RT Journal Article
SR Electronic
T1 Novel mediation analysis of human plasma proteome and metabolome reveals mediators of improved glycemia after gastric bypass surgery
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 817494
DO 10.1101/817494
A1 Jonathan M Dreyfuss
A1 Yixing Yuchi
A1 Hui Pan
A1 Xuehong Dong
A1 Donald C. Simonson
A1 Ashley Vernon
A1 Pratik Aryal
A1 Anish Konkar
A1 Yinong Sebastian
A1 Brandon W Higgs
A1 Joseph Grimsby
A1 Cristina M. Rondinone
A1 Simon Kasif
A1 Barbara B. Kahn
A1 Kathleen Foster
A1 Allison Goldfine
A1 Mary-Elizabeth Patti
YR 2019
UL http://biorxiv.org/content/early/2019/10/29/817494.abstract
AB Molecular mechanisms by which Roux-en-Y gastric bypass (RYGB) improves glycemic control and metabolism in type 2 diabetes (T2D) remain incompletely understood. In the SLIMM-T2D trial, participants with T2D were randomized to RYGB or nonsurgical management and their fasting plasma proteome and metabolome were analyzed for up to 3 years. To identify analytes that mediate improvement in outcomes, we developed a high-throughput mediation analysis method (Hitman), which is significantly more powerful than existing methods. Top-ranking analyte mediators of glycemia improvement were growth hormone receptor and prolylhydroxyproline, which were more significant than any clinical mediator, including BMI. Beta-alanine and Histidine Metabolism (both including CNDP1) were top differentially regulated pathways, and Valine, Leucine and Isoleucine Degradation was also a top differentially-regulated pathway and a top mediator of improvement in insulin resistance. The identified analytes may serve as novel targets for T2D therapy. More broadly, Hitman can identify analyte mediators of outcomes in randomized trials for which high-throughput data are available.