ACE insertion/deletion polymorphism and ischemic stroke susceptibility among populations from Turkey, Egypt, Iran, and Iraq: a systematic review and meta-analysis

Background Ischemic stroke is a major cause of mortality and long-term neurological disability worldwide. Although conventional vascular risk factors explain a substantial proportion of ischemic stroke burden, genetic susceptibility may contribute to inter-individual and population-level differences in risk. The angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphism is a biologically plausible vascular candidate variant because of its relationship with ACE activity, renin-angiotensin system regulation, endothelial function, vascular remodeling, and blood-pressure control. However, findings from Middle Eastern populations remain inconsistent. Objective To systematically evaluate and quantitatively synthesize the association between ACE I/D polymorphism and ischemic stroke susceptibility in populations from the Middle East, with inferences restricted to the countries represented in the eligible evidence—Turkey, Egypt, Iran, and Iraq. Methods This PRISMA 2020–based systematic review and meta-analysis was prospectively registered in PROSPERO (CRD420261406483). PubMed/MEDLINE, Scopus, and Web of Science were searched from inception to May 23, 2026 for observational genetic association studies reporting ACE I/D genotype or allele data in ischemic stroke cases and stroke-free Middle Eastern controls. Two reviewers independently conducted study selection, data extraction, and Newcastle-Ottawa Scale quality assessment. Random-effects ORs with 95% CIs were pooled under allele, dominant, recessive, homozygous, and heterozygous models, with sensitivity analyses excluding studies with HWE deviation, reconstructed counts, historical controls, and other strict-quality concerns. Results Ten studies including 1,317 ischemic stroke cases and 979 controls were included, representing Turkey, Egypt, Iran, and Iraq. Across all primary random-effects models, ACE I/D polymorphism was not significantly associated with ischemic stroke susceptibility. The pooled estimates were: allele contrast D vs. I, OR = 1.16 (95% CI: 0.97–1.38); dominant model DD + ID vs. II, OR = 1.20 (95% CI: 0.91–1.57); recessive model DD vs. ID + II, OR = 1.20 (95% CI: 0.89–1.61); homozygous model DD vs. II, OR = 1.26 (95% CI: 0.94–1.70); and heterozygous model ID vs. II, OR = 1.14 (95% CI: 0.84–1.55). Heterogeneity ranged from low to moderate across most models, with the highest heterogeneity observed in the recessive model. Sensitivity analyses, particularly the exclusion of two studies with control-group Hardy–Weinberg equilibrium deviation, consistently attenuated the pooled estimates toward the null and did not support a robust association. Conclusion Available evidence does not demonstrate a statistically robust association between ACE I/D polymorphism and ischemic stroke susceptibility in the populations studied in Turkey, Egypt, Iran, and Iraq. Although D-allele and DD-genotype carriers showed a weak non-significant trend toward increased risk, this pattern was not stable under sensitivity analyses. Given the null pooled findings, modest evidence base, predominance of unadjusted genotype-derived estimates, and absence of reliable stroke subtype-specific data, the current evidence does not support ACE I/D genotyping for clinical ischemic stroke risk prediction. These findings should not be generalized to Middle Eastern countries for which eligible evidence was unavailable.