The role of angiotensin I - converting enzyme (ACE) insertion/deletion gene polymorphism in hypertension and ACE inhibitor therapy: a narrative review
Abstract
Primary hypertension is the most prevalent type of hypertension, which is primarily attributed to genetic factors. The angiotensin-converting enzyme (ACE) gene has emerged as a prominent candidate among the genetic factors influencing blood pressure regulation. The ACE gene encodes the ACE, which plays a crucial role in the renin-angiotensin system. The ACE gene insertion/deletion (I/D) polymorphism is a variation of the ACE gene that affects blood pressure regulation. Individuals with II, ID, and DD genotypes may exhibit distinct ACE plasma concentrations, potentially contributing to variations in blood pressure levels and response to ACE inhibitor therapy. This article aimed to provide a comprehensive overview of the relationship between the ACE I/D gene with hypertension and angiotensin-converting enzym inhibitor (ACEI) effectiveness. This article presents a narrative review encompassing relevant studies published between 2013 and 2023. A systematic search was conducted using reputable databases such as PubMed, Science Direct, and Scopus. Inclusion criteria were applied, resulting in the selection of 25 articles that met the predefined criteria. The analysis included 25 studies, comprising 5 articles that investigated the impact of ACEI therapy and 20 articles that examined the ACE I/D gene polymorphism in hypertensive populations without ACEI therapy. It can be concluded that compared to the I allele, the D allele of the ACE I/D gene is associated with a higher level of essential hypertension and a reduced ACEI response.
References
James PA, Oparil S, Carter BL, Chusman WC, Dennison-Himmelfarb C, Handler J, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014; 311(5):507-20.
https://doi.org/10.1001/jama.2013.284427
DiPiro JT, ed. Pharmacotherapy: a pathophysiologic approach. Eleventh edition. McGraw Hill Medical; 2020.
Kolovou V, Lagou E, Mihas C, Vasiliki G, Katsiki N, Kollia A, et al. Angiotensinogen (AGT) M235T, AGT T174M and angiotensin-1-converting enzyme (ACE) I/D gene polymorphisms in essential hypertension: effects on ramipril efficacy. Open Cardiovasc Med J 2015; 9:118-26.
https://doi.org10.2174/1874192401509010118
National Center for Biotechnology Information. ACE angiotensin I converting enzyme [Homo sapiens (human)]. Published March 21, 2023. Accessed March 23, 2023.
https://www.ncbi.nlm.nih.gov/gene/1636
Ha SK, Park HC, Park HS, Kang BS, Lee TH, Hwang HJ, et al. ACE gene polymorphism and progression of diabetic nephropathy in Korean type 2 diabetic patients: effect of ACE gene DD on the progression of diabetic nephropathy. Am J Kidney Dis 2003; 41(5):943-9.
https://doi.org/10.1016/S0272-6386(03)00191-4
Rahimi Z. ACE insertion/deletion (I/D) polymorphism and diabetic nephropathy. J Nephropathol 2012; 1(3):143-51.
https://doi.org/10.5812/nephropathol.8109
Sarangarajan R, Winn R, Kiebish MA, Bountra C, Granger E, et al. Ethnic prevalence of angiotensin-converting enzyme deletion (D) polymorphism and COVID-19 risk: rationale for use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers. J Racial Ethn Health Disparities 2021; 8(4):973-80.
https://doi.org/10.1007/s40615-020-00853-0
Liu M, Yi J, Tang W. Association between angiotensin converting enzyme gene polymorphism and essential hypertension: a systematic review and meta-analysis. J Renin-Angiotensin Aldosterone Syst 2021; 22(1):1470320321995074.
https://doi.org/10.1177/1470320321995074
Heidari F, Vasudevan R, Mohd Ali SZ, Ismail P, Etemad A, Pishva SR, et al. Association of insertion/deletion polymorphism of angiotensin-converting enzyme gene among Malay male hypertensive subjects in response to ACE inhibitors. J Renin Angiotensin Aldosterone Syst 2015; 16(4):872-9.
https://doi.org/10.1177/1470320314538878
Schelleman H, Klungel OH, van Duijn CM, Witteman JC, Hofman A, de Boer A, et al. Drug-gene interaction between the insertion/deletion polymorphism of the angiotensin-converting enzyme gene and antihypertensive therapy. Ann Pharmacother 2006; 40(2):212-8.
https://doi.org/10.1345/aph.1G316
Krishnan R, Sekar D, karunanithy S, Subramanium S. Association of angiotensin converting enzyme gene insertion/deletion polymorphism with essential hypertension in south Indian population. Genes Dis 2016; 3(2):159-63.
https://doi.org/10.1016/j.gendis.2016.03.001
He Q, Fan C, Yu M, Wallar G, Zhang ZF, Wang L, et al. Associations of ACE gene insertion/deletion polymorphism, ACE activity, and ACE mRNA expression with hypertension in a Chinese Population. PLoS ONE 2013; 8(10):e75870.
https://doi.org/10.1371/journal.pone.0075870
Faizah MN. Identifikasi gen angiotensin converting enzyme (ACE) insersi/delesi (I/D) pada penderita hipertensi di Rumah Sakit dr. Saiful Anwar Malang.[Thesis] Published online 2013:9.
http://etheses.uin-malang.ac.id/id/eprint/459.
