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

Author:

Liu Jun1,van Klinken Jan Bert2,Semiz Sabina34,van Dijk Ko Willems25,Verhoeven Aswin6,Hankemeier Thomas178,Harms Amy C.78,Sijbrands Eric9ORCID,Sheehan Nuala A.10,van Duijn Cornelia M.16,Demirkan Ayşe15ORCID

Affiliation:

1. Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands

2. Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands

3. Genetics and Bioengineering Program, Faculty of Engineering and Natural Sciences, International University of Sarajevo, Sarajevo, Bosnia and Herzegovina

4. Department of Biochemistry and Clinical Analysis, Faculty of Pharmacy, University of Sarajevo, Sarajevo, Bosnia and Herzegovina

5. Department of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands

6. Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands

7. Division of Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands

8. Netherlands Metabolomics Centre, Leiden University, Leiden, the Netherlands

9. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands

10. Department of Health Sciences, University of Leicester, Leicester, U.K.

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.

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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