Meta-analysis of Epigenome-wide Association Studies of Carotid Intima-media Thickness

Overview

Journal Eur J Epidemiol

Specialty Public Health

Date 2021 Jun 6

PMID 34091768

Citations 11

Authors

Eliana Portilla-Fernandez

Shih-Jen Hwang

Rory Wilson

Jane Maddock

W David Hill

Alexander Teumer

Pashupati P Mishra

Jennifer A Brody

Roby Joehanes

Symen Ligthart

Mohsen Ghanbari

Maryam Kavousi

Anton J M Roks

A H Jan Danser

Daniel Levy

Annette Peters

Sahar Ghasemi

Ulf Schminke

Marcus Dorr

Hans J Grabe

Terho Lehtimaki

Mika Kahonen

Mikko A Hurme

Traci M Bartz

Nona Sotoodehnia

Joshua C Bis

Joachim Thiery

Wolfgang Koenig

Ken K Ong

Jordana T Bell

Christine Meisinger

Joanna M Wardlaw

John M Starr

Jochen Seissler

Cornelia Then

Wolfgang Rathmann

M Arfan Ikram

Bruce M Psaty

Olli T Raitakari

Henry Volzke

Ian J Deary

Andrew Wong

Melanie Waldenberger

Christopher J ODonnell

Abbas Dehghan

Affiliations

Soon will be listed here.

Abstract

Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta = -0.0264, p value = 3.5 × 10) in the discovery panel and was replicated in replication panel (beta = -0.07, p value = 0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value = 1.4 × 10). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.

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References

Revkin J, Shear C, Pouleur H, Ryder S, Orloff D . Biomarkers in the prevention and treatment of atherosclerosis: need, validation, and future. Pharmacol Rev. 2007; 59(1):40-53. DOI: 10.1124/pr.59.1.1. View

Relton C, Davey Smith G . Two-step epigenetic Mendelian randomization: a strategy for establishing the causal role of epigenetic processes in pathways to disease. Int J Epidemiol. 2012; 41(1):161-76. PMC: 3304531. DOI: 10.1093/ije/dyr233. View

Warren H, Evangelou E, Cabrera C, Gao H, Ren M, Mifsud B . Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk. Nat Genet. 2017; 49(3):403-415. PMC: 5972004. DOI: 10.1038/ng.3768. View

Augst A, Ariff B, McG Thom S, Xu X, Hughes A . Analysis of complex flow and the relationship between blood pressure, wall shear stress, and intima-media thickness in the human carotid artery. Am J Physiol Heart Circ Physiol. 2007; 293(2):H1031-7. DOI: 10.1152/ajpheart.00989.2006. View

Yavorska O, Burgess S . MendelianRandomization: an R package for performing Mendelian randomization analyses using summarized data. Int J Epidemiol. 2017; 46(6):1734-1739. PMC: 5510723. DOI: 10.1093/ije/dyx034. View

Willer C, Li Y, Abecasis G . METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010; 26(17):2190-1. PMC: 2922887. DOI: 10.1093/bioinformatics/btq340. View

Zudaire E, Cuesta N, Murty V, Woodson K, Adams L, Gonzalez N . The aryl hydrocarbon receptor repressor is a putative tumor suppressor gene in multiple human cancers. J Clin Invest. 2008; 118(2):640-50. PMC: 2157559. DOI: 10.1172/JCI30024. View

Dolinoy D, Faulk C . Introduction: The use of animals models to advance epigenetic science. ILAR J. 2013; 53(3-4):227-31. PMC: 3747759. DOI: 10.1093/ilar.53.3-4.227. View

Gaston V, Le Bouc Y, Soupre V, Burglen L, Donadieu J, Oro H . Analysis of the methylation status of the KCNQ1OT and H19 genes in leukocyte DNA for the diagnosis and prognosis of Beckwith-Wiedemann syndrome. Eur J Hum Genet. 2001; 9(6):409-18. DOI: 10.1038/sj.ejhg.5200649. View

10.

Brash A . Lipoxygenases: occurrence, functions, catalysis, and acquisition of substrate. J Biol Chem. 1999; 274(34):23679-82. DOI: 10.1074/jbc.274.34.23679. View

11.

Latvala A, Ollikainen M . Mendelian randomization in (epi)genetic epidemiology: an effective tool to be handled with care. Genome Biol. 2016; 17(1):156. PMC: 4944517. DOI: 10.1186/s13059-016-1018-9. View

12.

Glagov S, Zarins C, Giddens D, Ku D . Hemodynamics and atherosclerosis. Insights and perspectives gained from studies of human arteries. Arch Pathol Lab Med. 1988; 112(10):1018-31. View

13.

Faul F, Erdfelder E, Buchner A, Lang A . Statistical power analyses using G*Power 3.1: tests for correlation and regression analyses. Behav Res Methods. 2009; 41(4):1149-60. DOI: 10.3758/BRM.41.4.1149. View

14.

Houseman E, Accomando W, Koestler D, Christensen B, Marsit C, Nelson H . DNA methylation arrays as surrogate measures of cell mixture distribution. BMC Bioinformatics. 2012; 13:86. PMC: 3532182. DOI: 10.1186/1471-2105-13-86. View

15.

Psaty B, ODonnell C, Gudnason V, Lunetta K, Folsom A, Rotter J . Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium: Design of prospective meta-analyses of genome-wide association studies from 5 cohorts. Circ Cardiovasc Genet. 2009; 2(1):73-80. PMC: 2875693. DOI: 10.1161/CIRCGENETICS.108.829747. View

16.

OLeary D, Bots M . Imaging of atherosclerosis: carotid intima-media thickness. Eur Heart J. 2010; 31(14):1682-9. DOI: 10.1093/eurheartj/ehq185. View

17.

Zhao L, Funk C . Lipoxygenase pathways in atherogenesis. Trends Cardiovasc Med. 2004; 14(5):191-5. DOI: 10.1016/j.tcm.2004.04.003. View

18.

Stenvinkel P, Karimi M, Johansson S, Axelsson J, Suliman M, Lindholm B . Impact of inflammation on epigenetic DNA methylation - a novel risk factor for cardiovascular disease?. J Intern Med. 2007; 261(5):488-99. DOI: 10.1111/j.1365-2796.2007.01777.x. View

19.

Demerath E, Guan W, Grove M, Aslibekyan S, Mendelson M, Zhou Y . Epigenome-wide association study (EWAS) of BMI, BMI change and waist circumference in African American adults identifies multiple replicated loci. Hum Mol Genet. 2015; 24(15):4464-79. PMC: 4492394. DOI: 10.1093/hmg/ddv161. View

20.

Landgrave-Gomez J, Mercado-Gomez O, Guevara-Guzman R . Epigenetic mechanisms in neurological and neurodegenerative diseases. Front Cell Neurosci. 2015; 9:58. PMC: 4343006. DOI: 10.3389/fncel.2015.00058. View