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

Background: Diabetic nephropathy (DN) remains a major long-term complication of type 2 diabetes mellitus (T2DM), contributing significantly to end-stage renal disease globally. Timely identification is essential to prevent progression and enhance patient outcomes. One of the earliest clinical indicators of DN is microalbuminuria, typically measured by the urinary albumin-to-creatinine ratio (UACR). Variants in the angiotensin-converting enzyme (ACE) gene, particularly the insertion/deletion (I/D) polymorphisms, have been studied for their potential role in increasing susceptibility to DN. This protocol outlines a systematic review designed to investigate the relationship between ACE I/D genotypes and DN—operationally defined through UACR thresholds—and to examine secondary outcomes such as mortality and coexisting conditions in adults living with T2DM.Methods: The development of this protocol is informed by the PRISMA-P 2015 checklist. Relevant studies published from 1 January 1990 to 28 February 2025 will be retrieved through systematic searches of PubMed, EMBASE, and Web of Science, with supplementary searches conducted via Google Scholar to capture grey literature. Studies eligible for inclusion will be observational in nature, including cohort, case-control, and cross-sectional designs, and must evaluate the relationship between ACE insertion/deletion (I/D) polymorphisms (II, ID, DD) and diabetic nephropathy. Data will be extracted in accordance with the STREGA guidelines for genetic association studies. Two reviewers will independently carry out study selection, data extraction, and risk of bias evaluation using the ROBINS-E tool. Where data allow, meta-analyses will be undertaken using a random-effects model to account for heterogeneity. Planned subgroup and sensitivity analyses will explore differences based on population demographics, ACE genotypic distributions, and UACR-based nephropathy thresholds. If meta-analysis is not feasible, a narrative synthesis will be provided using the Centre for Reviews and Dissemination (CRD) approach, complemented by the SWiM (Synthesis Without Meta-analysis) framework. MOOSE guidelines will support the structured reporting of meta-analytic findings.Discussion: The findings of this review are expected to shed light on the clinical relevance of ACE I/D genotypes alongside UACR in identifying patients at elevated risk of diabetic nephropathy. The outcomes may support the development of more personalized risk stratification approaches in the management of T2DM. However, potential limitations include variability in study populations and methodologies.Registration and Funding: PROSPERO registration: CRD42024577680. Funded by the Fogarty International Center of the NIH (Award No. D43TW011632). The funder had no role in protocol development.