Abstract
CONTEXT: Roux-en-Y gastric bypass (RYGB) is among the most effective treatments for extreme obesity and obesity-related complications. However, despite its potential efficacy, many patients do not achieve and/or maintain sufficient weight loss. OBJECTIVE: Our objective was to identify genetic factors underlying the variability in weight loss outcomes after RYGB surgery. DESIGN: We conducted a genome-wide association study using a 2-stage phenotypic extreme study design. SETTING: Patients were recruited from a comprehensive weight loss program at an integrated health system. PATIENTS: Eighty-six obese (body mass index >35 kg/m(2)) patients who had the least percent excess body weight loss (%EBWL) and 89 patients who had the most %EBWL at 2 years after surgery were genotyped using Affymetrix version 6.0 single-nucleotide polymorphism (SNP) arrays. A second group from the same cohort consisting of 164 patients in the lower quartile of %EBWL and 169 from the upper quartile were selected for evaluation of candidate regions using custom SNP arrays. INTERVENTION: We performed RYGB surgery. MAIN OUTCOME MEASURES: We assessed %EBWL at 2 years after RYGB and SNPs. RESULTS: We identified 111 SNPs in the first-stage analysis whose frequencies were significantly different between 2 phenotypic extremes of weight loss (allelic χ(2) test P < .0001). Linear regression of %EBWL at 2 years after surgery revealed 17 SNPs that approach P < .05 in the validation stage and cluster in or near several genes with potential biological relevance including PKHD1, HTR1A, NMBR, and IGF1R. CONCLUSIONS: This is the first genome-wide association study of weight loss response to RYGB. Variation in weight loss outcomes after RYGB may be influenced by several common genetic variants.