Case-control study on the association of angiotensin-converting enzyme gene I/D rs4646944 single nucleotide polymorphism and young-onset cryptogenic ischemic stroke in an Algerian cohort

Mohamed Lebsir; Mohamed Larbi Rezgoun; Boubekeur Saddik Fekraoui; Brahim Djoudi; Yasmina Boukhenaf; Amina Ines Bernou; Karima Sifi

doi:10.1590/1677-5449.202501422

Original Article

Case-control study on the association of angiotensin-converting enzyme gene I/D rs4646944 single nucleotide polymorphism and young-onset cryptogenic ischemic stroke in an Algerian cohort

Estudo de caso-controle sobre associação do polimorfismo de nucleotídeo único I/D rs4646944 do gene da enzima conversora de angiotensina e acidente vascular isquêmico criptogênico de início precoce em coorte argelina

Mohamed Lebsir; Mohamed Larbi Rezgoun; Boubekeur Saddik Fekraoui; Brahim Djoudi; Yasmina Boukhenaf; Amina Ines Bernou; Karima Sifi

http://dx.doi.org/10.1590/1677-5449.202501422 J Vasc Bras, vol.25, e20250142, 2026

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Abstract

Background: Numerous studies have shown a link between the angiotensin-converting enzyme (ACE) and ischemic stroke. Cryptogenic ischemic stroke is the most commonly recorded form of ischemic stroke among young adults. The insertion/deletion (I/D) variant of ACE (rs4646994) has been linked to ischemic stroke.

Objectives: We examined the potential correlation between this single nucleotide polymorphism and cryptogenic ischemic stroke in young adults.

Methods: This case-control study included 42 young adults (< 50 years of age) diagnosed with cryptogenic ischemic stroke according to the TOAST classification, along with 42 healthy controls from the general population. The vascular risk factors included hypertension, diabetes mellitus, dyslipidemia, smoking, and cardiovascular diseases. Genomic deoxyribonucleic acid was extracted, and the ACE rs4646994 polymorphism was examined using polymerase chain reaction.

Results: Younger age (p = 0.004) and female sex (p = 0.007) were significantly connected to an increased risk of stroke, contrasting with typical stroke demographics. Hypertension (p = 0.002) and smoking (p = 0.04) emerged as important, modifiable risk factors. There was no notable distinction between patients and controls regarding the frequencies of alleles and genotypes of the ACE I/D single nucleotide polymorphism (p > 0.05). These results were not associated with cryptogenic ischemic stroke.

Conclusions: While aligning with the current literature, our results are constrained by the limited sample size, the case-control design, and the dependence on self-reported data, which could have led to bias. This genetic study of a population from eastern Algeria did not show a link between the ACEI/D single nucleotide polymorphism and cryptogenic ischemic stroke.

Keywords

angiotensin-converting enzyme polymorphism; cryptogenic ischemic stroke; young onset

Resumo

Contexto: Vários estudos demonstraram associação entre enzima conversora de angiotensina (ECA) e acidente vascular cerebral (AVC) isquêmico. AVC isquêmico criptogênico é a forma mais frequentemente registrada de AVC isquêmico entre adultos jovens. A variante de inserção/deleção (I/D) da ECA (rs4646994) tem sido associada ao AVC isquêmico.

Objetivos: Investigamos possível correlação entre esse polimorfismo de nucleotídeo único e AVC isquêmico criptogênico em adultos jovens.

Métodos: Caso-controle incluiu 42 adultos jovens (< 50 anos) diagnosticados com AVC isquêmico criptogênico segundo a classificação TOAST, juntamente com 42 controles saudáveis da população geral. Fatores de risco vascular incluíram hipertensão, diabetes melito, dislipidemia, tabagismo e doenças cardiovasculares. Ácido desoxirribonucleico genômico foi extraído, e polimorfismo rs4646994 foi analisado por meio da reação em cadeia da polimerase.

Resultados: Idade mais jovem (p = 0,004) e sexo feminino (p = 0,007) foram significativamente associados a risco aumentado de AVC, contrastando com perfil demográfico típico dessa condição. Hipertensão (p = 0,002) e tabagismo (p = 0,04) mostraram-se fatores de risco importantes e modificáveis. Não houve diferença significativa entre pacientes e controles quanto às frequências de alelos e genótipos do polimorfismo de I/D da ECA (p > 0,05). Esses resultados não demonstraram associação com AVC isquêmico criptogênico.

Conclusão: Embora estejam alinhados com a literatura atual, os resultados apresentam limitações decorrentes do tamanho reduzido da amostra, do delineamento do estudo e da dependência de dados autorreferidos, fatores que podem ter introduzido viés. Este estudo, realizado em uma população do leste da Argélia, não demonstrou associação entre polimorfismo de I/D da ECA e AVC isquêmico criptogênico.

