Association Between Angiotensin Converting Enzyme Insertion / Deletion Genotypes and Diabetic Nephropathy Defined by Urinary Albumin-to-Creatinine Ratio: A Systematic Review and Meta-Analysis

<ns3:p>Background Diabetic nephropathy (DN) is a major complication of type 2 diabetes mellitus (T2DM) and a leading cause of kidney failure. Evidence on the influence of ACE I/D polymorphisms in DN risk is inconsistent across populations. Methods A systematic review and meta-analysis was conducted following the PRISMA 2020 guidelines. Studies published between January 1990 to February 2025 were retrieved from PubMed, EMBASE and Web of Science. Eligible observational studies reported the frequency of ACE genotypes with DN in T2DM. Independent reviewers screened studies using Rayyan software, extracted data, and assessed risk of bias using the ROBINS-E tool. Reporting on the quality of studies was determined using the STREGA guidelines. Pooled odds ratio (OR) with 95% confidence intervals (CI) were calculated using random-effects models in R version 4.4.2. Subgroup, meta-regression, and sensitivity analyses addressed heterogeneity; Egger’s test assessed publication bias. Registered in PROSPERO (CRD42024577680). Funding from Fogarty International Center of the National Institutes of Health (D43TWO11632). Results Of the 46 studies included in this review, the combined sample size was 16,322 participants. The majority of studies (29 out of 46) were conducted in Asia. Only 5 studies reported DN–related comorbidities by ACE genotypes and one assessed mortality. Twenty-five of the included 46 studies contributed data to the meta-analysis. The ACE II genotype was protective against DN; II vs. ID [OR= 0.70 (CI: 0.63–0.77)] and II vs. DD [OR= 0.68 (CI: 0.55–0.84)]; Heterogeneity was (I<ns3:sup>2</ns3:sup> = 71.7%, τ<ns3:sup>2</ns3:sup> = 0.1776, p < 0.0001). Stronger associations were observed in studies using urinary Albumin-Creatinine-Ratio over Albumin-Excretion-Rate. Egger’s test showed no publication bias (p = 0.55). Conclusion The ACE II genotype is significantly protective against DN risk in T2DM. Standardization of urinary albumin measurement and further genotype-phenotype studies are needed to strengthen clinical utility of the ACE I/D polymorphisms.</ns3:p>