To the Editor: Childhood obesity is a serious public health concern that can have long-term impacts on physical and psychological health. Lifestyle interventions have been widely used to treat childhood obesity. Notably, individual responses to the same intervention differ by genetic background. Previous researchers have explored the moderating effects of several glucose-metabolism-related genes on childhood obesity interventions, including TCF7L2[1] and RPTOR.[2] Nevertheless, these studies have been limited in study designs (without a comparison group) and duration (no more than a year), and no studies have explored the effect of the INSR (another glucose-metabolism-related gene) variants. Moreover, previous studies have focused only on single nucleotide polymorphism (SNP)-based analyses instead of gene-based analyses on the present topic. As such, we examined the associations of the INSR gene variants with the response to lifestyle-based obesity intervention in Chinese children aged 8–10 years at both gene- and SNP-levels. This was a post hoc analysis embedded in our previously conducted, cluster-randomized, controlled trial (DECIDE-Children project, NCT03665857, https://clinicaltrials.gov/study/NCT03665857). In the DECIDE-Children project, DNA samples of 407 children from 8 primary schools in Beijing had been collected. Finally, this present study included 382 children (38.7% overweight or obese) with qualified DNA samples and eligible measurements of body mass index (BMI) [Supplementary Figure 1, https://links.lww.com/CM9/C71]. See the details of intervention components and integrity of the intervention in the Supplementary Table 1, https://links.lww.com/CM9/C71. Overall, integrity of this childhood obesity intervention was relatively satisfactory for all components targeting children, schools, and families. This study was ethically approved by the Peking University Institution Review Board (No. IRB00001052-20058), and written informed consent was obtained. The study outcomes included waist-related indicators (waist circumference, waist-to-hip ratio [whr], waist-to-height ratio [WHtR], waist circumference adjusted for BMI [WCadjBMI], and waist-to-hip ratio adjusted for BMI [WHRadjBMI]), BMI-related indicators (BMI [calculated as body weight (kg)/height squared (m2)], and body mass index Z-score [BMI Z-score]), and body fat percentage. See the details of outcome measurements in the Supplementary Material, https://links.lww.com/CM9/C71. First, we examined adjusted associations between INSR gene variants and obesity-related indicators at baseline. Then, we assessed the gene–group interactions on changes in obesity-related indicators from baseline to 9 months (immediately at the end of intervention) through both gene- and SNP-based analyses; that is, we examined whether the genetic effects differed between the intervention and control groups. Next, we examined the gene–group interactions on changes in obesity-related indicators from 9 months to 31 months (22 months after the end of intervention). We performed gene- and SNP-based analyses with MAGMA 1.10 (VU University & VU Medical Centre Amsterdam Center for Neurogenomics and Cognitive Research Neuroscience Campus Amsterdam) and R 4.1.0 (R Foundation for Statistical Computing, Vienna, Austria), respectively. We selected seven independent SNPs (linkage disequilibrium measured by r2 <0.80 considered to indicate no linkage disequilibrium Supplementary Figure 2, https://links.lww.com/CM9/C71) that met the quality control criteria for the INSR gene. These seven SNPs satisfied the requirement that the study have 80% power to detect a gene–group interaction effect size of 0.34 units for changes in WHRadjBMI at 9 months at a significance level of 0.05 (QUANTO 1.2.4, Department of Preventive Medicine, University of Southern California). To test the robustness of the study findings, we also conducted sensitivity analyses that focused on children with overweight or obesity. At baseline, nearly all obesity-related indicators were balanced across seven INSR SNPs' genotypes except for WCadjBMI and WHRadjBMI [Supplementary Tables 2–8, https://links.lww.com/CM9/C71]. At 9 months, children in the intervention group showed a decrease in body weight, BMI, BMI Z-score, and body fat percentage compared to the control group [Supplementary Tables 9-12, https://links.lww.com/CM9/C71]. From baseline to 9 months, the INSR gene significantly modified intervention effects on whr and WHRadjBMI (Pinteract <0.05, Table 1), while from 9 to 31 months, the INSR gene did not modify intervention effects in any of the obesity-related indicators [Supplementary Table 14, https://links.lww.com/CM9/C71]. Different findings emerged in children with overweight or obesity that the INSR gene significantly modified intervention effects on body weight, BMI, and BMI Z-score at 9 months (Pinteract <0.05) but not on waist-related indicators [Supplementary Table 13, https://links.lww.com/CM9/C71]. Table 1 - Moderation by INSR gene of intervention effects on changes in all of the obesity-related indicators from baseline to 9 months. Obesity-related indicators NSNPS NPARAM P interact P interv P contr Body weight 56 60 0.26188 0.16756 0.77256 BMI 56 62 0.23211 0.15978 0.66305 BMI Z-score 56 61 0.47621 0.32260 0.43798 Waist circumference 56 62 0.07281 0.69179 0.39569 whr 56 63 0.01642 0.35652 0.48179 WHtR 56 61 0.09446 0.62539 0.36564 WCadjBMI 56 61 0.24132 0.04099 0.98794 WHRadjBMI 56 61 0.00528 0.04001 0.73921 Body fat