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      Genome-Wide Association Study Identifies Chromosome 10q24.32 Variants Associated with Arsenic Metabolism and Toxicity Phenotypes in Bangladesh

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          Abstract

          Arsenic contamination of drinking water is a major public health issue in many countries, increasing risk for a wide array of diseases, including cancer. There is inter-individual variation in arsenic metabolism efficiency and susceptibility to arsenic toxicity; however, the basis of this variation is not well understood. Here, we have performed the first genome-wide association study (GWAS) of arsenic-related metabolism and toxicity phenotypes to improve our understanding of the mechanisms by which arsenic affects health. Using data on urinary arsenic metabolite concentrations and approximately 300,000 genome-wide single nucleotide polymorphisms (SNPs) for 1,313 arsenic-exposed Bangladeshi individuals, we identified genome-wide significant association signals (P<5×10 −8) for percentages of both monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) near the AS3MT gene (arsenite methyltransferase; 10q24.32), with five genetic variants showing independent associations. In a follow-up analysis of 1,085 individuals with arsenic-induced premalignant skin lesions (the classical sign of arsenic toxicity) and 1,794 controls, we show that one of these five variants (rs9527) is also associated with skin lesion risk (P = 0.0005). Using a subset of individuals with prospectively measured arsenic (n = 769), we show that rs9527 interacts with arsenic to influence incident skin lesion risk (P = 0.01). Expression quantitative trait locus (eQTL) analyses of genome-wide expression data from 950 individual's lymphocyte RNA suggest that several of our lead SNPs represent cis-eQTLs for AS3MT (P = 10 −12) and neighboring gene C10orf32 (P = 10 −44), which are involved in C10orf32-AS3MT read-through transcription. This is the largest and most comprehensive genomic investigation of arsenic metabolism and toxicity to date, the only GWAS of any arsenic-related trait, and the first study to implicate 10q24.32 variants in both arsenic metabolism and arsenical skin lesion risk. The observed patterns of associations suggest that MMA% and DMA% have distinct genetic determinants and support the hypothesis that DMA is the less toxic of these two methylated arsenic species. These results have potential translational implications for the prevention and treatment of arsenic-associated toxicities worldwide.

          Author Summary

          Exposure to arsenic through drinking water is a serious public health issue in many countries, including Bangladesh and the United States. Although there is substantial inter-individual variation in arsenic metabolism and toxicity, the biological basis of this variation is not well understood. Here, we have conducted the first genome-wide association study of arsenic-related traits within a unique population cohort of arsenic-exposed Bangladeshi individuals. Using data on 1,313 well-characterized individuals, we identify multiple association signals for urinary arsenic metabolite concentrations in the 10q24.32 regions, near the AS3MT (arsenite methyltransferase) gene. In a subsequent analysis of >2,000 individuals, we show for the first time that variants that influence arsenic metabolism can also influence risk for arsenical skin lesions (the classical sign of arsenic toxicity) through interaction with arsenic exposure. Using array-based genome-wide gene expression data, we show that several of our lead genetic variants are associated with expression of AS3MT and neighboring gene C10orf32, providing a potential mechanism by which 10q24.32 variants influence arsenic metabolism and toxicity. Knowledge of variation in this region and associated biological processes could be used to develop intervention and pharmacological strategies aimed at preventing large numbers of arsenic-related deaths in arsenic-exposed populations.

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          Most cited references 40

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          Arsenic exposure from drinking water, and all-cause and chronic-disease mortalities in Bangladesh (HEALS): a prospective cohort study.

          Millions of people worldwide are chronically exposed to arsenic through drinking water, including 35-77 million people in Bangladesh. The association between arsenic exposure and mortality rate has not been prospectively investigated by use of individual-level data. We therefore prospectively assessed whether chronic and recent changes in arsenic exposure are associated with all-cause and chronic-disease mortalities in a Bangladeshi population. In the prospective cohort Health Effects of Arsenic Longitudinal Study (HEALS), trained physicians unaware of arsenic exposure interviewed in person and clinically assessed 11 746 population-based participants (aged 18-75 years) from Araihazar, Bangladesh. Participants were recruited from October, 2000, to May, 2002, and followed-up biennially. Data for mortality rates were available throughout February, 2009. We used Cox proportional hazards model to estimate hazard ratios (HRs) of mortality, with adjustment for potential confounders, at different doses of arsenic exposure. 407 deaths were ascertained between October, 2000, and February, 2009. Multivariate adjusted HRs for all-cause mortality in a comparison of arsenic at concentrations of 10.1-50.0 microg/L, 50.1-150.0 microg/L, and 150.1-864.0 microg/L with at least 10.0 microg/L in well water were 1.34 (95% CI 0.99-1.82), 1.09 (0.81-1.47), and 1.68 (1.26-2.23), respectively. Results were similar with daily arsenic dose and total arsenic concentration in urine. Recent change in exposure, measurement of total arsenic concentrations in urine repeated biennially, did not have much effect on the mortality rate. Chronic arsenic exposure through drinking water was associated with an increase in the mortality rate. Follow-up data from this cohort will be used to assess the long-term effects of arsenic exposure and how they might be affected by changes in exposure. However, solutions and resources are urgently needed to mitigate the resulting health effects of arsenic exposure. US National Institutes of Health. Copyright 2010 Elsevier Ltd. All rights reserved.
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            Health Effects of Arsenic Longitudinal Study (HEALS): description of a multidisciplinary epidemiologic investigation.

