Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease

Golareh Agha; Michael M. Mendelson; Cavin K. Ward-Caviness; Roby Joehanes; Tian Xiao Huan; Rahul Gondalia; Elias Salfati; Jennifer A. Brody; Giovanni Fiorito; Jan Bressler; Brian H. Chen; Symen Ligthart; Simonetta Guarrera; Elena Colicino; Allan C. Just; Simone Wahl; Christian Gieger; Amy R. Vandiver; Toshiko Tanaka; Dena G. Hernandez; Luke C. Pilling; Andrew B. Singleton; Carlotta Sacerdote; Vittorio Krogh; Salvatore Panico; Rosario Tumino; Yun Li; Guosheng Zhang; James D. Stewart; James S. Floyd; Kerri L. Wiggins; Jerome I. Rotter; Michael Multhaup; Kelly Bakulski; Steven Horvath; Philip S. Tsao; Devin M. Absher; Pantel Vokonas; Joel Hirschhorn; M. Daniele Fallin; Chunyu Liu; Stefania Bandinelli; Eric Boerwinkle; Abbas Dehghan; Joel D. Schwartz; Bruce M. Psaty; Andrew P. Feinberg; Lifang Hou; Luigi Ferrucci; Nona Sotoodehnia; Giuseppe Matullo; Annette Peters; Myriam Fornage; Themistocles L. Assimes; Eric A. Whitsel; Daniel Levy; Andrea A. Baccarelli

doi:10.1161/CIRCULATIONAHA.118.039357

Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease

Golareh Agha, Michael M. Mendelson, Cavin K. Ward-Caviness, Roby Joehanes, Tian Xiao Huan, Rahul Gondalia, Elias Salfati, Jennifer A. Brody, Giovanni Fiorito, Jan Bressler, Brian H. Chen, Symen Ligthart, Simonetta Guarrera, Elena Colicino, Allan C. Just, Simone Wahl, Christian Gieger, Amy R. Vandiver, Toshiko Tanaka, Dena G. HernandezLuke C. Pilling, Andrew B. Singleton, Carlotta Sacerdote, Vittorio Krogh, Salvatore Panico, Rosario Tumino, Yun Li, Guosheng Zhang, James D. Stewart, James S. Floyd, Kerri L. Wiggins, Jerome I. Rotter, Michael Multhaup, Kelly Bakulski, Steven Horvath, Philip S. Tsao, Devin M. Absher, Pantel Vokonas, Joel Hirschhorn, M. Daniele Fallin, Chunyu Liu, Stefania Bandinelli, Eric Boerwinkle, Abbas Dehghan, Joel D. Schwartz, Bruce M. Psaty, Andrew P. Feinberg, Lifang Hou, Luigi Ferrucci, Nona Sotoodehnia, Giuseppe Matullo, Annette Peters, Myriam Fornage, Themistocles L. Assimes, Eric A. Whitsel, Daniel Levy, Andrea A. Baccarelli

Preventive Medicine

Research output: Contribution to journal › Article › peer-review

124 Scopus citations

Abstract

BACKGROUND: DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts. METHODS: Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts. RESULTS: Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts. CONCLUSION: Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.

Original language	English (US)
Pages (from-to)	645-657
Number of pages	13
Journal	Circulation
Volume	140
Issue number	8
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.118.039357
State	Published - Aug 20 2019

Keywords

coronary artery disease
coronary heart disease
epigenetics
gene expression regulation
genomics

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine
Physiology (medical)

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10.1161/CIRCULATIONAHA.118.039357

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Agha, G., Mendelson, M. M., Ward-Caviness, C. K., Joehanes, R., Huan, T. X., Gondalia, R., Salfati, E., Brody, J. A., Fiorito, G., Bressler, J., Chen, B. H., Ligthart, S., Guarrera, S., Colicino, E., Just, A. C., Wahl, S., Gieger, C., Vandiver, A. R., Tanaka, T., ... Baccarelli, A. A. (2019). Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease. Circulation, 140(8), 645-657. https://doi.org/10.1161/CIRCULATIONAHA.118.039357

@article{b0975a3290a446ec86824588db8cce83,

title = "Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease",

abstract = "BACKGROUND: DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts. METHODS: Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts. RESULTS: Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts. CONCLUSION: Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.",

keywords = "coronary artery disease, coronary heart disease, epigenetics, gene expression regulation, genomics",

author = "Golareh Agha and Mendelson, {Michael M.} and Ward-Caviness, {Cavin K.} and Roby Joehanes and Huan, {Tian Xiao} and Rahul Gondalia and Elias Salfati and Brody, {Jennifer A.} and Giovanni Fiorito and Jan Bressler and Chen, {Brian H.} and Symen Ligthart and Simonetta Guarrera and Elena Colicino and Just, {Allan C.} and Simone Wahl and Christian Gieger and Vandiver, {Amy R.} and Toshiko Tanaka and Hernandez, {Dena G.} and Pilling, {Luke C.} and Singleton, {Andrew B.} and Carlotta Sacerdote and Vittorio Krogh and Salvatore Panico and Rosario Tumino and Yun Li and Guosheng Zhang and Stewart, {James D.} and Floyd, {James S.} and Wiggins, {Kerri L.} and Rotter, {Jerome I.} and Michael Multhaup and Kelly Bakulski and Steven Horvath and Tsao, {Philip S.} and Absher, {Devin M.} and Pantel Vokonas and Joel Hirschhorn and Fallin, {M. Daniele} and Chunyu Liu and Stefania Bandinelli and Eric Boerwinkle and Abbas Dehghan and Schwartz, {Joel D.} and Psaty, {Bruce M.} and Feinberg, {Andrew P.} and Lifang Hou and Luigi Ferrucci and Nona Sotoodehnia and Giuseppe Matullo and Annette Peters and Myriam Fornage and Assimes, {Themistocles L.} and Whitsel, {Eric A.} and Daniel Levy and Baccarelli, {Andrea A.}",