Palavras-chave

polimorfismo ECA; acidente vascular cerebral isquêmico criptogênico; início precoce

References

1 Phipps MS, Cronin CA. Management of acute ischemic stroke. BMJ. 2020;368:l6983. https://doi.org/10.1136/bmj.l6983. PMid:32054610.

2 Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.S troke. 2014;45(7):2160-236. https://doi.org/10.1161/STR.0000000000000024. PMid:24788967.

3 Divišová P, Šaňák D, Král M, et al. Young cryptogenic ischemic stroke: a descriptive analysis of clinical and laboratory characteristics, outcomes and stroke recurrence. J Stroke Cerebrovasc Dis. 2020;29(9):105046. https://doi.org/10.1016/j.jstrokecerebrovasdis.2020.105046. PMid:32807456.

4 Cheng YC, Cole JW, Kittner SJ, Mitchell BD. Genetics of ischemic stroke in young adults. Circ Cardiovasc Genet. 2014;7(3):383-92. https://doi.org/10.1161/CIRCGENETICS.113.000390. PMid:24951665.

5 Della-Morte D, Guadagni F, Palmirotta R, et al. Genetics of ischemic stroke, stroke-related risk factors, stroke precursors and treatments. Pharmacogenomics. 2012;13(5):595-613. https://doi.org/10.2217/pgs.12.14. PMid:22462751.

6 Salem GM, Gab-Allah GK. Angiotensin converting enzyme polymorphism and ischemic stroke. Neurosciences (Riyadh). 2020;25(3):176-81. https://doi.org/10.17712/nsj.2020.3.20190117. PMid:32683396.

7 Indrajaya T. The role of ACE gene polymorphism on pathogenesis of ischemic stroke.Acta Med Indones. 2011;43(3):152-7. PMid:21979279.

8 Goyal A, Saluja A, Saraswathy KN, Bansal P, Dhamija RK. Role of ACE polymorphism in acute ischemic stroke. Neurol India. 2021;69(5):1217-21. https://doi.org/10.4103/0028-3886.329586. PMid:34747787.

9 Melake A, Berhane N. Angiotensin-converting enzyme gene insertion/deletion polymorphism and risk of ischemic stroke complication among patients with hypertension in the Ethiopian population. Front Neurol. 2023;14:1093993. https://doi.org/10.3389/fneur.2023.1093993. PMid:37034069.

10 Sayed-Tabatabaei FA, Oostra BA, Isaacs A, van Duijn CM, Witteman JC. ACE polymorphisms. Circ Res. 2006;98(9):1123-33. https://doi.org/10.1161/01.RES.0000223145.74217.e7. PMid:16690893.

11 Mostafa MA, El-Nabiel LM, Fahmy NA, Hamdy AH, El-Sebaie AH. ACE gene in Egyptian ischemic stroke patients. J Stroke Cerebrovasc Dis. 2016;25(9):2167-71. https://doi.org/10.1016/j.jstrokecerebrovasdis.2015.05.015. PMid:27468663.

12 Zhang Z, Xu G, Liu D, Fan X, Zhu W, Liu X. Angiotensin-converting enzyme insertion/deletion polymorphism contributes to ischemic stroke risk: a meta-analysis of 50 case-control studies. PLoS One. 2012;7(10):e46495. https://doi.org/10.1371/journal.pone.0046495. PMid:23049705.

13 Saadat M. Distribution of ACE insertion/deletion (I/D) polymorphism in Iranian populations. Mol Biol Res Commun. 2015;4(2):63-6. PMid:27843997.

14 Prabhakar P, De T, Nagaraja D, Christopher R. Angiotensin-converting enzyme gene insertion/deletion polymorphism and small vessel cerebral stroke in Indian population. Int J Vasc Med. 2014;2014:305309. https://doi.org/10.1155/2014/305309. PMid:24523965.

15 Qin H, Zhang L, Xu G, Pan X. Association of angiotensin-converting enzyme insertion/deletion polymorphism (rs4646994) with the risk of primary intracerebral hemorrhage. Neurol Res. 2013;35(6):545-52. https://doi.org/10.1179/1743132813Y.0000000184. PMid:23561051.

16 Martinez-Majander N, Artto V, Ylikotila P, et al. Association between migraine and cryptogenic ischemic stroke in young adults. Ann Neurol. 2021;89(2):242-53. https://doi.org/10.1002/ana.25937. PMid:33078475.

