Case-control study on the association of angiotensin-converting enzyme gene I/D <i>rs</i>4646944 single nucleotide polymorphism and young-onset cryptogenic ischemic stroke in an Algerian cohort

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

doi:10.1590/1677-5449.202501422

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ORIGINAL ARTICLES • J. Vasc. Bras. 25 • 2026 • https://doi.org/10.1590/1677-5449.202501422 linkcopy

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

SCIMAGO INSTITUTIONS RANKINGS

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

	All	Men	Women	p value
N	42	13 (31%)	29 (69%)	N/A
Age (years, mean SD)	38.31±8.51	42.77±8.11	36.31±8.03	0.021
Admission NIHSS (mean SD)	5.05±5.51	4.08±6.34	5.48±5.16	0.453
Smoking (n, %)	6 (14.2%)	6 (46.1%)	-	0.002
Alcohol use (n, %)	-	-	-	/
Drug use (n, %)	-	-	-	/
Arterial hypertension (n, %)	9 (21.4%)	1 (7.6%)	8 (27.5%)	0.218
Hyperlipidemia (n, %)	2 (4.7%)	-	2 (6.9%)	0.491
Obesity (BMI > 30)	5 (11.9%)	1 (7.6%)	4 (13.7%)	0.528
Diabetes mellitus (n, %)	2 (4.76%)	1 (7.6%)	1 (3.4%)	0.540
Migraine	20 (47.6%)	3 (23.08%)	17 (58.6%)	0.151
Dementia	-	-	-	/
Family history of stroke	5 (11.90%)	-	5 (17.2%)	0.181

Variables	CIS (N = 42)	Controls (N = 42)	X²	OR	CI	p value
Hypertension (N, %)
Yes	9 (21.4%)	3 (7.1%)	3.500	3.545	0.886-14.184	> 0.05
No	33 (78.6%)	39 (92.9%)	3.500	3.545	0.886-14.184	> 0.05
Diabetes (N, %)
Yes	2 (4.8%)	1 (2.4%)	0.346	2.050	0.179-23.512	> 0.05
No	2 (4.8%)	1 (2.4%)	0.346	2.050	0.179-23.512	> 0.05	40 (95.2)	41 (97.6%)
Smoking (N, %)
Yes	6 (14.3%)	7 (16.7%)	0.091	0.833	0.255-2.727	> 0.05
No	36 (85.7%)	35 (83.3%)	0.091	0.833	0.255-2.727	> 0.05
Migraine (N, %)
Yes	20 (47.6%)	0 (00%)	26.250	0.344	0.245-0.482	< 0.05
No			26.250	0.344	0.245-0.482	< 0.05
22 (52.4%)	42 (100%)
Obesity (N, %)
Yes	5 (11.9%)	0 (00%)	5.316	0.468	0.370-0.592	< 0.05
No	37 (88.1%)	42 (100%)	5.316	0.468	0.370-0.592	< 0.05
Family history of stroke (N, %)
Yes	5 (11.9%)	0 (00%)	5.316	0.468	0.370-0.592	< 0.05
No	37 (88.1%)	42 (100%)	5.316	0.468	0.370-0.592	< 0.05

		CIS N (%)	Control N (%)	X²(df)	p-value	OR (95%CI)
Genotypes	DD	34 (80.95)	33 (78.57)	0.074(1)	0.786	1.159 (0.399-3.366)
	ID	08 (19.05)	09 (21.43)	0.074(1)	0.786	0.863 (0.297-2.505)
	II	-	-	-	-	-
Allele	D	76 (90.48)	75 (89.29)	0.065(1)	0.798	0.877 (0.321-2.395)
Allele	I	08 (09.52)	09 (10.71)	0.065(1)	0.798	0.877 (0.321-2.395)

Risk factor	p value	OR	95% CI
Risk factor	p value	OR	Lower	Upper
Age	0.004	0.421	0.233	0.760
HTN	0.002	0.375	0.203	0.693
Migraine	0.08	0.42	0.230	2.150
Smoking	0.04	4.364	1.017	18.730
Sex	0.007	0.347	0.160	0.750
ACE Mutation	0.766	0.762	0.127	4.567
Diabetes mellitus	0.907	1.190	0.063	22.468
Obesity	0.07	1.079	0.000	7.329
Family history of stroke	0.09	0.31	0.000	0.999

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[1] NIHSS = National Institutes of Health Stroke Scale; BMI = body mass index; n = number. Continuous variables are expressed as mean (SD). Dashes (–) indicate no recorded cases. Values in bold are statistically significant (p < 0.05).