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


Participant Characteristics

Table 1 and Table 2 report the demographic characteristics for both the DPP and Look AHEAD participants. Table 1 describes the sample used in the weight-change analyses (years 1–4), while Table 2 reports characteristics for the subsample used in the weight-regain analyses (years 2–4). As previously reported in the full DPP[8] and Look AHEAD[11,12,17] cohorts, both short- and long-term weight loss was greater within the lifestyle arm, as was weight regain. Supplementary Table 2 reports the associations of each SNP with baseline BMI; 17 of these SNPs were nominally associated with BMI (P < 0.05). Two and seven SNPs showed evidence of multiyear heterogeneity for weight loss and weight regain, respectively, across the DPP and Look AHEAD (P < 0.05; Supplementary Tables 3 and 4

Weight Loss in Combined Analysis of the DPP and Look AHEAD

The intronic rs1885988 variant (at MTIF3 and a close proxy for GIANT marker rs12016871) modified weight-loss response to lifestyle intervention (Table 3). The effect within the combined interventions reached statistical significance in year 3 (P = 2 × 10−4 for year 3 pooled effect within lifestyle arms), after multiple-test correction. Each copy of the minor G allele was associated with a mean −1.14 kg (95% CI −1.75, −0.53) lower weight in the lifestyle arm versus a mean 0.33 kg (−0.30, 0.95) higher weight in the comparison arm (P = 0.30), resulting in a nominally significant interaction (P = 9 × 10−4 for SNP×treatment interaction at year 3). Hence, the mean differences in year-3 weight change between the lifestyle intervention and comparison arms were estimated at −1.48 kg (−2.35, −0.61) between AA homozygotes and AG heterozygotes, and −2.96 kg (−4.71, −1.22) between AA and GG homozygotes.

Longitudinal analyses (Fig. 1) showed that rs1885988 was consistently associated with weight loss within the lifestyle but not the comparison arms (P = 2.4 × 10−3 and P = 0.11 for multiyear tests of pooled SNP effects, respectively), leading to a consistent pattern of between-arm differences in weight change in favor of the lifestyle intervention (P = 4.3 × 10−3 for multiyear test of pooled SNP×treatment interaction). No other SNP×lifestyle interaction effects on weight loss showed similarly consistent patterns across all 4 years of follow-up, although several were nominally significant (Supplementary Table 3

Figure 1.

Model-based estimates of MTIF3 genotype effects on weight change among 60-year-old participants following lifestyle and control intervention in the Look AHEAD (A) and the DPP (B) trials. Baseline weight chosen to be representative of males and females in each study (see Table 1). Ancestry-informative principal components set at study-specific means.

Weight Regain in Combined Analysis of the DPP and Look AHEAD

No SNP×treatment arm interactions reached statistical significance in longitudinal analysis after correction for multiple testing. The strongest SNP×treatment interaction was for the FUBP1-DNAJB4 rs12401738 (P = 0.014 for multiyear test of pooled SNP×treatment interaction) (Table 3). Treatment arm–specific analyses showed that the minor allele at FUBP1-DNAJB4 rs12401738 was consistently associated with weight regain within the comparison but not the lifestyle arms (P = 0.03 and P = 0.20 for multiyear test of pooled SNP effects, respectively) (Table 3). Specifically, each copy of the minor A allele was associated with lesser weight regain mean −0.84 kg (95% CI −1.44, −0.25) in year 2 (P = 5.3 × 10−3), −1.15 kg (−2.00, −0.30) in year 3 (P = 7.7 × 10−3), and −0.96 kg (−1.98, −0.06) in year 4 (P = 0.065) among participants within the comparison arm. Many other pooled SNP×treatment interaction effects on weight regain were nominally significant within either the DPP or the Look AHEAD (Supplementary Table 4