The amount of weight loss attained after Roux-en-Y gastric bypass (RYGB) surgery follows a wide and normal distribution, and recent evidence indicates that this weight loss is due to physiological, rather than mechanical, mechanisms. To identify potential genetic factors associated with weight loss after RYGB, we performed a genome-wide association study (GWAS) of 693 individuals undergoing RYGB and then replicated this analysis in an independent population of 327 individuals undergoing RYGB. We found that a 15q26.1 locus near ST8SIA2 and SLCO3A1 was significantly associated with weight loss after RYGB. Expression of ST8SIA2 in omental fat of these individuals at baseline was significantly associated with weight loss after RYGB. Gene expression analysis in RYGB and weight-matched, sham-operated (WMS) mice revealed that expression of St8sia2 and Slco3a1 was significantly altered in metabolically active tissues in RYGB-treated compared to WMS mice. These findings provide strong evidence for specific genetic influences on weight loss after RYGB and underscore the biological nature of the response to RYGB.
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