期刊
DIABETES
卷 66, 期 11, 页码 2915-2926出版社
AMER DIABETES ASSOC
DOI: 10.2337/db17-0199
关键词
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资金
- Netherlands Consortium for Systems Biology
- Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research
- European Commission Sixth Framework Programme STRP [018947, LSHG-CT-200601947]
- European Community Seventh Framework Programme [HEALTH-F4-2007-201413]
- European Commission under the program Quality of Life and Management of the Living Resources of Fifth Framework Programme [QLG2-CT-2002-01254]
- FP7 project EUROHEADPAIN [602633]
- Netherlands Organisation for Scientific Research and the Russian Foundation for Basic Research [NWO-RFBR 047.017.043]
- Biobanking and BioMolecular resources Research Infrastructure the Netherlands (BBMRI-NL
- European Community's Seventh Framework Programme
- ENGAGE Consortium [HEALTH-F4-2007-201413]
- European Commission FP7 grant LipidomicNet [2007-202272]
- Personalized pREvention of Chronic DIseases consortium (PRECeDI)
- Erasmus Mundus-Western Balkans (ERAWEB) mobility program academic scholarship
- Veni grant from ZonMw
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.
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