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

• Published in: Diabetes (New York, N.Y.) Vol. 66; no. 11; pp. 2915 - 2926
• Main Authors: Liu, Jun, van Klinken, Jan Bert, Semiz, Sabina, van Dijk, Ko Willems, Verhoeven, Aswin, Hankemeier, Thomas, Harms, Amy C, Sijbrands, Eric, Sheehan, Nuala A, van Duijn, Cornelia M, Demirkan, Ayşe
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01-11-2017
• Subjects: Adult; Aged; Alanine; Blood Glucose - metabolism; Cholesterol; Clinical trials; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Fasting; Female; Gene Expression Regulation; Genetic Variation; Genome, Human; Glucose; High density lipoprotein; Homeostasis; Humans; Laboratory testing; Lecithin; Male; Mendelian Randomization Analysis; Metabolites; Metabolomics; Middle Aged; Phosphatidylcholine; Phospholipids; Sensitivity analysis; Triglycerides
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/DB17-0199

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 (
= 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.