПФкашельфармакогеномикаполиморфизм геновACE inhibitorscoughpharmacogenomicsgene polymorphismReferencesDicpinigaitis PV. Angiotensin-converting enzyme inhibitor-induced cough: ACCP evidence-based clinical practice guidelines. Chest. 2006; 129(1 Suppl):169S-173S. https://doi.org/10.1378/chest.129.1_suppl.169S.Dicpinigaitis PV. Angiotensin-converting enzyme inhibitor-induced cough: ACCP evidence-based clinical practice guidelines. Chest. 2006; 129(1 Suppl):169S-173S. https://doi.org/10.1378/chest.129.1_suppl.169S.Hu Y, Liang L, Liu S, et al. Angiotensin-converting enzyme inhibitor induced cough compared with placebo, and other antihypertensives: A systematic review, and network meta-analysis. J Clin Hypertens (Greenwich). 2023;25(8):661-688. https://doi.org/10.1111/jch.14695.Hu Y, Liang L, Liu S, et al. Angiotensin-converting enzyme inhibitor induced cough compared with placebo, and other antihypertensives: A systematic review, and network meta-analysis. J Clin Hypertens (Greenwich). 2023;25(8):661-688. https://doi.org/10.1111/jch.14695.Brugts JJ, Arima H, Remme W, et al. The incidence and clinical predictors of ACE-inhibitor induced dry cough by perindopril in 27,492 patients with vascular disease. Int J Cardiol. 2014;176(3):718-23. https://doi.org/10.1016/j.ijcard.2014.07.108.Brugts JJ, Arima H, Remme W, et al. The incidence and clinical predictors of ACE-inhibitor induced dry cough by perindopril in 27,492 patients with vascular disease. Int J Cardiol. 2014;176(3):718-23. https://doi.org/10.1016/j.ijcard.2014.07.108.Wyskida K, Jura-Szołtys E, Smertka M, et al. Factors that favor the occurrence of cough in patients treated with ramipril--a pharmacoepidemiological study. Med Sci Monit. 2012;18(9):PI21-8. https://doi.org/10.12659/msm.883336.Wyskida K, Jura-Szołtys E, Smertka M, et al. Factors that favor the occurrence of cough in patients treated with ramipril--a pharmacoepidemiological study. Med Sci Monit. 2012;18(9):PI21-8. https://doi.org/10.12659/msm.883336.Omboni S, Borghi C. Zofenopril and incidence of cough: a review of published and unpublished data. Ther Clin Risk Manag. 2011;7:459-71. https://doi.org/10.2147/TCRM.S25976.Omboni S, Borghi C. Zofenopril and incidence of cough: a review of published and unpublished data. Ther Clin Risk Manag. 2011;7:459-71. https://doi.org/10.2147/TCRM.S25976.Bangalore S, Kumar S, Messerli FH. Angiotensin-converting enzyme inhibitor associated cough: deceptive information from the Physicians' Desk Reference. Am J Med. 2010;123(11):1016-30. https://doi.org/10.1016/j.amjmed.2010.06.014.Bangalore S, Kumar S, Messerli FH. Angiotensin-converting enzyme inhibitor associated cough: deceptive information from the Physicians' Desk Reference. Am J Med. 2010;123(11):1016-30. https://doi.org/10.1016/j.amjmed.2010.06.014.Yılmaz İ. Angiotensin-Converting Enzyme Inhibitors Induce Cough. Turk Thorac J. 2019;20(1):36-42. https://doi.org/10.5152/TurkThoracJ.2018.18014.Yılmaz İ. Angiotensin-Converting Enzyme Inhibitors Induce Cough. Turk Thorac J. 2019;20(1):36-42. https://doi.org/10.5152/TurkThoracJ.2018.18014.Сычев И.В., Денисенко Н.П., Качанова А.А., и др. Клиникоанамнестические предикторы развития сухого кашля у пациентов с кардиоваскулярной патологией на фоне приема эналаприла. Безопасность и риск фармакотерапии. 2023;11(2):231-240. https://doi.org/10.30895/2312-7821-2023-11-2-231-240.Sychev IV, Denisenko NP, Kachanova AA, et al. Clinical signs and medical history as predictors of enalapril-associated dry cough in cardiovascular patients. Safety and Risk of Pharmacotherapy. 2023;11(2):231-240. (In Russ.). https://doi.org/10.30895/2312-7821-2023-11-2-231-240.Packard KA, Wurdeman RL, Arouni AJ. ACE inhibitor-induced bronchial reactivity in patients with respiratory dysfunction. Ann Pharmacother. 2002;36(6):1058-67. doi: 10.1345/aph.1A332.Packard KA, Wurdeman RL, Arouni AJ. ACE inhibitor-induced bronchial reactivity in patients with respiratory dysfunction. Ann Pharmacother. 