Biological mechanisms underlying inherited genetic effects on arsenic metabolism

砷代谢遗传效应的生物学机制

基本信息

批准号：
10727165
负责人：
Brandon Lee Pierce
金额：
$ 45.74万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-02 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10727165
关键词：
Affect Alleles Arsenic Arsenic Poisoning Arsenicals Arsenites Biological Carbon Cardiovascular Diseases Catabolism Cell Line Cellular biology Classification Clinical Clustered Regularly Interspaced Short Palindromic Repeats Code Country Disease Dose Enzymes Epidemiology Excision Exons Exposure to Gene Targeting Genes Genetic Genetic Predisposition to Disease Genetic Transcription Genetic Variation Goals Health Histidine Homozygote Human Impact evaluation Impaired cognition Individual Individual Differences Inherited Intervention Investigation Link Liver Lung Malignant Neoplasms Maps Mediating Metabolism Methionine Methylation Methyltransferase Minor Outcome Pathway interactions Persons Predisposition Process Prostate Protein Truncation Proteins Publishing Risk Risk Estimate Role Sampling Signal Transduction Single Nucleotide Polymorphism Site Skin Therapeutic Therapeutic Intervention Tissues Toxic effect Translations Urine Valine Variant Water consumption candidate selection causal variant cognitive development contaminated water design environmental toxicology epidemiology study experience exposed human population folic acid metabolism genetic variant genome wide association study human tissue improved innovation mRNA Expression methyl group multi-ethnic protein expression protein structure therapy development toxicant

项目摘要

PROJECT SUMMARY/ABSTRACT Over 100 million people in over 70 countries consume water that is contaminated with inorganic arsenic (iAs), a toxicant that has been linked to health risks that include cancer, cardiovascular disease, and impaired cognitive development. Susceptibility to iAs toxicity is partially determined by genetic factors that influence an individual’s ability to metabolize iAs, a process that facilitates the removal of arsenic from the body (in urine). A major focus of epidemiological research on iAs exposure has been identifying inherited genetic variation that influences arsenic metabolism efficiency (AME) in order to (1) enable classification of individuals based on toxicity risk and (2) elucidate the biological mechanism underlying inter-individual differences in AME to inform the development of interventions that reduce toxicity risk. While prior studies have successfully identified genetic variants associated with AME and toxicity risk, their biological mechanisms are not fully understood. The long-term goal of this project is to utilize emerging and innovative gene-editing approaches to functionally elucidate the mechanisms by which SNPs impact cellular arsenic metabolism in humans. The objective of this proposal is to functionally define the causal FTCD and AS3MT SNPs that we have previously established as strongly associated with AME in human populations exposed to arsenic. Our central hypotheses are (1) the minor allele at FTCD SNP rs61735836 modifies enzymatic activity thus reducing arsenic methylation and (2) the causal AS3MT SNP(s) reduce AS3MT RNA and protein expression, also leading to reduced arsenic methylation. Completion of these studies will define a mechanistic framework for the investigation of additional SNPs related to arsenic metabolism. Identifying causal variants that affect AME and understanding their mechanisms will be broadly relevant to the many diseases for which arsenic exposure impacts risk, because these SNPs likely impact internal dose of arsenic.

项目概要/摘要 70 多个国家的 1 亿多人饮用的水受到无机物污染砷 (iAs)，一种与健康风险相关的有毒物质，包括癌症、心血管疾病疾病和认知发育受损是部分原因。由影响个体代谢 iAs 能力的遗传因素决定，这是一个过程有助于从体内（尿液中）去除砷。关于砷暴露的研究一直在确定影响砷的遗传变异代谢效率 (AME)，以便 (1) 根据毒性对个体进行分类 (2) 阐明 AME 个体间差异背后的生物学机制为降低毒性风险的干预措施的制定提供信息，而先前的研究已经表明了这一点。成功鉴定出与 AME 和毒性风险相关的遗传变异，其生物学特性该项目的长期目标是利用新兴机制。以及创新的基因编辑方法，从功能上阐明其机制 SNP 影响人类细胞砷代谢。该提案的目的是：从功能上定义我们之前建立的因果 FTCD 和 AS3MT SNP 与暴露于砷的人群中的 AME 密切相关。假设是 (1) FTCD SNP rs61735836 的次要等位基因因此改变酶活性减少砷甲基化和 (2) 因果 AS3MT SNP 减少 AS3MT RNA 和蛋白质表达，也导致砷甲基化的完成。将定义一个机制框架来研究与砷相关的其他 SNP 识别影响 AME 的因果变异并了解其机制。与砷暴露影响风险的许多疾病广泛相关，因为这些 SNP 可能会影响砷的内部剂量。