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Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) associated with waist circumference and waist-to-hip ratio adjusted for body mass index (WCadjBMI, WHRadjBMI), but it remains unclear whether these SNPs relate to change in WCadjBMI or WHRadjBMI with lifestyle intervention. We hypothesized that polygenic scores (PS) comprised of 59 SNPs previously associated with central adiposity would predict less of a reduction in WCadjBMI or WHRadjBMI at eight-to-ten weeks in two lifestyle intervention trials, NUGENOB and DiOGenes, and at one year in 5 lifestyle intervention trials, Look AHEAD, Diabetes Prevention Program, Diabetes Prevention Study, DIETFITS, and PREDIMED-Plus. One standard deviation higher PS related to smaller one-year change in WCadjBMI in the lifestyle intervention arms at year 1, and thus predicted poorer response (beta=0.007, SE=0.003, p=0.03) among White participants overall and in White men (beta=0.01, SE=0.004, p=0.01). At average weight loss, this amounted to 0.20-0.28 cm per standard deviation. No significant findings emerged in White women, African American men, for the 8-10 week outcomes or for WHRadjBMI. Findings were heterogeneous in African American women. These results indicate that polygenic risk relates to change in WCadjBMI with lifestyle intervention but the effects are small and not of sufficient magnitude to be clinically significant.

Lifestyle intervention, combining calorie restriction and physical activity to induce weight loss, is the frontline treatment for overweight or obesity and well-known to reduce waist circumference (WC). Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with WC adjusted for body mass index (WCadjBMI), but it remains unclear whether these SNPs relate to the change in WCadjBMI with lifestyle intervention. Here, we examined whether 59 SNPs previously associated with WCadjBMI in GWAS predicted change in WCadjBMI at one year in 5 lifestyle intervention trials and at 8-10 weeks in two lifestyle intervention trials. Look AHEAD, Diabetes Prevention Program, Diabetes Prevention Study, DIETFITS, and PrediMed Plus contributed one-year data, and NUGENOB and DiOGenes contributed 8-10 week data. Genetic risk scores (GRS) combined associated alleles for each SNP weighted by association with WCadjBMI from Shungin et al, 2015 and meta-analyses with random effects for each trial were used to pool results. Among White participants, higher GRS related to smaller year one change in WCadjBMI in the lifestyle intervention arms, and thus predicted poorer response (p=0.009). With a point estimate of 0.002 (SE=0.001) across trials, for a person with an initial BMI of 34 and a year 1 reduction in BMI of 2.5, each weighted risk allele in the GRS contributed to a 0.06 cm (SE=0.03) higher WC at year 1. With a 25th%ile, median, and 75th%ile GRS of 42.77, 46.75, and 50.48, this translates to 0.46 cm less change in WC between the 25th%ile and 75th%ile. No significant findings emerged in men and women separately, in the African-American subset, for the 8-10 week outcomes, or for the individuals SNPs after correcting for multiple comparisons. These results may help to define the molecular pathways through which lifestyle intervention impacts central adiposity. Disclosure J. Mccaffery: None. T. Hansen: None. T. O. Kilpelainen: None. D. Corella: None. W. H. M. Saris: Advisory Panel; Self; Friesland Campina International, Consultant; Self; Nutrition et sante. T. I. A. Sørensen: None. J. Tuomilehto: None. R. R. Wing: None. T. Agurs-collins: None. K. A. Jablonski: None. Q. Pan: None. A. Astrup: Consultant; Self; Groupe Éthique et Santé, France, Employee; Self; Novo Nordisk Foundation, Other Relationship; Self; Flaxslim ApS, Denmark, Gelesis, Personalized Weight Management Research Consortium ApS (Gluco-Diet. dk). M. R. Christiansen: None. L. M. Corso: None. J. C. Florez: Consultant; Self; Goldfinch Bio, Inc., Other Relationship; Self; Novo Nordisk. P. W. Franks: Advisory Panel; Self; Zoe Global Limited, Consultant; Self; Eli Lilly and Company, Novo Nordisk. C. D. Gardner: None. Funding WESTAT/National Cancer Institute

Objective: Aim is to predict successful weight loss by metabolic signatures at baseline and to identify which differences in metabolic status may underlie variations in weight loss success. Methods: In DiOGenes, a randomized, controlled trial, weight loss was induced using a low calorie diet (800 kcal) for 8-weeks. Men (N5236) and women (N5431) as well as groups with overweight/obesity and morbid obesity were studied separately. The relation between the metabolic status before weight loss and weight loss was assessed by stepwise regression on multiple datasets, including anthropometric parameters, NMR-based plasma metabolites, and LC-MS-based plasma lipid species. Results: Maximally, 57% of the variation in weight loss success can be predicted by baseline parameters. The most powerful predictive models were obtained in subjects with morbid obesity. In these models, the metabolites most predictive for weight loss were acetoacetate, triacylglycerols, phosphatidylcholines, specific amino acids, and creatine and creatinine. This metabolic profile suggests that high energy metabolism activity results in higher amounts of weight loss. Conclusions: Possible predictive (pre-diet) markers were found for amount of weight loss for specific subgroups.