17 Vasudeva K, Balyan R, Munshi A. ACE-triggered hypertension incites stroke: genetic, molecular, and therapeutic aspects. Neuromolecular Med. 2020;22(2):194-209. https://doi.org/10.1007/s12017-019-08583-1. PMid:31802381.

18 Miot HA. Tamanho da amostra em estudos clínicos e experimentais. J Vasc Bras. 2011;10(4):275-8. https://doi.org/10.1590/S1677-54492011000400001. PMid:30787944.

19 Bhushan S, Xiao Z, Gao K, et al. Role and interaction between ACE1, ACE2 and their related genes in cardiovascular disorders. Curr Probl Cardiol. 2023;48(8):101162. https://doi.org/10.1016/j.cpcardiol.2022.101162. PMid:35245599.

20 Nguyen Dinh Cat A, Montezano AC, Burger D, Touyz RM, Angiotensin II. NADPH oxidas, and redox signaling in the vasculature. Antioxid Redox Signal. 2013;19(10):1110-20. https://doi.org/10.1089/ars.2012.4641. PMid:22530599.

21 Gorgui J, Gorshkov M, Khan N, DaskalopoulouS S. Hypertension as a risk factor for ischemic stroke in women. Can J Cardiol. 2014;30(7):774-82. https://doi.org/10.1016/j.cjca.2014.01.007. PMid:24970789.

22 Su C, Liu WC, Li GM, Huang Y. Association between the angiotensin-converting enzyme I/D polymorphism and risk of cerebral small vessel disease: a meta-analysis based on 7186 subjects. J Stroke Cerebrovasc Dis. 2021;30(3):105579. https://doi.org/10.1016/j.jstrokecerebrovasdis.2020.105579. PMid:33412396.

23 Putaala J. Ischemic stroke in the young: current perspectives on incidence, risk factors, and cardiovascular prognosis. Eur Stroke J. 2016;1(1):28-40. https://doi.org/10.1177/2396987316629860. PMid:31008265.

24 Yuan H, Wang X, Xia Q, Ge P, Wang X, Cao X. Angiotensin converting enzyme (I/D) gene polymorphism contributes to ischemic stroke risk in Caucasian individuals: a meta-analysis based on 22 case-control studies. Int J Neurosci. 2016;126(6):488-98. PMid:26000917.

25 Celiker G, Can U, Verdi H, Yazici AC, Ozbek N, Atac FB. Prevalence of thrombophilic mutations and ACE I/D polymorphism in Turkish ischemic stroke patients. Clin Appl Thromb Hemost. 2009;15(4):415-20. https://doi.org/10.1177/1076029608315163. PMid:18387982.

26 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. PMid:27030424.

27 Indrajaya T. The role of ACE gene polymorphism on pathogenesis of ischemic stroke. Acta Med Indones. 2011;43(3):152-7. PMid:21979279.

28 Isordia-Salas I, Santiago Germán D, Cerda-Mancillas MC, et al. Gene polymorphisms of angiotensin-converting enzyme and angiotensinogen and risk of idiopathic ischemic stroke. Gene. 2019;688:163-70. https://doi.org/10.1016/j.gene.2018.11.080. PMid:30521887.

29 Stankovic S, Stankovic A, Asanin M, Jovanovic-Markovic Z, Alavantic D, Majkic-Singh N. Angiotensin I-Converting Enzyme Gene Polymorphism and Activity in Patients with Ischemic Stroke. EJIFCC. 2011;21(4):108-17. PMid:27683381.

30 Vijayan M, Chinniah R, Ravi PM, et al. ACE-II genotype and I allele predicts ischemic stroke among men in south India. Meta Gene. 2014;2:661-9. https://doi.org/10.1016/j.mgene.2014.09.003. PMid:25606450.

31 Yadav S, Hasan N, Marjot T, et al. Detailed analysis of gene polymorphisms associated with ischemic stroke in South Asians. PLoS One. 2013;8(3):e57305. https://doi.org/10.1371/journal.pone.0057305. PMid:23505425.

32 Kalita J, Somarajan BI, Kumar B, Mittal B, Misra UK. A study of ACE and ADD1 polymorphism in ischemic and hemorrhagic stroke. Clin Chim Acta. 2011;412(7-8):642-6. https://doi.org/10.1016/j.cca.2010.12.022. PMid:21194526.

33 Das S, Roy S, Sharma V, Kaul S, Jyothy A, Munshi A. Association of ACE gene I/D polymorphism and ACE levels with hemorrhagic stroke: comparison with ischemic stroke.Neurol Sci. 2015;36(1):137-42. https://doi.org/10.1007/s10072-014-1880-8. PMid:25015258.

