250-OR: Higher Genetic Risk Score Predicts Smaller Waist Circumference Change over One Year across Five Lifestyle Intervention Clinical Trials
Authors: MCCAFFERY JEANNE , JABLONSKI KATHLEEN A. , PAN QING , ASTRUP ARNE , CHRISTIANSEN MALENE R. , CORSO LAUREN M. , FLOREZ JOSE C. , FRANKS PAUL W. , GARDNER CHRISTOPHER D. , HANSEN TORBEN , KILPELAINEN TUOMAS O. , CORELLA DOLORES , SARIS WIM H.M. , SØRENSEN THORKILD I.A. , TUOMILEHTO JAAKKO , WING RENA R. , AGURS-COLLINS TANYA 
Published: June 2021

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