Genetic Predisposition to Weight Loss and Regain With Lifestyle Intervention: Analyses From the Diabetes Prevention Program and the Look AHEAD Randomized Controlled Trials

Abstract

Clinically relevant weight loss is achievable through lifestyle modification, but unintentional weight regain is common. We investigated whether recently discovered genetic variants affect weight loss and/or weight regain during behavioral intervention. Participants at high-risk of type 2 diabetes (Diabetes Prevention Program [DPP]; N = 917/907 intervention/comparison) or with type 2 diabetes (Look AHEAD [Action for Health in Diabetes]; N = 2,014/1,892 intervention/comparison) were from two parallel arm (lifestyle vs. comparison) randomized controlled trials. The associations of 91 established obesity-predisposing loci with weight loss across 4 years and with weight regain across years 2–4 after a minimum of 3% weight loss were tested. Each copy of the minor G allele of MTIF3 rs1885988 was consistently associated with greater weight loss following lifestyle intervention over 4 years across the DPP and Look AHEAD. No such effect was observed across comparison arms, leading to a nominally significant single nucleotide polymorphism×treatment interaction (P = 4.3 × 10−3). However, this effect was not significant at a study-wise significance level (Bonferroni threshold P < 5.8 × 10−4). Most obesity-predisposing gene variants were not associated with weight loss or regain within the DPP and Look AHEAD trials, directly or via interactions with lifestyle.

Exposing the exposures responsible for type 2 diabetes and obesity

“…Nevertheless, there is some evidence that "healthy" diets modify the impact of individual BMI-associated variants in observational studies (30) and clinical trials (31). Interactions have been reported between BMI-associated genetic risk scores and diverse exposures including sugarsweetened beverages (32), fried foods (33), and television viewing (34), though replication data are sparse.…”

“…However, such studies are challenging to perform and interpret (41) and need further replication. Despite promising epidemiological data, the largest clinical trial analysis found no evidence that FTO variation influences weight loss after lifestyle intervention (31).…”

Unmet needs in obesity management

“…Within 1 year, 50% of people who engage in a weight‐loss intervention will experience weight regain (Palascha, van Kleef, & van Trijp, ). Current research indicates weight maintenance and regain are complex, and affected by the interaction of a variety of physiologic, genetic, and psychosocial factors (Brantley et al., ; Palascha et al., ; Papandonatos et al., ; Rogge & Gautam, ). Studies to determine more effective strategies to promote and maintain weight loss are ongoing; emerging results may offer insight.…”

The impact of genetic polymorphisms on weight regain after successful weight loss

“…This gene has also been identified as an obesity susceptibility gene due to its relationship with BMI (74,75) . Papandonatos and colleagues showed that the G allele of the MTIF3 rs1885988 was associated with greater weight loss following lifestyle intervention over 4 years of follow-up (76) . In other words, their result implies that G allele of the MTIF3 rs1885988 is related to lower-risk of weight regain.…”