Genetic Susceptibility to Cardiovascular Effects of Arsenic Exposure Project summary cardiovascular disease (CVD) is the leading cause of death worldwide. Recent experimental studies support the hypothesis that As exposure leads to oxidative stress and vascular inflammation, a central mechanism to the development of atherosclerosis and CVD. Studies of other health effects of As exposure have suggested effect-modification by As methylation capacity and genetic susceptibility. However, epidemiologic studies of genetic susceptibility to the effects of As exposure on CVD risk are lacking. In the year 2000, we established the Health Effects of Arsenic Longitudinal Study (HEALS), a prospective cohort study of 11,746 participants (original cohort), in Araihazar, Bangladesh. In 2007, HEALS recruited another 8,288 participants (expansion cohort) to include a total of 20,034 participants. More than 90% of the cohort have exposed to As exposure at low-to-moderate levels (<300 5g/L), providing us with a unique opportunity to assess health effects of As exposure from drinking water at the levels of public health interest. As part of the parent study, cardiovascular outcomes of the cohort participants are being ascertained, and carotid artery intima-medial thickness (IMT) is being measured for 1,160 participants randomly selected from the original cohort. On the basis of these resources, our substantial pilot data, as well as cohort analyses which show a positive association between As exposure and CVD incidence and mortality, we propose a series of analyses to assess the genetic susceptibility to the effects of As exposure on the risk of atherosclerosis and CVD. We will evaluate whether the cardiovascular effects of As exposure differ by polymorphisms in genes related to As methylation (GSTM1, GSTT1, GSTO1, GSTP1, MTHFR, and AS3MT genes) and genes related to oxidative stress (NOS3, SOD2, and CYBA) and inflammation/endothelial dysfunction (TNF, IL6, ICAM1, and VCAM1) using a cross-sectional study of IMT with the subcohort of 1,160 participants, and a case-cohort study of CVD risk with 692 cases and the same subcohort of 1,160 participants from the original cohort. The strongest gene- As interaction will be tested again in a second case-cohort study with 305 cases and another subcohort of 520 participants selected from the expansion cohort. To further characterize the underlying mechanisms by which As exposure causes CVD, we will conduct a cross-sectional study with 300 subjects to evaluate the associations between As exposure and serum/urinary phenotypic markers for oxidative stress and inflammation. The proposed study will provide valuable knowledge about the pathophysiology and mechanism by which As exposure may lead to CVD and may also lead to improved prevention and risk assessment of As exposure.

Public Health Relevance

The proposed project aims to assess whether low-to-moderate level of inorganic arsenic from drinking water increases the risk of cardiovascular disease in genetic susceptible groups to oxidative stress, inflammation, and low As metabolism capacity. The proposed study will contribute to the knowledge about the pathophysiology and mechanism by which arsenic exposure may lead to cardiovascular diseases. The findings may also improve risk assessment of health effects of arsenic exposure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES017541-04
Application #
8295945
Study Section
Special Emphasis Panel (ZES1-JAB-G (R3))
Program Officer
Mcallister, Kimberly A
Project Start
2009-09-11
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$425,399
Indirect Cost
$88,893
Name
New York University
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
McClintock, Tyler R; Chen, Yu; Parvez, Faruque et al. (2014) Association between arsenic exposure from drinking water and hematuria: results from the Health Effects of Arsenic Longitudinal Study. Toxicol Appl Pharmacol 276:21-7
Ge, Wenzhen; Parvez, Faruque; Wu, Fen et al. (2014) Association between anthropometric measures of obesity and subclinical atherosclerosis in Bangladesh. Atherosclerosis 232:234-41
McClintock, Tyler R; Parvez, Faruque; Wu, Fen et al. (2014) Association between betel quid chewing and carotid intima-media thickness in rural Bangladesh. Int J Epidemiol 43:1174-82
Wu, Fen; Molinaro, Peter; Chen, Yu (2014) Arsenic Exposure and Subclinical Endpoints of Cardiovascular Diseases. Curr Environ Health Rep 1:148-162
Chen, Yu; Ge, Wenzhen; Parvez, Faruque et al. (2014) A prospective study of arm circumference and risk of death in Bangladesh. Int J Epidemiol 43:1187-96
Wu, Fen; Jasmine, Farzana; Kibriya, Muhammad G et al. (2014) Interaction between arsenic exposure from drinking water and genetic susceptibility in carotid intima-media thickness in Bangladesh. Toxicol Appl Pharmacol 276:195-203
Wu, Fen; Chen, Yu; Parvez, Faruque et al. (2013) A prospective study of tobacco smoking and mortality in Bangladesh. PLoS One 8:e58516
Chen, Yu; Wu, Fen; Liu, Mengling et al. (2013) A prospective study of arsenic exposure, arsenic methylation capacity, and risk of cardiovascular disease in Bangladesh. Environ Health Perspect 121:832-8
Chen, Yu; Wu, Fen; Graziano, Joseph H et al. (2013) Arsenic exposure from drinking water, arsenic methylation capacity, and carotid intima-media thickness in Bangladesh. Am J Epidemiol 178:372-81
Chen, Yu; Wu, Fen; Parvez, Faruque et al. (2013) Arsenic exposure from drinking water and QT-interval prolongation: results from the Health Effects of Arsenic Longitudinal Study. Environ Health Perspect 121:427-32

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