Arsenic Exposure, Blood DNA Methylation, and Cardiovascular Disease

Arce Domingo-Relloso; Kiran Makhani; Angela L Riffo-Campos; Maria Tellez-Plaza; Kathleen Oros Klein; Pooja Subedi; Jinying Zhao; Katherine A Moon; Anne K Bozack; Karin Haack; Walter Goessler; Jason G Umans; Lyle G Best; Ying Zhang; Miguel Herreros-Martinez; Ronald A Glabonjat; Kathrin Schilling; Marta Galvez-Fernandez; Jack W Kent Jr; Tiffany R Sanchez; Kent D Taylor; W Craig Johnson; Peter Durda; Russell P Tracy; Jerome I Rotter; Stephen S Rich; David Van Den Berg; Silva Kasela; Tuuli Lappalainen; Ramachandran S Vasan; Roby Joehanes; Barbara V Howard; Daniel Levy; Kurt Lohman; Yongmei Liu; M Daniele Fallin; Shelley A Cole; Koren K Mann; Ana Navas-Acien

doi:10.1161/CIRCRESAHA.122.320991

Arsenic Exposure, Blood DNA Methylation, and Cardiovascular Disease

Circ Res. 2022 Jul 8;131(2):e51-e69. doi: 10.1161/CIRCRESAHA.122.320991. Epub 2022 Jun 6.

Authors

Arce Domingo-Relloso^{1

2

3}, Kiran Makhani⁴, Angela L Riffo-Campos^{5

6}, Maria Tellez-Plaza², Kathleen Oros Klein⁴, Pooja Subedi⁷, Jinying Zhao⁷, Katherine A Moon⁸, Anne K Bozack⁹, Karin Haack¹⁰, Walter Goessler¹¹, Jason G Umans^{12

13}, Lyle G Best¹⁴, Ying Zhang¹⁵, Miguel Herreros-Martinez¹⁶, Ronald A Glabonjat¹, Kathrin Schilling¹, Marta Galvez-Fernandez^{1

2}, Jack W Kent Jr¹⁰, Tiffany R Sanchez¹, Kent D Taylor¹⁷, W Craig Johnson¹⁸, Peter Durda¹⁹, Russell P Tracy¹⁹, Jerome I Rotter¹⁷, Stephen S Rich²⁰, David Van Den Berg²¹, Silva Kasela^{22

23}, Tuuli Lappalainen^{22

23}, Ramachandran S Vasan^{24

25}, Roby Joehanes^{26

27}, Barbara V Howard^{12

13}, Daniel Levy^{26

27}, Kurt Lohman²⁸, Yongmei Liu²⁸, M Daniele Fallin²⁹, Shelley A Cole¹⁰, Koren K Mann^{4