2002;36(6):1058-67. doi: 10.1345/aph.1A332.Borghi C, Cicero AF, Agnoletti D, Fiorini G. Pathophysiology of cough with angiotensin-converting enzyme inhibitors: How to explain within-class differences? Eur J Intern Med. 2023;110:10-15. https://doi.org/10.1016/j.ejim.2023.01.005.Borghi C, Cicero AF, Agnoletti D, Fiorini G. Pathophysiology of cough with angiotensin-converting enzyme inhibitors: How to explain within-class differences? Eur J Intern Med. 2023;110:10-15. https://doi.org/10.1016/j.ejim.2023.01.005.Rigat B, Hubert C, Alhenc-Gelas F, et al. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest. 1990;86(4):1343-6. https://doi.org/10.1172/JCI114844.Rigat B, Hubert C, Alhenc-Gelas F, et al. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest. 1990;86(4):1343-6. https://doi.org/10.1172/JCI114844.Brown NJ, Blais C Jr, Gandhi SK, Adam A. ACE insertion/deletion genotype affects bradykinin metabolism. J Cardiovasc Pharmacol. 1998;32(3):373-7. https://doi.org/10.1097/00005344-199809000-00006.Brown NJ, Blais C Jr, Gandhi SK, Adam A. ACE insertion/deletion genotype affects bradykinin metabolism. J Cardiovasc Pharmacol. 1998;32(3):373-7. https://doi.org/10.1097/00005344-199809000-00006.Mukae S, Aoki S, Itoh S, et al. Bradykinin B(2) receptor gene polymorphism is associated with angiotensin-converting enzyme inhibitorrelated cough. Hypertension. 2000;36(1):127-31. https://doi.org/10.1161/01.hyp.36.1.127.Mukae S, Aoki S, Itoh S, et al. Bradykinin B(2) receptor gene polymorphism is associated with angiotensin-converting enzyme inhibitorrelated cough. Hypertension. 2000;36(1):127-31. https://doi.org/10.1161/01.hyp.36.1.127.Mas S, Gassò P, Alvarez S, et al. Pharmacogenetic predictors of angiotensin-converting enzyme inhibitor-induced cough: the role of ACE, ABO, and BDKRB2 genes. Pharmacogenet Genomics. 2011;21(9):531-8. https://doi.org/10.1097/FPC.0b013e328348c6db.Mas S, Gassò P, Alvarez S, et al. Pharmacogenetic predictors of angiotensin-converting enzyme inhibitor-induced cough: the role of ACE, ABO, and BDKRB2 genes. Pharmacogenet Genomics. 2011;21(9):531-8. https://doi.org/10.1097/FPC.0b013e328348c6db.Grilo A, Sáez-Rosas MP, Santos-Morano J, et al. Identification of genetic factors associated with susceptibility to angiotensin-converting enzyme inhibitors-induced cough. Pharmacogenet Genomics. 2011 Jan;21(1):10-7. https://doi.org/10.1097/FPC.0b013e328341041c.Grilo A, Sáez-Rosas MP, Santos-Morano J, et al. Identification of genetic factors associated with susceptibility to angiotensin-converting enzyme inhibitors-induced cough. Pharmacogenet Genomics. 2011 Jan;21(1):10-7. https://doi.org/10.1097/FPC.0b013e328341041c.Nishio K, Kashiki S, Tachibana H, Kobayashi Y. Angiotensinconverting enzyme and bradykinin gene polymorphisms and cough: A meta-analysis. World J Cardiol. 2011 Oct 26;3(10):329-36. https://doi.org/10.4330/wjc.v3.i10.329.Nishio K, Kashiki S, Tachibana H, Kobayashi Y. Angiotensinconverting enzyme and bradykinin gene polymorphisms and cough: A meta-analysis. World J Cardiol. 2011 Oct 26;3(10):329-36. https://doi.org/10.4330/wjc.v3.i10.329.Mahmoudpour SH, Leusink M, van der Putten L, et al. Pharmacogenetics of ACE inhibitor-induced angioedema and cough: a systematic review and meta-analysis. Pharmacogenomics. 2013 Feb;14(3):249-60. https://doi.org/10.2217/pgs.12.206.Mahmoudpour SH, Leusink M, van der Putten L, et al. Pharmacogenetics of ACE inhibitor-induced angioedema and cough: a systematic review and meta-analysis. Pharmacogenomics. 2013 Feb;14(3):249-60. https://doi.org/10.2217/pgs.12.206.Li YF, Zhu XM, Liu F, et al. Angiotensin-converting enzyme (ACE) gene insertion/deletion polymorphism and ACE inhibitor-related cough: a meta-analysis. PLoS One. 2012;7(6):e37396. https://doi.org/10.1371/journal.pone.0037396.Li YF, Zhu XM, Liu F, et al. Angiotensin-converting enzyme (ACE) gene insertion/deletion polymorphism and ACE inhibitor-related cough: a meta-analysis. PLoS One. 2012;7(6):e37396. https://doi.org/10.1371/journal.pone.0037396.Mu G, Xiang Q, Zhou S, et al. Association between genetic polymorphisms and angiotensin-converting enzyme inhibitor-induced cough: a systematic review and meta-analysis. Pharmacogenomics. 