34 Tuncer N, Tuglular S, Kilic G, Sazci A, Us O, Kara I. Evaluation of the angiotensin-converting enzyme insertion/deletion polymorphism and the risk of ischaemic stroke. J Clin Neurosci. 2006;13(2):224-7. https://doi.org/10.1016/j.jocn.2005.08.005. PMid:16446094.

35 Seckin D, Ilhan N, Ozbay Y. The relationship between ACE insertion/deletion polymorphism and coronary artery disease with or without myocardial infarction. Clin Biochem. 2006;39(1):50-4. https://doi.org/10.1016/j.clinbiochem.2005.10.003. PMid:16303122.

36 Karagiannis A, Balaska K, Tziomalos K, Tokalaki-Nikolaidou L, Papayeoryiou A, Zamboulis C. Lack of an association between angiotensin-converting enzyme gene insertion/deletion polymorphism and ischaemic stroke. Eur Neurol. 2004;51(3):148-52. https://doi.org/10.1159/000077203. PMid:15007267.

37 Pera J, Slowik A, Dziedzic T, Wloch D, Szczudlik A. ACE I/D polymorphism in different etiologies of ischemic stroke. Acta Neurol Scand. 2006;114(5):320-2. https://doi.org/10.1111/j.1600-0404.2006.00672.x. PMid:17022779.

38 Isordia-Salas I, Santiago Germán D, Jiménez Alvarado RM, Leaños Miranda A. Genetic variants associated with high susceptibility of premature ischemic stroke. J Renin Angiotensin Aldosterone Syst. 2023;2023:9002021. https://doi.org/10.1155/2023/9002021. PMid:38025202.

39 Edinur HA, Mat Ghani SNA, Chambers GK. Ethnicity-based classifications and medical genetics: One Health approaches from a Western Pacific perspective. Front Genet. 2022;13:970549. https://doi.org/10.3389/fgene.2022.970549. PMid:36147511.

40 Saab YB, Gard PR, Overall ADJ. The geographic distribution of the ACE II genotype: a novel finding. Genet Res (Camb). 2007;89(4):259-67. https://doi.org/10.1017/S0016672307009019. PMid:18208631.

41 Semmame O, Sedrati K, Ziada H, Abadi N, Satta D. Association of angiotensin-converting enzyme gene insertion/deletion polymorphism with cervical cancer in an Algerian population. South Asian J Exp Biol. 2022;12(5):604-11. https://doi.org/10.38150/sajeb.12(5).p671-676.

42 Meroua HM, Rayene A, Brahim D, et al. Association of insertion/deletion (I/D) polymorphism of angiotensin-converting enzyme gene (ACE) with Parkinson’s disease and factors risk in eastern Algeria: case–control study. Egypt J Med Hum Genet. 2024;25(1):66. https://doi.org/10.1186/s43042-024-00536-z.

43 Benenemissi IH, Sifi K, Sahli LK, Semmam O, Abadi N, Satta D. Angiotensin-converting enzyme insertion/deletion gene polymorphisms and the risk of glioma in an Algerian population. Pan Afr Med J. 2019;32:197. https://doi.org/10.11604/pamj.2019.32.197.15129. PMid:31312309.

44 Shanmugam V, Sell KW, Saha BK. Mistyping ACE heterozygotes. PCR Methods Appl. 1993;3(2):120-1. https://doi.org/10.1101/gr.3.2.120. PMid:8268786.

45 Elkind MS, Sacco RL. Stroke risk factors and stroke prevention. Semin Neurol. 1998;18(4):429-40. https://doi.org/10.1055/s-2008-1040896. PMid:9932614.

46 Dichgans M, Pulit SL, Rosand J. Stroke genetics: discovery, biology, and clinical applications. Lancet Neurol. 2019;18(6):587-99. https://doi.org/10.1016/S1474-4422(19)30043-2. PMid:30975520.

Submitted date:
03/19/2026

Accepted date:
07/22/2026

Sociedade Brasileira de Angiologia e Cirurgia Vascular (SBACV)"> Sociedade Brasileira de Angiologia e Cirurgia Vascular (SBACV)">

Case-control study on the association of angiotensin-converting enzyme gene I/D rs4646944 single nucleotide polymorphism and young-onset cryptogenic ischemic stroke in an Algerian cohort

Estudo de caso-controle sobre associação do polimorfismo de nucleotídeo único I/D rs4646944 do gene da enzima conversora de angiotensina e acidente vascular isquêmico criptogênico de início precoce em coorte argelina

Mohamed Lebsir; Mohamed Larbi Rezgoun; Boubekeur Saddik Fekraoui; Brahim Djoudi; Yasmina Boukhenaf; Amina Ines Bernou; Karima Sifi

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