Arsenic Exposure, Blood DNA Methylation, and Cardiovascular Disease

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.).

PMID: 35658476
PMCID: PMC10203287
DOI: 10.1161/CIRCRESAHA.122.320991

Arsenic Exposure, Blood DNA Methylation, and Cardiovascular Disease

Arce Domingo-Relloso et al. Circ Res. 2022.

. 2022 Jul 8;131(2):e51-e69.

doi: 10.1161/CIRCRESAHA.122.320991. Epub 2022 Jun 6.

Authors

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.).

PMID: 35658476
PMCID: PMC10203287
DOI: 10.1161/CIRCRESAHA.122.320991

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.

PubMed Disclaimer

Figures

**Figure 1.**
Protein-protein interaction network of differentially methylated positions associated with CVD and with arsenic in the Strong Heart Study. Arsenic-associated and CVD-associated DMPs were annotated to the nearest protein coding gene and included in a protein-protein interaction network. The interactions between nodes were obtained using STRING database v11.0,60 selecting all active interaction sources with a confidence score of 0.4. The network was analyzed and displayed using edge weighted spring embedded layout with Cytoscape v3.8.2.61.

**Figure 2.**
Summary of significant DMPs in mouse model of in utero arsenic exposure by gene element and the direction of differential methylation.

See this image and copyright information in PMC

References

1. Podgorski J, Berg M. Global threat of arsenic in groundwater. Science 2020;368(6493):845–850. - PubMed
1. IARC Working Group. 2009. Arsenic, metals, fibres, and dusts. IARC Monogr Eval Carcinog Risks Hum 100:11–465. - PMC - PubMed
1. Moon KA, Navas-Acien A, Grau-Pérez M, Francesconi KA, Goessler W, Guallar E, Umans JG, Best LG, Newman JD. Low-moderate urine arsenic and biomarkers of thrombosis and inflammation in the Strong Heart Study. Rahman M, ed. PLOS ONE 2017;12(8):e0182435. - PMC - PubMed
1. National Research Council. Critical aspects of EPA’s IRIS assessment of inorganic arsenic: Interim report. National Academies Press; 2013.
1. Chen C-J, Chiou H-Y, Chiang M-H, Lin L-J, Tai T-Y. Dose-Response Relationship Between Ischemic Heart Disease Mortality and Long-term Arsenic Exposure. Arteriosclerosis, Thrombosis, and Vascular Biology 1996;16(4):504–510. - PubMed

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Arsenic Exposure, Blood DNA Methylation, and Cardiovascular Disease

Affiliations

Arsenic Exposure, Blood DNA Methylation, and Cardiovascular Disease

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous