TY - JOUR
T1 - Arsenic Exposure, Blood DNA Methylation, and Cardiovascular Disease
AU - Domingo-Relloso, Arce
AU - Makhani, Kiran
AU - Riffo-Campos, Angela L.
AU - Tellez-Plaza, Maria
AU - Klein, Kathleen Oros
AU - Subedi, Pooja
AU - Zhao, Jinying
AU - Moon, Katherine A.
AU - Bozack, Anne K.
AU - Haack, Karin
AU - Goessler, Walter
AU - Umans, Jason G.
AU - Best, Lyle G.
AU - Zhang, Ying
AU - Herreros-Martinez, Miguel
AU - Glabonjat, Ronald A.
AU - Schilling, Kathrin
AU - Galvez-Fernandez, Marta
AU - Kent, Jack W.
AU - Sanchez, Tiffany R.
AU - Taylor, Kent D.
AU - Johnson, W. Craig
AU - Durda, Peter
AU - Tracy, Russell P.
AU - Rotter, Jerome I.
AU - Rich, Stephen S.
AU - Van Den Berg, David
AU - Kasela, Silva
AU - Lappalainen, Tuuli
AU - Vasan, Ramachandran S.
AU - Joehanes, Roby
AU - Howard, Barbara V.
AU - Levy, Daniel
AU - Lohman, Kurt
AU - Liu, Yongmei
AU - Fallin, M. Daniele
AU - Cole, Shelley A.
AU - Mann, Koren K.
AU - Navas-Acien, Ana
N1 - Funding Information:
The Strong Heart Study was supported by grants from the National Heart, Lung, and Blood Institute (NHLBI; contract numbers 75N92019D00027, 75N92019D00028, 75N92019D00029, and 75N92019D00030) and previous grants (R01HL090863, R01HL109315, R01HL109301, R01HL109284, R01HL109282, and R01HL109319 and cooperative agreements: U01HL41642, U01HL41652, U01HL41654, U01HL65520, and U01HL65521) and by the National Institute of Environmental Health Sciences (grant numbers R01ES021367, R01ES025216, P42ES010349, P30ES009089). The Framingham Heart Study is conducted and supported by the NHLBI in collaboration with Boston University (Contract No. N01-HC-25195, HHSN268201500001I, and 75N92019D00031). The laboratory work for this investigation was funded by the Division of Intramural Research, NHLBI, National Institutes of Health (NIH), and an NIH Director’s Challenge Award (D. Levy, Principal Investigator). The WHI (Women’s Health Initiative) is funded by the NHLBI, NIH, US Department of Health and Human Services through contracts, HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. A full list of the WHI investigators can be found at: https://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Long%20List.pdf . The datasets used for the analyses described in this manuscript in FHS and WHI were obtained from the NIH dbGaP at http://www.ncbi.nlm.nih.gov/sites/entrez?db=gap through accession phs000007.v30.p11 and phs000200.WHI.v11.p3, respectively. Molecular data for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the NHLBI. MESA (Multi-Ethnic Study of Atherosclerosis; phs001416.v1.p1) was performed at the Broad Institute of MIT and Harvard (3U54HG003067-13S1). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1, contract HHSN268201800002I; Broad RNA Seq, Proteomics HHSN268201600034I, University of Washington RNA Seq HHSN268201600032I, University of Southern California DNA Methylation HHSN268201600034I, Broad Metabolomics HHSN268201600038I). Phenotype harmonization, data management, sample-identity QC, and general study coordination, were provided by the TOPMed Data Coordinating Center (3R01HL-120393; U01HL-120393; contract HHSN268180001I). MESA and the MESA SHARe (SNP Health Association Resource) projects are conducted and supported by the NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, CA) and the Broad Institute of Harvard and Massachusetts Institute of Technology (Boston, MA) using the Affymetrix Genome-Wide Human single nucleotide polymorphism (SNP) Array 6.0. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, The Clinical and Translational Science Institute grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Infrastructure for the CHARGE Consortium (Cohorts for Heart and Aging Research in Genomic Epidemiology) is supported in part by the NHLBI grant R01HL105756. Also supported in part by the National Institutes for Diabetes and Digestive and Kidney Diseases contract R01-HL151855-01 and contract R01HL146860. A. Domingo-Relloso was supported by a fellowship from la Caixa Foundation (ID 100010434; fellowship code LCF/BQ/DR19/11740016). A.L. Riffo-Campos was supported by Maria Zambrano grant Number ZA21-063 for the requalification of the Spanish university system–NextGeneration European Union; and by ANID (National Agency of Development and Research)–Millennium Science Initiative Program - Nº NCS2021_013–SocioMed. K.K. Mann and K. Makhani were supported by a fellowship from the Fonds de recherche du Québec–Santé; by a grant from the Canadian Institutes of Health Research (no. PJT-166142); and by the Shuk Tak Liang Fellowship. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIH (United States) or the National Health Institute Carlos III (Spain). The funders had no role in the planning, conducting, analysis, interpretation, or writing of this study.
Publisher Copyright:
© 2022 Lippincott Williams and Wilkins. All rights reserved.
PY - 2022/7/8
Y1 - 2022/7/8
N2 - 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.
AB - 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.
KW - DNA methylation
KW - arsenic
KW - cardiovascular diseases
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U2 - 10.1161/CIRCRESAHA.122.320991
DO - 10.1161/CIRCRESAHA.122.320991
M3 - Article
C2 - 35658476
AN - SCOPUS:85134321203
SN - 0009-7330
VL - 131
SP - E51-E69
JO - Circulation Research
JF - Circulation Research
IS - 2
ER -