BACKGROUND: Studies of weight-control diets that are high in protein or low in glycemic index have reached varied conclusions, probably owing to the fact that the studies had insufficient power. METHODS: We enrolled overweight adults from eight European countries who had lost at least 8% of their initial body weight with a 3.3-MJ (800-kcal) low-calorie diet. Participants were randomly assigned, in a two-by-two factorial design, to one of five ad libitum diets to prevent weight regain over a 26-week period: a low-protein and low-glycemic-index diet, a low-protein and high-glycemic-index diet, a high-protein and low-glycemic-index diet, a high-protein and high-glycemic-index diet, or a control diet. RESULTS: A total of 1209 adults were screened (mean age, 41 years; body-mass index [the weight in kilograms divided by the square of the height in meters], 34), of whom 938 entered the low-calorie-diet phase of the study. A total of 773 participants who completed that phase were randomly assigned to one of the five maintenance diets; 548 completed the intervention (71%). Fewer participants in the high-protein and the low-glycemic-index groups than in the low-protein-high-glycemic-index group dropped out of the study (26.4% and 25.6%, respectively, vs. 37.4%; P=0.02 and P=0.01 for the respective comparisons). The mean initial weight loss with the low-calorie diet was 11.0 kg. In the analysis of participants who completed the study, only the low-protein-high-glycemic-index diet was associated with subsequent significant weight regain (1.67 kg; 95% confidence interval [CI], 0.48 to 2.87). In an intention-to-treat analysis, the weight regain was 0.93 kg less (95% CI, 0.31 to 1.55) in the groups assigned to a high-protein diet than in those assigned to a low-protein diet (P=0.003) and 0.95 kg less (95% CI, 0.33 to 1.57) in the groups assigned to a low-glycemic-index diet than in those assigned to a high-glycemic-index diet (P=0.003). The analysis involving participants who completed the intervention produced similar results. The groups did not differ significantly with respect to diet-related adverse events. CONCLUSIONS: In this large European study, a modest increase in protein content and a modest reduction in the glycemic index led to an improvement in study completion and maintenance of weight loss. (Funded by the European Commission; ClinicalTrials.gov number, NCT00390637.).

BackgroundNumerous gene loci are related to single measures of body weight and shape. We investigated if 55 SNPs previously associated with BMI or waist measures, modify the effects of fat intake on weight loss and waist reduction under energy restriction.Methods and findingsRandomized controlled trial of 771 obese adults. (RegistrationISRCTN25867281.) One SNP was selected for replication in another weight loss intervention study of 934 obese adults. The original trial was a 10-week 600 kcal/d energy-deficient diet with energy percentage from fat (fat%) in range of 20-25 or 40-45. The replication study used an 8-weeks diet of 880 kcal/d and 20 fat%; change in fat% intake was used for estimation of interaction effects. The main outcomes were intervention weight loss and waist reduction. In the trial, mean change in fat% intake was -12/+4 in the low/high-fat groups. In the replication study, it was -23/-12 among those reducing fat% more/less than the median. TFAP2B-rs987237 genotype AA was associated with 1.0 kg (95% CI, 0.4; 1.6) greater weight loss on the low-fat, and GG genotype with 2.6 kg (1.1; 4.1) greater weight loss on the high-fat (interaction p-value; p = 0.00007). The replication study showed a similar (non-significant) interaction pattern. Waist reduction results generally were similar. Study-strengths include (i) the discovery study randomised trial design combined with the replication opportunity (ii) the strict dietary intake control in both studies (iii) the large sample sizes of both studies. Limitations are (i) the low minor allele frequency of the TFAP2B polymorphism, making it hard to investigate non-additive genetic effects (ii) the different interventions preventing identical replication-discovery study designs (iii) some missing data for non-completers and dietary intake. No adverse effects/outcomes or side-effects were observed.ConclusionsUnder energy restriction, TFAP2B may modify the effect of dietary fat intake on weight loss and waist reduction.