Genetic Predisposition to Weight Loss and Regain With Lifestyle Intervention

Analyses From the Diabetes Prevention Program and the Look AHEAD Randomized Controlled Trials

George D. Papandonatos; Qing Pan; Nicholas M. Pajewski; Linda M. Delahanty; Inga Peter; Bahar Erar; Shafqat Ahmad; Maegan Harden; Ling Chen; Pierre Fontanillas; GIANT Consortium, Lynne E. Wagenknecht; Steven E. Kahn; Rena R. Wing; Kathleen A. Jablonski; Gordon S. Huggins; William C. Knowler; Jose C. Florez; Jeanne M. McCaffery; Paul W. Franks


Diabetes. 2015;64(12):4312-4321. 

In This Article

Abstract and Introduction


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.


Adipose tissue is essential for fecundity and survival.[1,2] Chronic excess adiposity (obesity) was probably uncommon throughout the majority of human evolution because foods were hunted or gathered by hand and those of very high–energy density may have been scarce. Hence, the human genome probably evolved to protect against leanness by promoting efficient energy expenditure and utilization. The heritability of BMI is ~50–90%,[3] underscoring the strong, biologically encoded nature of obesity.

Recently published[4,5] large-scale meta-analyses have identified ~100 common obesogenic loci, but the clinical relevance of most of these is undetermined. Genetic data might be clinically valuable if it helped identify patients who are likely to respond well or poorly to clinical interventions, thereby facilitating targeted treatment. Testing if specific genotypes modify treatment effects in randomized controlled trials (RCTs) could help determine this.

The objective of these analyses was to test the genotype associations and treatment interactions for a comprehensive set of BMI-associated loci with intentional weight loss and weight regain in the Diabetes Prevention Program (DPP) and the Look AHEAD (Action for Health in Diabetes) studies, two RCTs of intensive lifestyle intervention conducted in multiethnic cohorts of overweight or obese adults with prediabetes or type 2 diabetes at enrollment.