percentage 56 61 0.31767 0.06371 0.31850 The human INSR gene, located on chromosome 19, base pair position (NCBI137): 7,112,266–7,294,011. BMI Z-score: Body mass index Z-score; BMI: Body mass index; NPARAM: Number of relevant parameters used in the model; NSNPS: The number of SNPs annotated to gene; Pcontr: Multiple P value for gene term in control group; Pinteract: Multiple P value for interact term; Pinterv: Multiple P value for gene term in intervention group; SNP: Single nucleotide polymorphism; WCadjBMI: Waist circumference adjusted for BMI; whr: waist-to-hip ratio; WHRadjBMI: Waist-to-hip ratio adjusted for BMI; WHtR: Waist-to-height ratio. In addition to the above gene-based analyses, our SNP-based analyses showed that none of the associations reached the threshold P value after Bonferonni correction (n = 7; Pthreshold = 0.05/7) except for INSR rs7508679 (Puncorr = 0.002; Pcorr = 0.014). Similar findings were found in children with overweight or obesity [Supplementary Tables 15–22, https://links.lww.com/CM9/C71]. In the present study, we found that the INSR gene modified the effects of the intervention on changes in waist-related indicators at the gene level rather than at the SNP level. Two possible reasons are considered. First, the moderate sample size limited the power of detecting the SNP-group interactions on the changes in indicators. Second, the effect of a single locus on the changes in indicators was so small that the results were not statistically significant after correction for multiple tests, which made its true value easy to ignore. In contrast, gene-based analysis showed the aggregated effect of these SNPs so that the potential effects could be detected more easily. Interestingly, our findings among children with overweight or obesity were distinct from those in the whole population. This might be due to the differences in the baseline BMI value and diet/physical activity behaviors of the participants. Based on our review of studies that have explored genetic effects on the response to childhood obesity interventions, the existing studies were mostly based on single-group studies, limiting the ability to elucidate the gene–group interactions on changes in obesity-related indicators.[3] Our study design allowed us to analyze the distinct effect of the INSR genotype on obesity by comparing indicators between children randomized to the intervention and control groups. Additionally, the study design of our study is a cluster intervention trial so we have the ability to control for "contamination" (mutual influence between individuals in different intervention groups within the same cluster) compared with individual randomized controlled trials. Several lines of evidence suggest that the observed interactions between the INSR gene and childhood obesity intervention are biologically plausible. For example, an obesity intervention among obese adults revealed that INSR variants interacted with drug treatment to affect changes in weight after the intervention.[4] Evidence from animal studies and observational studies has also shown that INSR variants are associated with insulin resistance or decreased insulin sensitivity, which can affect normal glucose metabolism.[5,6] Additionally, it has been proven that diet and/or physical activity behaviors can regulate insulin secretion and glucose metabolism.[7,8] Therefore, the biological pathways linking lifestyle and INSR genotypes to obesity largely overlap, and interactions between them may occur via these pathways. The observed genetic effects on the response to the intervention from baseline to 9 months were not sustained until the period after the end of the intervention in this study. This might lie in the practical barrier of maintaining a healthy diet and physical activity behaviors after the end of the intervention. Our study findings should be interpreted with caution. First, the sample size of intervention studies is relatively smaller than that of observational studies due to the complexity of their implementation in real-world settings, and our study is not an exception to this limitation.[3] However, our study involved multiple obesity-related indicators and showed consistent patterns with each other, making our findings less likely to be biased. Second, all study participants were from the Han Chinese population in Beijing, China, limiting the generalizability. Finally, the functional mechanisms underlying the study findings and the cumulative effects of multiple genes on childhood obesity prevention, such as exploring the role of polygenic risk scores in childhood obesity prevention, need to be clarified in future studies.[9] In conclusion, our study indicates that children carrying the accumulated risk alleles in the INSR gene were more responsive to a lifestyle intervention for obesity prevention than non-carriers, but the effect appeared to be attenuated in the long term. Future long-term, large-scale interventional studies are needed to determine the role of this gene in preventing childhood obesity in individuals of other ethnicities. Funding This work was supported by grants from the National Natural Science Foundation of China (Nos.82373694, 81903343), Young Elite Scientists Sponsorship Program by CAST (2023QNRC001), Beijing Office for Education Sciences Planning (No.BECA23111), and the Fundamental Research Funds for the Central Universities (No.BMU2021YJ030). Conflicts of interest None.
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