Repositorio
Institucional

Domingo-Relloso, Arce

Makhani, Kiran

Riffo-Campos, Angela L.

Tellez-Plaza, Maria

Klein, Kathleen Oros

Subedi, Pooja

Zhao, Jinying

Moon, Katherine A.

Bozack, Anne K.

Haack, Karin

Goessler, Walter

Umans, Jason G.

Best, Lyle G.

Zhang, Ying

Herreros-Martinez, Miguel

Glabonjat, Ronald A.

Schilling, Kathrin

Galvez-Fernandez, Marta

Kent, Jack W., Jr.

Sanchez, Tiffany R.

Taylor, Kent D.

Johnson, W. Craig

Durda, Peter

Tracy, Russell P.

Rotter, Jerome I.

Rich, Stephen S.

Van Den Berg, David

Kasela, Silva

Lappalainen, Tuuli

Vasan, Ramachandran S.

Joehanes, Roby

Howard, Barbara V.

Levy, Daniel

Lohman, Kurt

Liu, Yongmei

Fallin, M. Daniele

Cole, Shelley A.

Mann, Koren K.

Navas-Acien, Ana

Arsenic Exposure, Blood DNA Methylation, and Cardiovascular Disease

LIPPINCOTT WILLIAMS & WILKINS

CIRCULATION RESEARCH

en

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.

artículo original

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. N01HC-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 (3U54HG00306713S1). 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, N01HC-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 -N degrees NCS2021_013-SocioMed. K.K. Mann and K. Makhani were supported by a fellowship from the Fonds de recherche du Quebec-Sante, 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.

El estudio Strong Heart fue financiado por subvenciones del Instituto Nacional del Corazón, los Pulmones y la Sangre (NHLBI, números de contrato 75N92019D00027, 75N92019D00028, 75N92019D00029 y 75N92019D00030) y subvenciones anteriores (R01HL090863, R01HL109315, 109301, R01HL109284, R01HL109282 y R01HL109319 y cooperativos acuerdos: U01HL41642, U01HL41652, U01HL41654, U01HL65520 y U01HL65521) y por el Instituto Nacional de Ciencias de la Salud Ambiental (números de subvención R01ES021367, R01ES025216, P42ES010349, P30ES009089). El Framingham Heart Study es realizado y respaldado por el NHLBI en colaboración con la Universidad de Boston (contrato n.° N01HC-25195, HHSN268201500001I y 75N92019D00031). El trabajo de laboratorio para esta investigación fue financiado por la División de Investigación Intramuros, NHLBI, los Institutos Nacionales de Salud (NIH) y un Premio del Desafío del Director de los NIH (D. Levy, Investigador Principal). La WHI (Iniciativa de Salud de la Mujer) está financiada por el NHLBI, los NIH, el Departamento de Salud y Servicios Humanos de EE. UU. a través de contratos, HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C y HHSN268201600004C. Puede encontrar una lista completa de los investigadores de WHI en: https://www.whi.org/researchers/Documents%20%20Write% 20a% 20Paper/WHI%20Investigator%20Long%20List.pdf. Los conjuntos de datos utilizados para los análisis descritos en este manuscrito en FHS y WHI se obtuvieron del NIH dbGaP en http://www.ncbi.nlm.nih.gov/sites/entrez?db=gap mediante el acceso phs000007. v30.p11 y phs000200.WHI.v11.p3, respectivamente. El NHLBI apoyó los datos moleculares para el programa Trans-Omics in Precision Medicine (TOPMed). MESA (Estudio multiétnico de aterosclerosis, phs001416.v1. p1) se realizó en el Broad Institute del MIT y Harvard (3U54HG00306713S1). 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 Metilación del ADN HHSN268201600034I, Metabolómica amplia HHSN268201600038I). La armonización del fenotipo, la gestión de datos, el control de calidad de la identidad de la muestra y la coordinación general del estudio estuvieron a cargo del Centro de coordinación de datos de TOPMed (3R01HL-120393, U01HL-120393, contrato HHSN268180001I). Los proyectos MESA y MESA SHARe (SNP Health Association Resource) son realizados y respaldados por el NHLBI en colaboración con investigadores de MESA. El soporte para MESA lo brindan los contratos 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D0000. 3, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004 , N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01HC-95169, UL1-TR-000040, UL1-TR-001079, UL1 -TR-001420. La financiación para el genotipado SHARe fue proporcionada por el contrato NHLBI N02-HL-64278. La genotipificación se realizó en Affymetrix (Santa Clara, CA) y el Broad Institute de Harvard y el Instituto de Tecnología de Massachusetts (Boston, MA) utilizando el conjunto 6.0 de polimorfismo de nucleótido único (SNP) humano de todo el genoma de Affymetrix. El suministro de datos de genotipado fue apoyado en parte por el Centro Nacional para el Avance de las Ciencias Traslacionales, la subvención UL1TR001881 del Instituto de Ciencias Clínicas y Traslacionales y la subvención DK063491 del Instituto Nacional de Diabetes y Enfermedades Digestivas y Renales del Centro de Investigación de Diabetes (DRC) al sur de California. Centro de Investigación de Endocrinología de la Diabetes, La infraestructura para el Consorcio CHARGE (Cohortes para la Investigación del Corazón y el Envejecimiento en Epidemiología Genómica) está financiada en parte por la subvención R01HL105756 del NHLBI. También respaldado en parte por el contrato R01-HL151855-01 y el contrato R01HL146860 de los Institutos Nacionales de Diabetes y Enfermedades Digestivas y Renales. A. Domingo-Relloso contó con una beca de la Fundación la Caixa (ID 100010434, código de beca LCF/BQ/DR19/11740016). A.L. Riffo-Campos contó con el apoyo de la beca María Zambrano Número ZA21-063 para la recualificación del sistema universitario español-NextGeneration Unión Europea, y por ANID (Agencia Nacional de Desarrollo e Investigación)-Programa Iniciativa Científica del Milenio -N grados NCS2021_013-SocioMed. KK Mann y K. Makhani contaron con el apoyo de una beca del Fonds de recherche du Quebec-Sante, por una subvención de los Institutos Canadienses de Investigación en Salud (nº PJT-166142), y por la Beca Shuk Tak Liang. El contenido de este manuscrito es responsabilidad exclusiva de los autores y no representa necesariamente las opiniones oficiales de los NIH (Estados Unidos) o del Instituto Nacional de Salud Carlos III (España). Los financiadores no tuvieron ningún papel en la planificación, realización, análisis, interpretación o redacción de este estudio.

