Weight Loss Following Roux‐en‐Y Gastric Bypass Causally Implicated with Serum Levels of IL‐22: A Mendelian Randomization and Phenome‐Wide Association Study

ObjectiveLaparoscopic Roux‐en‐Y gastric bypass (RYGB) modulates the low‐grade inflammatory state associated with severe obesity. This study sought to investigate whether weight loss is causally implicated with changes in serum levels of inflammatory molecules.MethodsUsing the largest genome‐wide association study (n = 1,020 individuals), this study curated five genetic variants associated with weight loss following RYGB. Phenome‐wide association studies (PheWAS) were performed to identify other phenotypes associated with these variants. Subsequently, two‐sample Mendelian randomization was used to study the causal effects of weight loss on the serum levels of 382 inflammatory proteins (measured in 3,033 individuals). This is the first systematic quasi‐experimental investigation of weight loss following RYGB and serum markers of inflammation.ResultsThe PheWAS analysis revealed that four of the five variants are associated with phenotypes relating to metabolism and inflammation, including insulin response and levels of C‐reactive protein. Two‐sample Mendelian randomization of the 382 serum inflammatory markers revealed that weight loss following RYGB increases serum levels of interleukin 22 (IL‐22) (beta = 0.021, P < 10−3; 95% CI: 0.010‐0.031). Sensitivity analyses further supported the results and the causal direction.ConclusionsWeight loss following RYGB may cause an increase in IL‐22 serum levels, suggesting that weight loss directly contributes to immune modulation following bypass. These results demonstrate the utility of genetic studies to disentangling molecular cause and effect following bariatric surgery. image