Genetics of arsenic metabolism: fine-mapping and rare variant analysis

砷代谢的遗传学：精细定位和罕见变异分析

基本信息

批准号：
8674046
负责人：
Brandon Lee Pierce
金额：
$ 65.47万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-06 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8674046
关键词：
American American Indians Arsenic Arsenicals Bayesian Method Binding Biological Biological Markers Cardiovascular Diseases ChIP-seq Chromatin Chromosomes, Human, Pair 10 Chronic Classification Code Country DNA Data Databases Development Dietary Intervention Dose Elements Enzymes Epidemiologic Studies Epidemiology European Excretory function Family Food Contamination Functional RNA Future Gene Expression Genes Genetic Genetic Predisposition to Disease Genomics Genotype Health Heritability Hypersensitivity Individual Individual Differences Institution Intervention Knowledge Laboratories Link Malignant Neoplasms Maps Metabolism Methods Methylation Molecular Molecular Genetics Native Americans Outcome Pathway interactions Pattern Play Population Population Group Positioning Attribute Predisposition Prevention Process Relative (related person)Research Research Personnel Resources Risk Role Sample Size Sampling Signal Transduction Skin Cancer Specimen Squamous Cell Testing Toxic effect Urine Variant Water arsenite methyltransferase base cancer risk case control drinking water experience genetic association genetic variant genome wide association study genome-wide global health improved interest member mortality novel public health relevance rare variant respiratory skin lesion therapy development toxicant transcription factor urinary

项目摘要

DESCRIPTION (provided by applicant): Contamination of food and drinking water with arsenic is a serious global health issue, as arsenic exposure increases risk for cancer, cardiovascular disease, respiratory conditions, and overall mortality. Susceptibility to arsenic toxicity is partilly determined by genetic factors that influence an individual's capacity to metabolize arsenic, a process that facilitates the excretion of arsenic in urine. Identifying such genetic factors will enable classification of individuals based on toxicity risk and elucidate the biological mechanism underlying susceptibility to arsenic toxicity, informing the development of interventions that reduce toxicity. Prior research has demonstrated that there are at least two independent association signals in the 10q24.32 region (which contains the arsenic methytransferase gene; AS3MT). However, prior studies have been unable to identify the causal variants in this region due to lack of (1) complete data on all genetic variants in the region, (2) large sample sizes from multiple population groups, and (3) comprehensive functional annotation for non-coding variants. Furthermore, the potential effects of rare variants in this region have never been assessed. We propose to fill these knowledge gaps by sequencing this region in >4,500 individuals from three arsenic- exposed population groups: Bangladeshis, Native Americans, and European Americans. Within each of these groups, we will assess associations between variants in this region and arsenic methylation capacity (i.e., urinary arsenic metabolite percentages). Variations in patterns of association across ancestry groups will allow us to narrow-in on causal variants shared across populations and examine evidence for population-specific signals. Statistical evidence of causal association will be assessed using a Bayesian approach. Evidence of functionality will be assessed using annotation of non-coding variants based on prior evidence of local transcription factor binding (ChIP-Seq), DNaseI hypersensitivity, chromatin marks, and cis-gene expression. Evidence for gene-arsenic interaction will be assessed. We will determine if rare coding variants in the AS3MT gene collectively influence arsenic methylation capacity using gene-level association tests. To assess the implications of these variants for arsenic-related health outcomes, we will test associations between the 10q24.32 variants identified in aims 1-2 and risk for arsenical skin lesions (among Bangladeshi cases and controls) and squamous cell skin cancer (among European American cases and controls). Identifying potential causal variants and assessing the effects of rare variants is a logical and essential next step for elucidating the critical role of the 10q24.32 regon in arsenic metabolism and toxicity. The knowledge we are proposing to generate will enhance risk prediction, guide the development future research and prevention efforts, and clarify the biological mechanisms that underlie inter-individual differences in susceptibility to arsenic toxicity.

描述（由申请人提供）：食品和饮用水的砷污染是一个严重的全球健康问题，因为砷暴露会增加患癌症、心血管疾病、呼吸系统疾病和总体死亡率的风险。对砷中毒的易感性部分是由影响个体砷代谢能力的遗传因素决定的，砷代谢过程促进砷从尿液中排出。识别此类遗传因素将能够根据毒性风险对个体进行分类，并阐明砷毒性易感性的生物学机制，为减少毒性的干预措施的开发提供信息。先前的研究表明，10q24.32 区域（包含砷甲基转移酶基因；AS3MT）中至少有两个独立的关联信号。然而，先前的研究无法识别该地区的因果变异，因为缺乏（1）该地区所有遗传变异的完整数据，（2）来自多个人群，以及（3）非编码变异的综合功能注释。此外，从未评估过该区域罕见变异的潜在影响。我们建议通过对来自三个砷暴露人群（孟加拉国人、美洲原住民和欧洲裔美国人）的超过 4,500 名个体的该区域进行测序来填补这些知识空白。在每个组中，我们将评估该区域的变异与砷甲基化能力（即尿砷代谢物百分比）之间的关联。不同祖先群体之间关联模式的变化将使我们能够缩小人群之间共享的因果变异的范围，并检查人群特定信号的证据。将使用贝叶斯方法评估因果关联的统计证据。将根据局部转录因子结合 (ChIP-Seq)、DNaseI 超敏性、染色质标记和顺式基因表达的先前证据，使用非编码变体注释来评估功能证据。将评估基因-砷相互作用的证据。我们将使用基因水平关联测试来确定 AS3MT 基因中的罕见编码变异是否共同影响砷甲基化能力。为了评估这些变异对砷相关健康结果的影响，我们将测试目标 1-2 中确定的 10q24.32 变异与砷皮肤病变（孟加拉国病例和对照）和鳞状细胞皮肤癌（孟加拉国病例和对照）风险之间的关联。欧洲美国病例和对照）。识别潜在的因果变异并评估罕见变异的影响是阐明 10q24.32 区域在砷代谢和毒性中关键作用的合理且重要的下一步。我们提议产生的知识将加强风险预测，指导未来研究和预防工作的发展，并阐明砷毒性易感性个体间差异的生物学机制。