Personalised nutrition that incorporates genetic results into dietary interventions holds significant potential to optimise weight management and metabolic outcomes. While traditional calorie-restricted diets remain effective, emerging evidence suggests that variations in macronutrient distribution may offer additional benefits. Genetic variants help explain interindividual differences in dietary responses, with certain alleles showing enhanced weight loss and metabolic improvements with specific macronutrient distributions. However, comprehensive reviews of randomised controlled trials (RCTs) examining genotype-based dietary effects, particularly those focusing on macronutrient distribution metabolic pathway interactions, are lacking, limiting the development of robust evidence-based guidelines for nutrigenetic counselling. This systematic review aims to assess the influence of genetic variants on weight loss outcome in adults in response to varying macronutrient distribution diets (eg, low-fat, low-carbohydrate, high-protein diets) using evidence from RCTs.

We will systematically review RCTs examining weight loss outcomes of macronutrient-varied diets in adults with genotype stratifications to risk and protective allele. Multiple databases, PubMed, Cochrane Library, Scopus, Science Direct and Google Scholar, will be used. Reviewers will screen studies, extract data on study characteristics, weight loss, metabolic marker outcomes and genetic data, and assess the risk of bias using the Cochrane Risk of Bias Tool 2.0 tool.

All eligible RCTs will first be summarised in structured tables describing study characteristics, macronutrient distribution and genetic variants and will be analysed with narrative synthesis. For quantitative analysis, interventions will be grouped into three predefined diet types (high-protein, low to moderate carbohydrate and low-fat diet). Because heterogeneity across diet categories is expected, pooled effects will be estimated separately within each diet subgroup using random-effects meta-analysis, expressed as mean differences in weight change (kg). Within each subgroup, and when at least 10 studies or data are available, random-effects meta-regression will be used to examine potential moderators, including intervention duration, physical activity and ancestry. Heterogeneity will be evaluated using I² and ², and publication bias assessed when feasible. Evidence certainty will be graded using Grading of Recommendations Assessment, Development and Evaluation.

Ethical approval is not required for this protocol as it involves the analysis of data from primary studies. The findings will be disseminated through publication in peer-reviewed journals. Any enquiries regarding research integrity of this protocol may be directed to the Head of the Doctoral Program in Medical Health and Sciences, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada via the institutional email address s3fk@ugm.ac.id, as the responsible academic authority for research integrity.

CRD420251050587.