Shanmuganathan R, Kumaresan R, Giri P. Prevalence of angiotensin converting enzyme (ACE) gene insertion/deletion polymorphism in South Indian population with hypertension and chronic kidney disease. J Postgrad Med 2015; 61(4):230-4.
https://doi.org/10.4103/0022-3859.166510
Assie WNA, Alkhashab F, Azzawie AFA. Detection of the association between ACE gene polymorphism and lipid profiles level in some Iraqi hypertensive patients. Trop J Nat Prod Res 2021; 5(6):1019-23.
Singh M, Singh AK, Singh S, Pandey P, Chandra S, Gambhir IS. Angiotensin-converting enzyme gene I/D polymorphism increases the susceptibility to hypertension and additive diseases: a study on North Indian patients. Clin Exp Hypertens 2016; 38(3):305-11.
https://doi.org/10.3109/10641963.2015.1107085
Birhan TA, Molla MD, Abdulkadir M, Tesfa KH. Association of angiotensin-converting enzyme gene insertion/deletion polymorphisms with risk of hypertension among the Ethiopian population. PLOS ONE 2022; 17(11):e0276021.
https://doi.org/10.1371/journal.pone.0276021
Mustafa SA, Abdulwahid MJ, Amin NA. Polymorphism of the insertion/deletion angiotensin converting enzyme (ACE) gene and hypertension in a population from Erbil city. Zanco J Pure Appl Sci 2015; 27(6):41-6.
Kooffreh ME, Anumudu CI, Kumar PL. Insertion/deletion polymorphism of the angiotensin-converting enzyme gene and the risk of hypertension among residents of two cities, South-South Nigeria. Adv Biomed Res 2014; 3(1):118.
https://doi.org/10.4103/2277-9175.133184
Roger NAG, Clement OEL, Felix OA. Correlation between the insertion/deletion polymorphism of the angiotensin conversion enzyme gene and hypertension among the Gabonese population. Int J Biosci IJB 2018; 12(2):44-52.
https://doi.org/10.12692/ijb/12.2.44-52
Tchelougou D, Kologo JK, Karou SD, Yameogo VN, Bisseye C, Djigma FW, et al. Renin-angiotensin system genes polymorphisms and essential hypertension in Burkina Faso, West Africa. Int J Hypertens 2015; 2015:979631.
https://doi.org/10.1155/2015/979631
Patel DD, Parchwani DN, Dikshit N, Parchwani T. Analysis of the pattern, alliance and risk of rs1799752 (ACE I/D polymorphism) with essential hypertension. Indian J Clin Biochem 2022; 37(1):18-28.
https://doi.org/10.1007/s12291-020-00927-0
Pinheiro DS, Santos RS, Jardim PCBV, Silva EG, Reis AAS, Pedrino GR, et al. The combination of ACE I/D and ACE2 G8790A polymorphisms revels susceptibility to hypertension: a genetic association study in Brazilian patients. PLoS ONE 2019; 14(8):e0221248.
https://doi.org/10.1371/journal.pone.0221248
Sun F, He N, Zhang K, Wu N, Zhao J, Qiu C. Association of ACE gene A2350G and I/D polymorphisms with essential hypertension in the northernmost province of China. Clin Exp Hypertens 2018; 40(1):32-8.
https://doi.org/10.1080/10641963.2017.1291659
Hussain M, Awan FR, Gujjar A, Hafeez S, Islam M. A case control association study of ACE gene polymorphism (I/D) with hypertension in Punjabi population from Faisalabad, Pakistan. Clin Exp Hypertens 2018; 40(2):186-91.
https://doi.org/10.1080/10641963.2017.1356842
Rana G, Yadav S, Joshi S, Saraswathy KN. Association of DD genotype of angiotensin-converting enzyme gene (I/D) polymorphism with hypertension among a North Indian population. J Community Genet 2018; 9(1):51-5.
https://doi.10.1007/s12687-017-0321-9
Hadian B, Zafarmohtashami A, Chaghervand Z, Nouryazdan N. Angiotensin-converting enzyme gene insertion/deletion polymorphism and hypertension disease. Arch Physiol Biochem 2022; 128(5):1165-9.
https://doi.org/10.1080/13813455.2020.1762225
Oscanoa TJ, Cieza EC, Lizaraso-Soto FA, Guevara ML, Fujita RM, Romero-Ortuno R. Lack of association between angiotensin-converting enzyme (ACE) genotype and essential hypertension in Peruvian older people. Arter Hypertens 2020; 24(3):115-9.