2019 Feb;20(3):189-212. https://doi.org/10.2217/pgs-2018-0157.Mu G, Xiang Q, Zhou S, et al. Association between genetic polymorphisms and angiotensin-converting enzyme inhibitor-induced cough: a systematic review and meta-analysis. Pharmacogenomics. 2019 Feb;20(3):189-212. https://doi.org/10.2217/pgs-2018-0157.Luo JQ, He FZ, Luo ZY, et al. Rs495828 polymorphism of the ABO gene is a predictor of enalapril-induced cough in Chinese patients with essential hypertension. Pharmacogenet Genomics. 2014 Jun;24(6):306-13. https://doi.org/10.1097/FPC.0000000000000050.Luo JQ, He FZ, Luo ZY, et al. Rs495828 polymorphism of the ABO gene is a predictor of enalapril-induced cough in Chinese patients with essential hypertension. Pharmacogenet Genomics. 2014 Jun;24(6):306-13. https://doi.org/10.1097/FPC.0000000000000050.Chung CM, Wang RY, Chen JW, et al. A genome-wide association study identifies new loci for ACE activity: potential implications for response to ACE inhibitor. Pharmacogenomics J. 2010 Dec;10(6):537-44. https://doi.org/10.1038/tpj.2009.70.Chung CM, Wang RY, Chen JW, et al. A genome-wide association study identifies new loci for ACE activity: potential implications for response to ACE inhibitor. Pharmacogenomics J. 2010 Dec;10(6):537-44. https://doi.org/10.1038/tpj.2009.70.Hallberg P, Persson M, Axelsson T, et al. Genetic variants associated with angiotensin-converting enzyme inhibitor-induced cough: a genomewide association study in a Swedish population. Pharmacogenomics. 2017 Feb;18(3):201-213. https://doi.org/10.2217/pgs-2016-0184.Hallberg P, Persson M, Axelsson T, et al. Genetic variants associated with angiotensin-converting enzyme inhibitor-induced cough: a genomewide association study in a Swedish population. Pharmacogenomics. 2017 Feb;18(3):201-213. https://doi.org/10.2217/pgs-2016-0184.Mosley JD, Shaffer CM, Van Driest SL, et al. A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitorinduced cough. Pharmacogenomics J. 2016 Jun;16(3):231-7. https://doi.org/10.1038/tpj.2015.51.Mosley JD, Shaffer CM, Van Driest SL, et al. A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitorinduced cough. Pharmacogenomics J. 2016 Jun;16(3):231-7. https://doi.org/10.1038/tpj.2015.51.Ghouse J, Tragante V, Muhammad A, et al. Polygenic risk score for ACE-inhibitor-associated cough based on the discovery of new genetic loci. Eur Heart J. 2022 Dec 1;43(45):4707-4718. https://doi.org/10.1093/eurheartj/ehac322.Ghouse J, Tragante V, Muhammad A, et al. Polygenic risk score for ACE-inhibitor-associated cough based on the discovery of new genetic loci. Eur Heart J. 2022 Dec 1;43(45):4707-4718. https://doi.org/10.1093/eurheartj/ehac322.Kaczyńska K, Zając D, Wojciechowski P, et al. Neuropeptides and breathing in health and disease. Pulm Pharmacol Ther. 2018 Feb;48:217-224. https://doi.org/10.1016/j.pupt.2017.12.001Kaczyńska K, Zając D, Wojciechowski P, et al. Neuropeptides and breathing in health and disease. Pulm Pharmacol Ther. 2018 Feb;48:217-224. https://doi.org/10.1016/j.pupt.2017.12.001Mu G, Xiang Q, Zhang Z, et al. PNPT1 and PCGF3 variants associated with angiotensin-converting enzyme inhibitor-induced cough: a nested case-control genome-wide study. Pharmacogenomics. 2020 Jun;21(9):601-614. https://doi.org/10.2217/pgs-2019-0167.Mu G, Xiang Q, Zhang Z, et al. PNPT1 and PCGF3 variants associated with angiotensin-converting enzyme inhibitor-induced cough: a nested case-control genome-wide study. Pharmacogenomics. 2020 Jun;21(9):601-614. https://doi.org/10.2217/pgs-2019-0167.

The authors declare that there are no conflicts of interest present.