Interaction of Diet/Lifestyle Intervention and TCF7L2 Genotype on Glycemic Control and Adiposity among Overweight or Obese Adults: Big Data from Seven Randomized Controlled Trials Worldwide.

Objective. The strongest locus which associated with type 2 diabetes (T2D) by the common variant rs7903146 is the transcription factor 7-like 2 gene (TCF7L2). We aimed to quantify the interaction of diet/lifestyle interventions and the genetic effect of TCF7L2 rs7903146 on glycemic traits, body weight, or waist circumference in overweight or obese adults in several randomized controlled trials (RCTs).Methods. From October 2016 to May 2018, a large collaborative analysis was performed by pooling individual-participant data from 7 RCTs. These RCTs reported changes in glycemic control and adiposity of the variant rs7903146 after dietary/lifestyle-related interventions in overweight or obese adults. Gene treatment interaction models which used the genetic effect encoded by the allele dose and common covariates were applicable to individual participant data in all studies.Results. In the joint analysis, a total of 7 eligible RCTs were included ($n=\mathrm{4,114}$). Importantly, we observed a significant effect modification of diet/lifestyle-related interventions on the TCF7L2 variant rs7903146 and changes in fasting glucose. Compared with the control group, diet/lifestyle interventions were related to lower fasting glucose by -3.06 (95% CI, -5.77 to -0.36) mg/dL (test for heterogeneity and overall effect: $I^2=45.1\%$, $p<0.05$; $z=2.20$, $p=0.028$) per one copy of the TCF7L2 T risk allele. Furthermore, regardless of genetic risk, diet/lifestyle interventions were associated with lower waist circumference. However, there was no significant change for diet/lifestyle interventions in other glycemic control and adiposity traits per one copy of TCF7L2 risk allele.Conclusions. Our findings suggest that carrying the TCF7L2 T risk allele may have a modestly greater benefit for specific diet/lifestyle interventions to improve the control of fasting glucose in overweight or obese adults.