Blood lipids influence DNA methylation in circulating cells

被引：137

作者：

Dekkers, Koen F. ^{[1
]}

van Iterson, Maarten ^{[1
]}

Slieker, Roderick C. ^{[1
]}

Moed, Matthijs H. ^{[1
]}

Bonder, Marc Jan ^{[2
]}

van Galen, Michiel ^{[3
]}

Mei, Hailiang ^{[4
]}

Zhernakova, Daria V. ^{[2
]}

van den Berg, Leonard H. ^{[5
]}

Deelen, Joris ^{[1
]}

van Dongen, Jenny ^{[6
]}

van Heemst, Diana ^{[7
]}

Hofman, Albert ^{[8
]}

Hottenga, Jouke J. ^{[6
]}

van der Kallen, Carla J. H. ^{[9
,10
]}

Schalkwijk, Casper G. ^{[9
,10
]}

Stehouwer, Coen D. A. ^{[9
,10
]}

Tigchelaar, Ettje F. ^{[2
]}

Uitterlinden, Andre G. ^{[11
]}

Willemsen, Gonneke ^{[6
]}

Zhernakova, Alexandra ^{[2
]}

Franke, Lude ^{[2
]}

't Hoen, Peter A. C. ^{[3
]}

Jansen, Rick ^{[12
]}

van Meurs, Joyce ^{[11
]}

Boomsma, Dorret I. ^{[6
]}

van Duijn, Cornelia M. ^{[8
]}

van Greevenbroek, Marleen M. J. ^{[9
,10
]}

Veldink, Jan H. ^{[5
]}

Wijmenga, Cisca ^{[2
]}

van Zwet, Erik W. ^{[14
]}

Slagboom, P. Eline ^{[1
]}

Jukema, J. Wouter ^{[15
]}

Heijmans, Bastiaan T. ^{[1
]}

机构：

[1] Leiden Univ, Med Ctr, Mol Epidemiol Sect, Einthovenweg 20, Leiden, Netherlands

[2] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Broerstr 5, Groningen, Netherlands

[3] Leiden Univ, Med Ctr, Dept Human Genet, Einthovenweg 20, Leiden, Netherlands

[4] Leiden Univ, Med Ctr, Sequence Anal Support Core, Einthovenweg 20, Leiden, Netherlands

[5] Univ Med Ctr Utrecht, Dept Neurol, Brain Ctr Rudolf Magnus, Heidelberglaan 100, Utrecht, Netherlands

[6] Vrije Univ Amsterdam, Dept Biol Psychol, Neurosci Campus Amsterdam,Boelelaan 1117, Amsterdam, Netherlands

[7] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Einthovenweg 20, Leiden, Netherlands

[8] ErasmusMC, Dept Genet Epidemiol, S Gravendijkwal 230, Rotterdam, Netherlands

[9] Maastricht Univ, Med Ctr, Dept Internal Med, P Debyelaan 25, Maastricht, Netherlands

[10] Maastricht Univ, Med Ctr, Sch Cardiovasc Dis CARIM, P Debyelaan 25, Maastricht, Netherlands

[11] ErasmusMC, Dept Internal Med, S Gravendijkwal 230, Rotterdam, Netherlands

[12] Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Neurosci Campus Amsterdam,Boelelaan 1117, Amsterdam, Netherlands

[13] BIOS Consortium, Einthovenweg 20, Leiden, Netherlands

[14] Leiden Univ, Med Ctr, Dept Med Stat & Bioinformat, Einthovenweg 20, Leiden, Netherlands

[15] Leiden Univ, Med Ctr, Dept Cardiol, Einthovenweg 20, Leiden, Netherlands

来源：

GENOME BIOLOGY | 2016年 / 17卷

关键词：

DNA methylation; Lipids; Mendelian randomization; Gene expression; EPIGENOME-WIDE ASSOCIATION; MENDELIAN RANDOMIZATION; CPT1A LOCUS; CHOLESTEROL; PLASMA; PATTERNS; EXPOSURE; SURVIVAL; SYSTEM; TIME;

D O I：

10.1186/s13059-016-1000-6

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

Background: 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. Results: 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. Conclusions: 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.

引用

页数：12

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