Between 30 and 50 million people in Bangladesh have been chronically exposed to high levels of arsenic, a class I human carcinogen, through contaminated drinking water. Although not clearly understood, based on current evidence, arsenic most likely exerts its carcinogenic effect through oxidative stress mediated DNA damage. While skin cancer and its precursor lesions are the most common arsenic-related conditions, there are wide variations in risk. We propose to examine the novel hypotheses that variants in the oxidative stress genes involved in arsenic-induced oxidative DNA damage and in DNA repair genes involved in the repair of this damage, are related to the risk of skin cancers and their precursor skin lesions, either independently or by modifying the effects of arsenic and these effects may be influenced by host antioxidant status measured by serum carotenoids, tocopherol and selenium. These hypotheses are supported by our strong preliminary data. Using existing resources (stored genomic DNA and comprehensive arsenic exposure and clinical data) from our ongoing prospective cohort study of 12,000 individuals, we propose to examine our hypotheses through a series of case-control and case-cohort analyses among 1,200 already identified skin lesions cases, 400 yet-to-be diagnosed skin cancer cases and 1,200 already identified random cohort members as controls. We will genotype the skin lesion, skin cancer and control subjects for 13 polymorphisms in the 4 oxidative stress genes (MPO, CAT, MnSOD, and GPX) and 6 DNA repair genes (OGG1, XPD, XRCC1, XRCC3, LIG1 and LIG4) using the high-throughput FP-TDI method established in our laboratory. The effect of the polymorphisms on arsenic-induced skin cancers and premalignant skin lesions, both independently and jointly with arsenic exposure, will be evaluated by estimating relatives risks from Cox's proportional hazards regression models. The proposed study is the first to investigate these novel hypotheses and has several scientific, methodological, logistic and practical strengths. Data generated will have implications not only for the massive public health issue relevant for millions of people in an underdeveloped country but also for arsenic exposed populations in other countries, including the US.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA102484-04
Application #
7484806
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Starks, Vaurice
Project Start
2004-04-01
Project End
2009-02-28
Budget Start
2007-09-01
Budget End
2008-02-29
Support Year
4
Fiscal Year
2007
Total Cost
$394,292
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Ponomarenko, Olena; La Porte, Paul F; Singh, Satya P et al. (2017) Selenium-mediated arsenic excretion in mammals: a synchrotron-based study of whole-body distribution and tissue-specific chemistry. Metallomics 9:1585-1595
Kibriya, Muhammad G; Jasmine, Farzana; Parvez, Faruque et al. (2017) Association between genome-wide copy number variation and arsenic-induced skin lesions: a prospective study. Environ Health 16:75
Chen, Yu; Wu, Fen; Saito, Eiko et al. (2017) Association between type 2 diabetes and risk of cancer mortality: a pooled analysis of over 771,000 individuals in the Asia Cohort Consortium. Diabetologia 60:1022-1032
Gao, Jianjun; Tong, Lin; Argos, Maria et al. (2015) The Genetic Architecture of Arsenic Metabolism Efficiency:A SNP-Based Heritability Study of Bangladeshi Adults. Environ Health Perspect 123:985-92
Pesola, Gene R; Argos, Maria; Chen, Yu et al. (2015) Dipstick proteinuria as a predictor of all-cause and cardiovascular disease mortality in Bangladesh: A prospective cohort study. Prev Med 78:72-7
Pierce, Brandon L; Tong, Lin; Chen, Lin S et al. (2014) Mediation analysis demonstrates that trans-eQTLs are often explained by cis-mediation: a genome-wide analysis among 1,800 South Asians. PLoS Genet 10:e1004818
Zheng, Wei; McLerran, Dale F; Rolland, Betsy A et al. (2014) Burden of total and cause-specific mortality related to tobacco smoking among adults aged ? 45 years in Asia: a pooled analysis of 21 cohorts. PLoS Med 11:e1001631
Pierce, Brandon L; Tong, Lin; Argos, Maria et al. (2013) Arsenic metabolism efficiency has a causal role in arsenic toxicity: Mendelian randomization and gene-environment interaction. Int J Epidemiol 42:1862-71
Naujokas, Marisa F; Anderson, Beth; Ahsan, Habibul et al. (2013) The broad scope of health effects from chronic arsenic exposure: update on a worldwide public health problem. Environ Health Perspect 121:295-302
Lin, Yingsong; Fu, Rong; Grant, Eric et al. (2013) Association of body mass index and risk of death from pancreas cancer in Asians: findings from the Asia Cohort Consortium. Eur J Cancer Prev 22:244-50

Showing the most recent 10 out of 65 publications