            Health Effects of Arsenic Longitudinal Study (HEALS), a multidisciplinary and large prospective cohort study in Araihazar, Bangladesh, was established to evaluate the effects of full-dose range arsenic (As) exposure on various health outcomes, including premalignant and malignant skin tumors, total mortality, pregnancy outcomes, and children's cognitive development. In this paper, we provide descriptions of the study methods including study design, study population, data collection, response rates, and exposure and outcome assessments. We also present characteristics of the study participants including the distribution of exposure and the prevalence of skin lesion at baseline recruitment. A total of 11,746 married men and women between 18 and 75 years of age participated in the study at baseline (a response rate of 98%) and completed a full questionnaire interview that included a food frequency questionnaire, with a response rate of 98%. Among the 98% of the participants who completed the clinical evaluation, over 90% provided blood samples and spot urine samples. Higher educational status, male gender, and presence of premalignant skin lesions were associated with an increased likelihood of providing blood and urine samples. Older participants were less likely to donate a blood sample. About one-third of the participants consumed water from a well with As concentration in each of three groups: >100 microg/l, 25-100 microg/l, and <25 microg/l. Average urinary As concentrations were 140 and 136 microg/l for males and females, respectively. HEALS has several unique features, including a prospective study design, comprehensive assessments of both past and future changes in As exposure at the individual level, a large repository of biological samples, and a full dose range of As exposures in the study population. HEALS is a valuable resource for examining novel research questions on the health effects of As exposure.
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              Cancer potential in liver, lung, bladder and kidney due to ingested inorganic arsenic in drinking water.

               C Chen,  Gary Chen,  M Wu (1992)
              In order to compare risk of various internal organ cancers induced by ingested inorganic arsenic and to assess the differences in risk between males and females, cancer potency indices were calculated using mortality rates among residents in an endemic area of chronic arsenicism on the southwest coast of Taiwan, and the Armitage-Doll multistage model. Based on a total of 898,806 person-years as well as 202 liver cancer, 304 lung cancer, 202 bladder cancer and 64 kidney cancer deaths, a significant dose-response relationship was observed between arsenic level in drinking water and mortality of the cancers. The potency index of developing cancer of the liver, lung, bladder and kidney due to an intake of 10 micrograms kg day of arsenic was estimated as 4.3 x 10(-3), 1.2 x 10(-2), 1.2 x 10(-2), and 4.2 x 10(-3), respectively, for males; as well as 3.6 x 10(-3), 1.3 x 10(-2), 1.7 x 10(-2), and 4.8 x 10(-3), respectively, for females in the study area. The multiplicity of inorganic arsenic-induced carcinogenicity without showing any organotropism deserves further investigation.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                February 2012
                February 2012
                23 February 2012
                : 8
                : 2
                Affiliations
                [1 ]Department of Health Studies, The University of Chicago, Chicago, Illinois, United States of America
                [2 ]Comprehensive Cancer Center, The University of Chicago, Chicago, Illinois, United States of America
                [3 ]Columbia University and University of Chicago Research Office in Bangladesh, Dhaka, Bangladesh
                [4 ]Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York, United States of America
                [5 ]International Center for Diarrheal Disease Research, Dhaka, Bangladesh
                [6 ]Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, United States of America
                [7 ]Departments of Medicine and Human Genetics, The University of Chicago, Chicago, Illinois, United States of America
                University of Oxford, United Kingdom
                Author notes

                Conceived and designed the experiments: HA JHG MGK. Performed the experiments: MGK FJ RR SR RP-B VS MR-Z. Analyzed the data: BLP LT FP MA. Contributed reagents/materials/analysis tools: AA IQ SKH SA TI MY MR JAB MVG. Wrote the paper: BLP HA.

                Article
                PGENETICS-D-11-02123
                10.1371/journal.pgen.1002522
                3285587
                22383894
                Pierce et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 10
                Categories
                Research Article
                Medicine
                Epidemiology
                Global Health
                Public Health
                Toxicology

                Genetics

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