30}, Ana Navas-Acien¹

Affiliations

¹ Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, NY (A.D.-R., R.A.G., K.S., M.G.-F., T.R.S., A.N.-A.).
² Integrative Epidemiology Group, Department of Chronic Diseases Epidemiology, National Center for Epidemiology, Carlos III Health Institute, Madrid, Spain (A.D.-R., M.T.-P., M.G.-F.).
³ Department of Statistics and Operations Research (A.D.-R.), University of Valencia, Spain.
⁴ Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada (K.M., K.O.K., K.K.M.).
⁵ Department of Computer Science, ETSE (A.L.R.-C.), University of Valencia, Spain.
⁶ Millennium Nucleus on Sociomedicine (SocioMed) and Vicerrectoría Académica, Universidad de La Frontera, Temuco, Chile (A.L.R.-C.).
⁷ Department of Epidemiology, College of Public Health and Health Professions and College of Medicine, University of Florida, Gainesville (P.S., J.Z.).
⁸ Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (K.A.M.).
⁹ Department of Environmental Health Sciences, School of Public Health, University of California, Berkeley (A.K.B.).
¹⁰ Population Health Program, Texas Biomedical Research Institute, San Antonio' TX (K.H., J.W.K., S.A.C.).
¹¹ Institute of Chemistry - Analytical Chemistry for Health and Environment, University of Graz, Austria (W.G.).
¹² MedStar Health Research Institute, Hyattsville, MD. Now with Georgetown-Howard Universities Center for Clinical and Translational Science, Washington, DC (J.G.U., B.W.H.).
¹³ Georgetown-Howard Universities Center for Clinical and Translational Science, Washington, DC (J.G.U., B.V.H.).
¹⁴ Missouri Breaks Industries and Research, Inc, Eagle Butte, SD (L.G.B.).
¹⁵ Department of Biostatistics and Epidemiology, The University of Oklahoma Health Sciences Center (Y.Z.).
¹⁶ Bioinformatics Unit, Institute for Biomedical Research INCLIVA, Valencia, Spain (M.H.-M.).
¹⁷ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA (K.D.T., J.I.R.).
¹⁸ Department of Biostatistics, University of Washington, Seattle (W.C.J.).
¹⁹ Department of Pathology Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, VT (P.D., R.P.T.).
²⁰ Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA (S.S.R.).
²¹ Department of Population and Public Health Sciences, Keck School of Medicine of USC, University of Southern California, Los Angeles' CA (D.V.D.B.).
²² New York Genome Center (S.K., T.L.).
²³ Department of Systems Biology, Columbia University' NY (S.K., T.L.).
²⁴ National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA (R.S.V.).
²⁵ Sections of Preventive Medicine and Epidemiology and Cardiovascular Medicine, Department of Medicine, Department of Epidemiology, Boston University Schools of Medicine and Public Health, MA (R.S.V.).
²⁶ Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (R.J., D.L.).
²⁷ Framingham Heart Study, MA (R.J., D.L.).
²⁸ Department of Medicine, Duke University Medical Center, Durham, NC (K.L., Y.L.).
²⁹ Departments of Mental Health and Epidemiology, Johns Hopkins University, Baltimore, MD (M.D.F.).
³⁰ Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada (K.K.M.).

Abstract

Background: Epigenetic dysregulation has been proposed as a key mechanism for arsenic-related cardiovascular disease (CVD). We evaluated differentially methylated positions (DMPs) as potential mediators on the association between arsenic and CVD.

Methods: Blood DNA methylation was measured in 2321 participants (mean age 56.2, 58.6% women) of the Strong Heart Study, a prospective cohort of American Indians. Urinary arsenic species were measured using high-performance liquid chromatography coupled to inductively coupled plasma mass spectrometry. We identified DMPs that are potential mediators between arsenic and CVD. In a cross-species analysis, we compared those DMPs with differential liver DNA methylation following early-life arsenic exposure in the apoE knockout (apoE^-/-) mouse model of atherosclerosis.

Results: A total of 20 and 13 DMPs were potential mediators for CVD incidence and mortality, respectively, several of them annotated to genes related to diabetes. Eleven of these DMPs were similarly associated with incident CVD in 3 diverse prospective cohorts (Framingham Heart Study, Women's Health Initiative, and Multi-Ethnic Study of Atherosclerosis). In the mouse model, differentially methylated regions in 20 of those genes and DMPs in 10 genes were associated with arsenic.

Conclusions: Differential DNA methylation might be part of the biological link between arsenic and CVD. The gene functions suggest that diabetes might represent a relevant mechanism for arsenic-related cardiovascular risk in populations with a high burden of diabetes.

Keywords: DNA methylation; arsenic; cardiovascular diseases.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Animals
Apolipoproteins E
Arsenic* / toxicity
Atherosclerosis* / chemically induced
Atherosclerosis* / genetics
Cardiovascular Diseases* / chemically induced
Cardiovascular Diseases* / genetics
DNA Methylation
Female
Humans
Male
Mice
Middle Aged
Prospective Studies

Substances

Apolipoproteins E
Arsenic

Abstract

Publication types

MeSH terms

Substances

Grants and funding