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- Title
A Mendelian Randomization Study of Metabolite Profiles, Fasting Glucose, and Type 2 Diabetes.
- Authors
Jun Liu; 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; Liu, Jun; Bert van Klinken, Jan; Willems van Dijk, Ko
- 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.
- Subjects
MENDEL'S law; METABOLITES; TYPE 2 diabetes; TRIGLYCERIDES; CHOLESTEROL; PHOSPHOLIPIDS; BLOOD sugar; GENES; GENETICS; HUMAN genome
- Publication
Diabetes, 2017, Vol 66, Issue 11, p2915
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db17-0199