Abstract
Background: The transcription factor 7-like 2 gene (TCF7L2) is the strongest locus associated by the variant rs7903146 with type 2 diabetes (T2D) identified to date. Whether diet/lifestyle intervention modifies genetic effect of TCF7L2 variant on glucose homeostasis and adiposity is still controversial. Objective: To quantify the modification effects of the diet/lifestyle interventions on genetic association of TCF7L2 variant rs7903146 with glycemic control and adiposity changes in randomized controlled trials (RCTs). Design A large collaborative analysis of individual-participant data from seven RCTs. Setting RCTs conducted in adults reporting changes in glycemic traits, body weight, or waist circumference by TCF7L2 rs7903146 after dietary/lifestyle-based interventions. Gene-treatment interaction models were fitted to individual participant data from all studies, using allele dose coding for genetic effects and a common set of covariates. Results: We included seven eligible RCTs for the joint analysis (n=4,114 participants). Overall, a significant interaction between TCF7L2 rs7903146 and diet/lifestyle interventions on decrease in fasting glucose was observed. Compared with control, diet/lifestyle interventions reduced fasting glucose by -0.17 (95% CI, -0.32 to -0.02) mmol/L (test for heterogeneity: I2=45.1%, p<0.05; test for overall effect: z=2.20, p=0.028) for each copy of the TCF7L2 T risk allele. In addition, diet/lifestyle interventions reduced waist circumference regardless of genetic risk. However, changes in other glycemic traits, body weight and waist circumference for one copy of TCF7L2 risk allele in response to diet/lifestyle interventions were not significant. Conclusions: This large collaborative analysis suggests that carrying the TCF7L2 T risk allele confers modestly greater benefit in improving glycemic control in response to diet/lifestyle interventions. Funding Statement: The study was supported by grants from the Peking University Start-up Grant (BMU2018YJ002), the National Heart, Lung, and Blood Institute (HL071981, HL034594, HL126024), the National Institute of Diabetes and Digestive and Kidney Diseases (DK115679, DK091718, DK100383, DK078616), the Boston Obesity Nutrition Research Center (DK46200), and United States-Israel Binational Science Foundation Grant 2011036. Declaration of Interests: All authors declare: no support from companies for the submitted work; no relationships with companies that might have an interest in the submitted work in the previous three years; no spouses, partners, or children have no financial relationships that may be relevant to the submitted work; no non-financial interests that may be relevant to the submitted work. Ethics Approval Statement: Participants from all participating trials provided written, informed consent, and ethical approval was granted by local institutional review boards (see Supplemental Table 1).
Published Version
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