Inorganic arsenic in water and food are global health problems. Increasing epidemiologic and experimental evidence supports the role of low-moderate inorganic arsenic exposure as a cardiovascular disease (CVD) risk factor. In the Strong Heart Study (SHS), baseline urine arsenic concentrations were associated with incident CVD, supporting the need to investigate relevant mechanisms for arsenic related CVD, including epigenetic modifications. Objective: To investigate (1) if DNA epigenetic modifications mediate the association between arsenic and CVD and (2) if genetic variability modifies epigenetic mediation of arsenic related CVD in 3,574 SHS participants 45-74 years old and free of CVD at baseline. Preliminary studies: In a pilot study in the SHS, arsenic metabolism, measured by the relative proportion of arsenic species in urine, was associated with global DNA methylation and hydroxymethylation and arsenic exposure was associated with a hypomethylated region of AS3MT, the gene that codes a major methyltransferase involved in arsenic metabolism. In linkage and fine-mapping studies, genetic variants in the AS3MT region of the genome were associated with urine measures of arsenic metabolism. Design and setting: Population-based prospective cohort study of American Indian men and women from Arizona, Oklahoma and North/South Dakota recruited in 1989-1991 and followed through 2008 as part of the SHS. Data collection: Urine arsenic measures (reflecting long-term exposure), DNA samples to measure epigenetic modifications and genetic polymorphisms, CVD follow-up including coronary heart disease, stroke, peripheral artery disease and carotid plaque, and extensive data characterizing CVD and its risk factors are available. Epigenetic assessment: We will measure genome- wide blood DNA methylation at baseline using state-of-the-art high throughput technology to identify specific DNA methylation that may mediate the relationship between arsenic and incident CVD endpoints and validate the most promising regions using bisulfite pyrosequencing. Genetic assessment: We will measure 96 SNPs previously related to arsenic metabolism and toxicity in the Strong Heart Family Study, conducted in the same communities as the SHS. SNPs in candidate genes related to CVD are already available in the SHS. Statistical analysis: To evaluate if DNA epigenetic modifications mediate the association between arsenic and CVD, the following conditions will need to be met: (1) arsenic is associated with CVD (already confirmed), (2) arsenic is associated with DNA methylation, (3) DNA methylation is associated with CVD, conditional on arsenic exposure, and (4) attenuation of the arsenic-CVD association conditional on DNA methylation. Gene- epigene interactions will be assessed via general linear models and likelihood ratio tests. Significance: By investigating the contribution of arsenic epigenetics to CVD, this study can reveal novel mechanisms for arsenic health effects, identify susceptible populations, and inform risk assessment, with implications forthe prevention and control of arsenic exposure in drinking water and food in the US and abroad.

Public Health Relevance

Increasing evidence supports the role of arsenic exposure in cardiovascular disease development. We will evaluate if epigenetic modifications and their interactions with genetic markers mediate the association of arsenic with cardiovascular disease in American Indian communities. This study can provide insight into the arsenic-cardiovascular relationship and inform recommendations for arsenic levels in drinking water and food.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
7R01ES025216-03
Application #
9416700
Study Section
Special Emphasis Panel (ZRG1-PSE-Q (90))
Program Officer
Finn, Symma
Project Start
2015-06-15
Project End
2019-03-31
Budget Start
2017-01-12
Budget End
2017-03-31
Support Year
3
Fiscal Year
2016
Total Cost
$180,103
Indirect Cost
$49,525
Name
Columbia University (N.Y.)
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Balakrishnan, Poojitha; Navas-Acien, Ana; Haack, Karin et al. (2018) Arsenic-gene interactions and beta-cell function in the Strong Heart Family Study. Toxicol Appl Pharmacol 348:123-129
Oliver-Williams, Clare; Howard, Annie Green; Navas-Acien, Ana et al. (2018) Cadmium body burden, hypertension, and changes in blood pressure over time: results from a prospective cohort study in American Indians. J Am Soc Hypertens 12:426-437.e9
Jones, Miranda R; Tellez-Plaza, Maria; Vaidya, Dhananjay et al. (2018) Ethnic, geographic and dietary differences in arsenic exposure in the multi-ethnic study of atherosclerosis (MESA). J Expo Sci Environ Epidemiol :
Balakrishnan, Poojitha; Vaidya, Dhananjay; Voruganti, V Saroja et al. (2018) Genetic Variants Related to Cardiometabolic Traits Are Associated to B Cell Function, Insulin Resistance, and Diabetes Among AmeriCan Indians: The Strong Heart Family Study. Front Genet 9:466
Spratlen, Miranda J; Grau-Perez, Maria; Best, Lyle G et al. (2018) The Association of Arsenic Exposure and Arsenic Metabolism with the Metabolic Syndrome and its Individual Components: Prospective Evidence from the Strong Heart Family Study. Am J Epidemiol :
Sanchez, Tiffany R; Powers, Martha; Perzanowski, Matthew et al. (2018) A Meta-analysis of Arsenic Exposure and Lung Function: Is There Evidence of Restrictive or Obstructive Lung Disease? Curr Environ Health Rep 5:244-254
Spratlen, Miranda J; Grau-Perez, Maria; Umans, Jason G et al. (2018) Arsenic, one carbon metabolism and diabetes-related outcomes in the Strong Heart Family Study. Environ Int 121:728-740
Nigra, Anne E; Nachman, Keeve E; Love, David C et al. (2017) Poultry Consumption and Arsenic Exposure in the U.S. Population. Environ Health Perspect 125:370-377
Moon, Katherine A; Oberoi, Shilpi; Barchowsky, Aaron et al. (2017) A dose-response meta-analysis of chronic arsenic exposure and incident cardiovascular disease. Int J Epidemiol 46:1924-1939
Nachman, Keeve E; Love, David C; Baron, Patrick A et al. (2017) Nitarsone, Inorganic Arsenic, and Other Arsenic Species in Turkey Meat: Exposure and Risk Assessment Based on a 2014 U.S. Market Basket Sample. Environ Health Perspect 125:363-369

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