year = "2019",

month = aug,

day = "20",

doi = "10.1161/CIRCULATIONAHA.118.039357",

language = "English (US)",

volume = "140",

pages = "645--657",

journal = "Circulation",

issn = "0009-7322",

publisher = "Lippincott Williams and Wilkins",

number = "8",

}

Agha, G, Mendelson, MM, Ward-Caviness, CK, Joehanes, R, Huan, TX, Gondalia, R, Salfati, E, Brody, JA, Fiorito, G, Bressler, J, Chen, BH, Ligthart, S, Guarrera, S, Colicino, E, Just, AC, Wahl, S, Gieger, C, Vandiver, AR, Tanaka, T, Hernandez, DG, Pilling, LC, Singleton, AB, Sacerdote, C, Krogh, V, Panico, S, Tumino, R, Li, Y, Zhang, G, Stewart, JD, Floyd, JS, Wiggins, KL, Rotter, JI, Multhaup, M, Bakulski, K, Horvath, S, Tsao, PS, Absher, DM, Vokonas, P, Hirschhorn, J, Fallin, MD, Liu, C, Bandinelli, S, Boerwinkle, E, Dehghan, A, Schwartz, JD, Psaty, BM, Feinberg, AP, Hou, L, Ferrucci, L, Sotoodehnia, N, Matullo, G, Peters, A, Fornage, M, Assimes, TL, Whitsel, EA, Levy, D & Baccarelli, AA 2019, 'Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease', Circulation, vol. 140, no. 8, pp. 645-657. https://doi.org/10.1161/CIRCULATIONAHA.118.039357

TY - JOUR

T1 - Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease

AU - Agha, Golareh

AU - Mendelson, Michael M.

AU - Ward-Caviness, Cavin K.

AU - Joehanes, Roby

AU - Huan, Tian Xiao

AU - Gondalia, Rahul

AU - Salfati, Elias

AU - Brody, Jennifer A.

AU - Fiorito, Giovanni

AU - Bressler, Jan

AU - Chen, Brian H.

AU - Ligthart, Symen

AU - Guarrera, Simonetta

AU - Colicino, Elena

AU - Just, Allan C.

AU - Wahl, Simone

AU - Gieger, Christian

AU - Vandiver, Amy R.

AU - Tanaka, Toshiko

AU - Hernandez, Dena G.

AU - Pilling, Luke C.

AU - Singleton, Andrew B.

AU - Sacerdote, Carlotta

AU - Krogh, Vittorio

AU - Panico, Salvatore

AU - Tumino, Rosario

AU - Li, Yun

AU - Zhang, Guosheng

AU - Stewart, James D.

AU - Floyd, James S.

AU - Wiggins, Kerri L.

AU - Rotter, Jerome I.

AU - Multhaup, Michael

AU - Bakulski, Kelly

AU - Horvath, Steven

AU - Tsao, Philip S.

AU - Absher, Devin M.

AU - Vokonas, Pantel

AU - Hirschhorn, Joel

AU - Fallin, M. Daniele

AU - Liu, Chunyu

AU - Bandinelli, Stefania

AU - Boerwinkle, Eric

AU - Dehghan, Abbas

AU - Schwartz, Joel D.

AU - Psaty, Bruce M.

AU - Feinberg, Andrew P.

AU - Hou, Lifang

AU - Ferrucci, Luigi

AU - Sotoodehnia, Nona

AU - Matullo, Giuseppe

AU - Peters, Annette

AU - Fornage, Myriam

AU - Assimes, Themistocles L.

AU - Whitsel, Eric A.

AU - Levy, Daniel

AU - Baccarelli, Andrea A.

PY - 2019/8/20

Y1 - 2019/8/20

N2 - BACKGROUND: DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts. METHODS: Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts. RESULTS: Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts. CONCLUSION: Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.

AB - BACKGROUND: DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts. METHODS: Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts. RESULTS: Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts. CONCLUSION: Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.

KW - coronary artery disease

KW - coronary heart disease

KW - epigenetics

KW - gene expression regulation

KW - genomics

UR - http://www.scopus.com/inward/record.url?scp=85071560527&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85071560527&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.118.039357

DO - 10.1161/CIRCULATIONAHA.118.039357

M3 - Article

C2 - 31424985

AN - SCOPUS:85071560527

SN - 0009-7322

VL - 140

SP - 645

EP - 657

JO - Circulation

JF - Circulation

IS - 8

ER -

Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease

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