10.1161/CIRCRESAHA.122.320991

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arsenic

cardiovascular diseases

DNA methylation

CORONARY-HEART-DISEASE

ADAPTIVE ELASTIC-NET

UMBILICAL-CORD BLOOD

GENE-EXPRESSION

MYOCARDIAL-INFARCTION

CANCER-MORTALITY

DRINKING-WATER

RISK

ASSOCIATION

POPULATION

Sistemas cardíacos y cardiovasculares

Hematología

Enfermedad vascular periférica

arsénico

enfermedades cardiovasculares

metilación del ADN

ENFERMEDAD-CORONARIA

RED ELÁSTICA ADAPTATIVA

SANGRE DEL CORDÓN UMBILICAL

EXPRESIÓN-GÉNICA

INFARCIO-DE-MIOCARDIO

MORTALIDAD-CÁNCER

AGUA POTABLE

RIESGO

ASOCIACIÓN

POBLACIÓN

Arsenic Exposure, Blood DNA Methylation, and Cardiovascular Disease

E51

E69

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PMID: 35658476

ANID NCS2021_013

NHLBI 75N92019D00027

NHLBI 75N92019D00028

NHLBI 75N92019D00029

NHLBI 75N92019D00030

NIHES R01ES021367

NIHES R01ES025216

NIHES P42ES010349

NIHES P30ES009089

BU N01HC-25195

BU HHSN268201500001I

BU 75N92019D00031

NIH HHSN268201600018

NIH HHSN268201600001C

NIH HHSN268201600002C

NIH HHSN268201600003C

NIH HHSN268201600004C

IRC 3R01HL-117626-02S1

IRC HHSN268201800002I

IRC HHSN268201600034I

IRC HHSN268201600032I

IRC HHSN268201600038I

NHLBI N02-HL-64278

NHLBI R01HL105756

UCLA CSTI UL1TR001881

NIDKK DK06349

NIDKK R01-HL151855-01

NIDKK R01HL146860

CAIXA 100010434

CAIXA LCF/BQ/DR19/11740016

CIHR PJT-166142

MIT 3U54HG00306713S1

WOS:000821208900004