495 Genetic Factors Predict Weight Loss After Roux-en-Y Gastric Bypass

Introduction: Although Roux-en-Y gastric bypass (RYBG) leads to substantial weight loss, the magnitude of this effect is highly variable. The determinants of weight loss following RYGB are poorly understood. Clinical factors have been able to account for only a fraction of the observed variation, and several studies have implicated additional biological determinants. In this study, we sought to determine the role of genetic contributions to weight loss after RYGB. Methods: We collected liver samples from 1018 patients undergoing RYGB. DNA from these samples was genotyped for 660,000 single nucleotide polymorphisms (SNPs). Percent excess weight loss (%EWL) for the nadir weight after surgery was calculated against a reference BMI of 25 kg/m2. We identified 40 genetically related individuals within this cohort, based on percentage of their genome shared. Using electronic medical records, we identified 20 additional individuals who were cohabitating and genetically unrelated. We used mixed effects models to determine whether degree of relatedness (1°, 2°, or 3°, or cohabitating) is associated with%EWL. In addition, we performed a genome-wide association study (GWAS) of the 789 non-related Caucasians within the total cohort. Results: The average difference in %EWL was 13.7%, 25.1% and 36.8% for 1°, 2°, and 3° relatives, and 25.4% for cohabitating individuals, respectively. There was a significant association of %EWL between 1° relatives (p=0.04, Intraclass Correlation Coefficient [ICC]=57.3%), which was not seen between 2° relatives (p=0.54, ICC=38.2%), 3° relatives (p=0.36, ICC=0%), or cohabitating individuals (p=0.53, ICC=0). The GWAS identified a single region on chromosome 6 that was significantly associated with %EWL (p=2.1x10-7; false discovery rate=9.2% for the highest ranked SNP in this region). Conclusions: These data suggest that there are genetic determinants of weight loss after RYGB. Despite the small number of related individuals, the significant correlation between outcomes of 1° relatives indicates that there is a significant genetic impact beyond any shared environmental influences. In addition, even in this modest-sized cohort, we identified a chromosomal region significantly associated with %EWL. These observations underscore the biological nature of the response to RYGB and suggest that variation in the genetic background of individuals influences weight loss after this operation. Identification of the genes involved in this response could provide information about the method of action of RYGB and facilitate strategies for selecting patients most likely to benefit from this effective yet invasive procedure.