A Mendelian Randomization Study of Metabolite Profiles, Fasting Glucose, and Type 2 Diabetes

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A Mendelian Randomization Study of Metabolite Profiles, Fasting Glucose, and Type 2 Diabetes

Type: Article / Letter to editor
Title: A Mendelian Randomization Study of Metabolite Profiles, Fasting Glucose, and Type 2 Diabetes
Author: Liu, J.Klinken, J.B. vanSemiz, S.Willems, van DijkK.Verhoeven, A.Hankemeier, T.Harms, A.C.Sijbrands, E.Sheehan, N.A.Duijn, C.M. vanDemirkan, A.
Journal Title: DIABETES
Issue: 11
Volume: 66
Start Page: 2915
End Page: 2926
Pages: 12
Issue Date: 2017
Abstract: Mendelian randomization (MR) provides us the opportunity to investigate the causal paths of metabolites in type 2 diabetes and glucose homeostasis. We developed and tested an MR approach based on genetic risk scoring for plasma metabolite levels, utilizing a pathway-based sensitivity analysis to control for nonspecific effects. We focused on 124 circulating metabolites that correlate with fasting glucose in the Erasmus Rucphen Family (ERF) study (n = 2,564) and tested the possible causal effect of each metabolite with glucose and type 2 diabetes and vice versa. We detected 14 paths with potential causal effects by MR, following pathway-based sensitivity analysis. Our results suggest that elevated plasma triglycerides might be partially responsible for increased glucose levels and type 2 diabetes risk, which is consistent with previous reports. Additionally, elevated HDL components, i.e., small HDL triglycerides, might have a causal role of elevating glucose levels. In contrast, large (L) and extra large (XL) HDL lipid components, i.e., XL-HDL cholesterol, XL-HDL–free cholesterol, XL-HDL phospholipids, L-HDL cholesterol, and L-HDL–free cholesterol, as well as HDL cholesterol seem to be protective against increasing fasting glucose but not against type 2 diabetes. Finally, we demonstrate that genetic predisposition to type 2 diabetes associates with increased levels of alanine and decreased levels of phosphatidylcholine alkyl-acyl C42:5 and phosphatidylcholine alkyl-acyl C44:4. Our MR results provide novel insight into promising causal paths to and from glucose and type 2 diabetes and underline the value of additional information from high-resolution metabolomics over classic biochemistry.
Handle: http://hdl.handle.net/1887/69176
 

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