Gene-Diet Interaction of FTO-rs9939609 Gene Variant and Hypocaloric Diet on Glycemic Control in Overweight and Obese Adults: A Systematic Review and Meta-Analysis of Clinical Trials
The relationship between overweight or obesity and glycemic status is well-established, with weight loss being a key factor in improving fasting glucose levels. Hypocaloric diets, regardless of their severity and macronutrient distribution, have been shown to enhance insulin resistance and glycemic status through weight loss. However, insulin resistance is a multifactorial condition influenced by both genetic and environmental factors. Individual responses to dietary interventions can vary significantly based on genetic predispositions. Among the genetic factors, the fat mass and obesity-associated gene (FTO) has been extensively studied, with common polymorphisms such as rs9939609 being linked to obesity and glycemic traits. This systematic review and meta-analysis aimed to explore the gene-diet interaction between the FTO-rs9939609 gene variant and hypocaloric diets on glycemic control in overweight and obese adults.
The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive search was conducted across multiple databases, including the Cochrane Central Register of Controlled Trials, PubMed, ISI Web of Science, Embase, Scopus, and Google Scholar, up to December 2018. The search strategy utilized a combination of keywords and medical subject heading (MeSH) terms related to FTO, obesity-associated gene, fasting blood glucose, insulin, homeostasis model assessment (HOMA), and glycemic control. Studies were included if they were published in English, utilized hypocaloric diets, and reported outcomes such as fasting blood sugar (FBS), serum insulin, and homeostasis model assessment of insulin resistance (HOMA-IR). Excluded studies included those without full-text availability, non-English articles, ecological studies, qualitative studies, opinion pieces, conference abstracts, review articles, and editorials.
Data extraction was performed independently by two reviewers, with discrepancies resolved through consensus. The extracted data included study characteristics such as the first author’s name, publication year, country, study design, quality score, sample size, type of diet, study duration, participants’ gender, age, and health status. The quality of the studies was assessed using the Jadad score, which evaluates randomization, blinding, and the description of withdrawals and dropouts. Statistical analysis was conducted using Stata, version 14 SE. The effect size was estimated as the mean difference (MD), and both fixed and random-effects meta-analyses were performed based on the heterogeneity among studies. Heterogeneity was assessed using the I² index and Cochrane’s Q test. Subgroup analyses, sensitivity analysis, and meta-regression were conducted to explore potential sources of heterogeneity. Publication bias was evaluated using Begg’s rank correlation, Egger’s linear regression, and funnel plots.
The initial search yielded 1434 studies, with 53 studies evaluated for eligibility after removing duplicates and screening titles and abstracts. Nine studies met the inclusion criteria and were included in the meta-analysis. These studies were conducted in Spain, Japan, and the United States, with one multi-center study involving eight clinical centers across seven European countries. The duration of the interventions ranged from 12 to 104 weeks, and all studies recruited overweight or obese participants. According to the Jadad scores, only one study was classified as high-quality, while the others were considered low-quality due to issues related to blinding in prescribing diets.
The pooled analysis of nine studies, involving 1799 subjects with AA/AT genotype and 921 subjects with TT genotype, revealed no significant difference between the genotypes in the effect of hypocaloric diets on FBS (weighted mean difference [WMD] = 0.01, 95% confidence interval [CI]: -1.08, 1.10, P = 0.984). Similarly, there was no significant difference in serum insulin levels between the genotypes (WMD = 0.20, 95% CI: -0.85, 1.26; P = 0.707). Although participants with the AA/AT genotype showed the greatest reduction in HOMA-IR compared to those with the TT genotype, this difference was not statistically significant (WMD = -0.38, 95% CI: -0.94, 0.16, P = 0.167).
Subgroup analyses were conducted to explore potential sources of heterogeneity. For FBS, studies with randomization showed no heterogeneity (I² = 0.0%, P = 0.637), while studies without randomization exhibited moderate heterogeneity (I² = 47.8%, P = 0.088). For serum insulin, studies with randomization showed a significant increase in serum insulin in the AA/AT group compared to the TT group (WMD = 1.17, 95% CI: 0.02, 2.33; P = 0.046), whereas studies without randomization showed lower serum insulin in the AA/AT group (WMD = -1.71, 95% CI: -2.81, -0.62; P = 0.002). For HOMA-IR, studies with randomization had high heterogeneity (I² = 94.7%, P < 0.001), while studies without randomization showed no heterogeneity (I² = 0.0%, P = 0.394). Meta-regression did not identify randomization, study duration, participants' age, or study quality as sources of heterogeneity for FBS, serum insulin, or HOMA-IR. Sensitivity analysis confirmed the robustness of the results, and no publication bias was detected based on funnel plots, Begg's test, and Egger's test.
The findings of this meta-analysis suggest that there is no significant difference between the AA/AT and TT genotypes of the FTO-rs9939609 gene variant in terms of FBS, serum insulin levels, and insulin resistance in response to hypocaloric diets among overweight and obese individuals. These results are consistent with some previous meta-analyses but contradict others, highlighting the complexity of gene-diet interactions. The inconsistent findings may be attributed to differences in macronutrient composition and dietary fat types in the hypocaloric diets, as well as the diversity of polymorphisms in the FTO gene. Additionally, the randomization schemes in clinical trials may have influenced the results, as randomization helps minimize selection bias and balance treatment assignments.
Despite the comprehensive nature of this meta-analysis, several limitations should be acknowledged. The included studies varied in intervention duration, race/ethnicity, sample size, and other individual characteristics, which may have contributed to heterogeneity. Furthermore, the limited number of published articles necessitated the inclusion of studies with varying calorie and macronutrient ratios, which could have affected the glycemic responses. Future research should focus on long-term randomized clinical trials with standardized macronutrient distributions to better understand the gene-diet interaction of the FTO-rs9939609 gene variant.
In conclusion, this systematic review and meta-analysis found no significant difference between the AA/AT and TT genotypes of the FTO-rs9939609 gene variant in terms of glycemic control in response to hypocaloric diets among overweight and obese individuals. However, the complex interplay between genetic and dietary factors warrants further investigation to optimize personalized dietary interventions for weight loss and glycemic control.
doi.org/10.1097/CM9.0000000000000617
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