Using Genetic Variants to Assess the Relationship Between Circulating Lipids and Type 2 Diabetes
Using Genetic Variants to Assess the Relationship Between Circulating Lipids and Type 2 Diabetes
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DOI：
10.2337/db14-1710
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发表时间：
2015-07-01
期刊：
影响因子：
7.7
通讯作者：
Ingelsson, Erik
中科院分区：
文献类型：
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作者：
Fall, Tove;Xie, Weijia;Ingelsson, Erik
血脂异常对2型糖尿病（T2D）及相关特征的影响尚不清楚。我们使用回归模型和140种脂质相关的遗传变异来估计循环HDL- c、LDL- c、甘油三酯和T2D及相关性状之间的关联。每个基因测试都校正了变异对其他两种脂质类型和肥胖替代物的影响。我们使用了最大的可用数据集：34,840例T2D病例和114,981例对照受试者，来自DIAGRAM（糖尿病遗传学复制和荟萃分析）联盟，以及来自MAGIC（葡萄糖和胰岛素相关性状荟萃分析联盟）和GENESIS（胰岛素敏感性遗传学）研究的133,010例非糖尿病患者的胰岛素分泌和敏感性。21组变异与糖尿病特征之间的关联中，有8组在名义水平上具有显著性，包括遗传决定的较低HDL-C （= -0.12, P = 0.03）和T2D之间的关联，以及遗传决定的较低LDL-C （= -0.21, P = 5 × 10(-6)）和T2D之间的关联。虽然其中一些可能代表因果关系，但我们讨论了为什么在循环脂质水平和糖尿病特征的背景下使用孟德尔随机化时必须谨慎使用。总之，我们发现了与脂质相关的遗传变异与T2D之间存在联系的证据，但在基于孟德尔随机化方法得出因果关系的明确结论之前，需要对特定脂质变异的潜在遗传机制有更深入的了解。
The effects of dyslipidemia on the risk of type 2 diabetes (T2D) and related traits are not clear. We used regression models and 140 lipid-associated genetic variants to estimate associations between circulating HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), and triglycerides and T2D and related traits. Each genetic test was corrected for effects of variants on the other two lipid types and surrogates of adiposity. We used the largest data sets available: 34,840 T2D case and 114,981 control subjects from the DIAGRAM (DIAbetes Genetics Replication And Meta-analysis) consortium and up to 133,010 individuals without diabetes for insulin secretion and sensitivity from the MAGIC (Meta-Analyses of Glucose and Insulin-related traits Consortium) and GENESIS (GENEticS of Insulin Sensitivity) studies. Eight of 21 associations between groups of variants and diabetes traits were significant at the nominal level, including those between genetically determined lower HDL-C ( = -0.12, P = 0.03) and T2D and genetically determined lower LDL-C ( = -0.21, P = 5 x 10(-6)) and T2D. Although some of these may represent causal associations, we discuss why caution must be used when using Mendelian randomization in the context of circulating lipid levels and diabetes traits. In conclusion, we found evidence of links between genetic variants associated with lipids and T2D, but deeper knowledge of the underlying genetic mechanisms of specific lipid variants is needed before drawing definite conclusions about causality based on Mendelian randomization methodology.