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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.