A Mendelian Randomization Study of Metabolite Profiles, Fasting Glucose, and Type 2 Diabetes
A Mendelian Randomization Study of Metabolite Profiles, Fasting Glucose, and Type 2 Diabetes
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DOI：
10.2337/db17-0199
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发表时间：
2017-11-01
期刊：
影响因子：
7.7
通讯作者：
Demirkan, Ayse
中科院分区：
文献类型：
--
作者：
Liu, Jun;van Klinken, Jan Bert;Demirkan, Ayse
孟德尔随机化（MR）为我们提供了研究代谢产物在2型糖尿病和葡萄糖稳态中的因果路径的机会。我们开发并测试了一种基于血浆代谢物水平遗传风险评分的MR方法，利用基于途径的敏感性分析来控制非特异性效应。我们在Erasmus鲁克芬家族（ERF）研究（n = 2，564）中关注了124种与空腹血糖相关的循环代谢物，并测试了每种代谢物与血糖和2型糖尿病的可能因果关系，反之亦然。我们检测到14个路径与潜在的因果关系的影响MR，以下路径为基础的敏感性分析。我们的研究结果表明，血浆甘油三酯升高可能是葡萄糖水平升高和2型糖尿病风险增加的部分原因，这与以前的报告一致。此外，HDL成分升高，即，小HDL甘油三酯，可能有升高葡萄糖水平的因果关系。相反，大（L）和超大（XL）HDL脂质组分，即，XL-HDL胆固醇、XL-HDL游离胆固醇、XL-HDL磷脂、L-HDL胆固醇和L-HDL游离胆固醇以及HDL胆固醇似乎对增加的空腹血糖具有保护作用，但对2型糖尿病没有保护作用。最后，我们证明了2型糖尿病的遗传易感性与丙氨酸水平升高和磷脂酰胆碱烷基酰基C42：5和磷脂酰胆碱烷基酰基C44：4水平降低有关。我们的MR结果为葡萄糖和2型糖尿病之间有前途的因果关系提供了新的见解，并强调了高分辨率代谢组学的额外信息在经典生物化学中的价值。
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.