Dekkers Koen F, van Iterson Maarten, Slieker Roderick C, Moed Matthijs H, Bonder Marc Jan, van Galen Michiel, Mei Hailiang, Zhernakova Daria V, van den Berg Leonard H, Deelen Joris, van Dongen Jenny, van Heemst Diana, Hofman Albert, Hottenga Jouke J, van der Kallen Carla J H, Schalkwijk Casper G, Stehouwer Coen D A, Tigchelaar Ettje F, Uitterlinden André G, Willemsen Gonneke, Zhernakova Alexandra, Franke Lude, 't Hoen Peter A C, Jansen Rick, van Meurs Joyce, Boomsma Dorret I, van Duijn Cornelia M, van Greevenbroek Marleen M J, Veldink Jan H, Wijmenga Cisca, van Zwet Erik W, Slagboom P Eline, Jukema J Wouter, Heijmans Bastiaan T
Molecular Epidemiology section, Leiden University Medical Center, Einthovenweg 20, Leiden, The Netherlands.
Department of Genetics, University of Groningen, University Medical Centre Groningen, Broerstraat 5, Groningen, The Netherlands.
Genome Biol. 2016 Jun 27;17(1):138. doi: 10.1186/s13059-016-1000-6.
Cells can be primed by external stimuli to obtain a long-term epigenetic memory. We hypothesize that long-term exposure to elevated blood lipids can prime circulating immune cells through changes in DNA methylation, a process that may contribute to the development of atherosclerosis. To interrogate the causal relationship between triglyceride, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol levels and genome-wide DNA methylation while excluding confounding and pleiotropy, we perform a stepwise Mendelian randomization analysis in whole blood of 3296 individuals.
This analysis shows that differential methylation is the consequence of inter-individual variation in blood lipid levels and not vice versa. Specifically, we observe an effect of triglycerides on DNA methylation at three CpGs, of LDL cholesterol at one CpG, and of HDL cholesterol at two CpGs using multivariable Mendelian randomization. Using RNA-seq data available for a large subset of individuals (N = 2044), DNA methylation of these six CpGs is associated with the expression of CPT1A and SREBF1 (for triglycerides), DHCR24 (for LDL cholesterol) and ABCG1 (for HDL cholesterol), which are all key regulators of lipid metabolism.
Our analysis suggests a role for epigenetic priming in end-product feedback control of lipid metabolism and highlights Mendelian randomization as an effective tool to infer causal relationships in integrative genomics data.
细胞可通过外部刺激被预激发以获得长期的表观遗传记忆。我们假设长期暴露于血脂升高状态可通过DNA甲基化的改变使循环免疫细胞发生预激发，这一过程可能促进动脉粥样硬化的发展。为了探究甘油三酯、低密度脂蛋白（LDL）胆固醇和高密度脂蛋白（HDL）胆固醇水平与全基因组DNA甲基化之间的因果关系，同时排除混杂因素和多效性，我们对3296名个体的全血进行了逐步孟德尔随机化分析。
该分析表明，差异甲基化是个体间血脂水平差异的结果，而非相反。具体而言，使用多变量孟德尔随机化方法，我们观察到甘油三酯对3个CpG位点的DNA甲基化有影响，LDL胆固醇对1个CpG位点有影响，HDL胆固醇对2个CpG位点有影响。利用大量个体（N = 2044）的RNA测序数据，这6个CpG位点的DNA甲基化与CPT1A和SREBF1（针对甘油三酯）、DHCR24（针对LDL胆固醇）以及ABCG1（针对HDL胆固醇）的表达相关，这些都是脂质代谢的关键调节因子。
我们的分析表明表观遗传预激发在脂质代谢的终产物反馈控制中发挥作用，并强调孟德尔随机化是推断整合基因组学数据中因果关系的有效工具。
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