https://doi.org/10.5603/AH.a2020.0011
Contini M, Compagnino E, Cattadori G, Magri D, Camera M, Apostolo A, et al. ACE-inhibition benefit on lung function in heart failure is modulated by ACE insertion/deletion polymorphism. Cardiovasc Drugs Ther 2016; 30(2):159-68.
https://doi.org/10.1007/s10557-016-6645-6
Gupta S, Chattopadhyaya I, Agrawal BK, Sehajpal PK, Goel RK. Correlation of renin angiotensin system (RAS) candidate gene polymorphisms with response to ramipril in patients with essential hypertension. J Postgrad Med 2015; 61(1):21-6.
https://doi.org/10.4103/0022-3859.147028
Heidari F, Vasudevan R, Mohd Ali SZ, Ismail P, Arkani M. RAS Genetic variants in interaction with ACE inhibitors drugs influences essential hypertension control. Arch Med Res 2017; 48(1):88-95.
https://doi.org/10.1016/j.arcmed.2017.03.003
Weizmann Institute of Science. ACE gene - angiotensin I converting enzyme. Gene Cards - The Human Gene Database. Published 2022.
https://www.genecards.org/cgi-bin/carddisp.pl?gene=ACE
Yusof HA, Muhamed AMC. Angiotensin-converting enzyme (ACE) insertion/deletion gene polymorphism across ethnicity: a narrative review of performance gene. Sport Sci Health 2021; 17(2):57-77.
https://doi.org/10.1007/s11332-020-00712-9
Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. 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
Baudin B. Angiotensin I-converting enzyme gene polymorphism and drug response. Clin Chem Lab Med 2000; 38(9):853-6.
https://doi.org/10.1515/CCLM.2000.123
Costa MFDM, Slocombe R. The use of angiotensin-I converting enzyme I/D genetic polymorphism as a biomarker of athletic performance in humans. Biosensors 2012; 2(4):396-404.
https://doi.org/10.3390/bios2040396
Ha SK. ACE insertion/deletion polymorphism and diabetic nephropathy: clinical implications of genetic information. J Diabetes Res 2014; 2014:846068.
https://doi.org/10.1155/2014/846068
Valdez-Velazquez LL, Quintero-Ramos A, Perez SA, Mendoza-Carrera F, Montoya-Fuentes H, Rivas F Jr, et al. Genetic polymorphisms of the renin-angiotensin system in preterm delivery and premature rupture of membranes. J Renin Angiotensin Aldosterone Syst 2007; 8(4):160-8.
https://doi.org/10.3317/jraas.2007.026
Zheng Y, Huang J. Angiotensin-converting enzyme gene insertion/deletion polymorphism and high-altitude pulmonary edema: An updated meta-analysis. J Renin Angiotensin Aldosterone Syst 2020; 21(1):147032031990003.
https://doi.org/10.1177/1470320319900039
Li Y. Angiotensin-converting enzyme gene insertion/deletion polymorphism and essential hypertension in the Chinese population: a meta-analysis including 21,058 participants. Intern Med J 2012; 42(4):439-44.
https://doi.org/10.1111/j.1445-5994.2011.02584.x
Göktaş O, Şentürk T, Ersoy C. Factors affecting hypertension in the adult population of the Marmara Region, Turkey: a descriptive field study. Int J Hypertens 2020; 2020:8869042.
https://doi.org/10.1155/2020/8869042
Pawening AS, Haqi DN. Risk factors that associated with hypertension in population of Tlatah Village, Purwosari, Bojonegoro. J Public Health Res Community Health Dev 2021; 4(2):137.
https://doi.org/10.20473/jphrecode.v4i2.22862
Goyal A, Cusick AS, Thielemier B. ACE inhibitors. StatPearls Publishing; 2022.
https://www.ncbi.nlm.nih.gov/books/NBK430896/
Jacobsen PK, Tarnow L, Parving HH. Time to consider ACE insertion/deletion genotypes and individual renoprotective treatment in diabetic nephropathy? Kidney Int 2006; 69(8):1293-5.
https://doi.org/10.1038/sj.ki.5000283
So WY, Ma RCW, Ozaki R, Tong PCY, Ng MCY, Ho CS, et al. Angiotensin-converting enzyme (ACE) inhibition in type 2, diabetic patients--interaction with ACE insertion/deletion polymorphism. Kidney Int 2006; 69(8):1438-43.
https://doi.org/10.1038/sj.ki.5000097
Konoshita T. Do genetic variants of the renin-angiotensin system predict blood pressure response to renin-angiotensin system–blocking drugs? A systematic review of pharmacogenomics in the renin-angiotensin system. Curr Hypertens Rep 2011; 13(5):356-61.
