Biomarkers for Arsenic Toxicity: Genetics, Epigenetics and Folate

砷毒性的生物标志物：遗传学、表观遗传学和叶酸

• 批准号: 8197853
• 负责人: Mary Gamble
• 金额: $ 45.73万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197853
• 关键词: Accounting; Adult; Affect; Age; Arsenic; Bangladesh; Biological; Biological Markers; Blood; Cacodylic Acid; Candidate Disease Gene; Carbon; Cardiovascular Diseases; Chronic; Clinical; Clinical Trials; Consensus; Controlled Clinical Trials; Country; Cystathionine; DNA; DNA Methylation; Development; Diagnostic; Disease; Disease Outcome; Drug Metabolic Detoxication; Epidemiology; Epigenetic Process; Evaluation; Exposure to; Folate; Folic Acid; Gender; Genes; Genetic; Genetic Polymorphism; Genotype; Goals; Guidelines; Half-Life; Hand; Health; High Prevalence; Human; Hyperhomocysteinemia; In Vitro; Individual; Intervention; Laboratory Animals; Leukocytes; Malignant Neoplasms; Measures; Metabolism; Methionine; Methylation; Methylenetetrahydrofolate reductase (NADPH); Methyltransferase; Mono-S; Nested Case-Control Study; Nutritional; Nutritional status; Outcome; Pathology; Pathway interactions; Population; Predisposition; Premalignant; Regulation; Risk; Role; Seminal; Single Nucleotide Polymorphism; Specimen; Supplementation; Testing; Therapeutic; Time; Toxic effect; Urine; Work; World Health Organization; cost; disorder risk; drinking water; follow-up; high risk; interest; methionine synthase reductase; monomethylarsonic acid; nutrition related genetics; programs; skin lesion; urinary

DESCRIPTION (provided by applicant): Current estimates indicate that as many as 100 million people in over 70 countries are drinking water with arsenic (As) concentrations up to 100 times the World Health Organization (WHO) guideline of 10 ug per liter. There is significant variability in progression from As exposure to clinical manifestations of disease, and it is thought that genetic and nutritional factors may together account for a substantial portion of this variability. Thus, this proposal seeks to develop biomarkers that predict risk for the development of arsenicosis. Ingested inorganic As (InAs) is methylated to methylarsonic (MMA) and dimethylarsinic (DMA) acids via folate- dependent one-carbon metabolism. A reduced capacity to fully methylate As to DMA is associated with reduced urinary elimination of As. DMAV is less toxic and has a much shorter circulating half-live than InAs, and it is rapidly excreted in urine. There is great inter-individual variability in As methylation capacity, and epidemiological evidence, including our own, suggests that people who are "good methylators" are at reduced risk for As-induced skin lesions, cancers and cardiovascular disease. However, a growing body of evidence from in vitro and laboratory animal studies indicates that the trivalent form of MMA, a requisite intermediate in the pathway toward DMA synthesis, is extremely toxic. Our work over the past several years in Bangladesh has made seminal findings regarding the strong impact of nutritional regulation of one-carbon metabolism on the inter-individual variability in As methylation, blood As levels, and risk for arsenic-induced skin lesions, e.g., our clinical trial demonstrated that folic acid supplementation lowered blood As and blood MMA concentrations. Our 1st aim is to conduct a nested case-control study of 1,000 incident premalignant skin lesion cases and 1,000 controls to test the hypotheses that the capacity to methylate As is influenced by As methyltransferase (AS3MT) genotypes and that AS3MT genotypes and As methylation are associated with risk for skin lesions. Our 2nd aim will examine whether polymorphisms in one-carbon metabolism candidate genes are associated with hyperhomocysteinemia (which is very common in this population, and is associated with reduced capacity to methylate As to DMA), with methylation of As, methylation of leukocyte DNA, and with risk for skin lesions. We will also examine whether these associations are influenced by folate status. Collectively, these aims will allow us to identify of a set of biomarkers (As metabolites, leukocyte DNA methylation, folate, B12, Hcys, and SNPs) to identify sub-groups of individuals who may be at increased risk for As-induced pathology utilizing biological specimens that are already in hand. These studies will also resolve the critical issue of whether or not a higher capacity to methylate As is beneficial. Results of these studies will create opportunities for evaluation of interventions among high risk groups. They will also result in the identification of biomarkers to facilitate targeted therapies that exploit the mechanisms involved in susceptibility, resulting in low-risk, low-cost therapeutic strategies that could potentially reduce disease risk for hundreds of thousands of people.

描述（由申请人提供）：当前的估计表明，超过70个国家 /地区的多达1亿人是砷（AS）浓度的饮用水，最多是世界卫生组织（WHO）指南每升10 ug的100倍。从暴露于疾病的临床表现方面的进展有显着差异，人们认为遗传和营养因素可能会占这种变异的很大一部分。因此，该提案试图开发预测砷症发展风险的生物标志物。通过叶酸依赖性的一碳代谢摄入的无机AS（INAS）被甲基化为甲基化（MMA）和二甲基氨基甲基（DMA）酸。 DMA完全甲基化的能力降低与尿液消除AS的减少有关。 DMAV的毒性较小，循环的半卵比INAS短得多，并且在尿液中迅速排泄。作为甲基化能力的个体间差异很大，包括我们自己的流行病学证据表明，“良好的甲基甲基机构”的人降低了AS诱导的皮肤病变，癌症和心血管疾病的风险。但是，来自体外和实验室动物研究的越来越多的证据表明，MMA的三价形式是DMA合成途径中必不可少的中间体，具有极高的毒性。在过去的几年中，我们在孟加拉国的工作已经对单碳代谢的营养调节对AS甲基化，血液作为水平以及砷诱导的皮肤损伤的风险的强烈影响提出了开创性的发现。我们的第一个目的是对1,000例事件前皮肤病变病例和1,000例对照进行嵌套的病例对照研究，以测试假设甲基化的能力，如AS甲基转移酶（AS3MT）基因型所影响的能力以及AS3MT基因型和AS3MT基因型和AS甲基化的能力与Skinyly的风险相关。我们的第二个目标将检查单碳代谢候选基因中的多态性是否与高质瘤性半胱氨酸血症有关（在该人群中非常普遍，并且与AS甲基化的甲基化能力降低了甲基化的能力），白细胞DNA的甲基化和甲基化的白细胞DNA甲基化以及皮肤生动的风险。我们还将检查这些关联是否受叶酸状况的影响。总的来说，这些目标将使我们能够识别一组生物标志物（作为代谢产物，白细胞DNA甲基化，叶酸，B12，HCY和SNP），以识别可能增加了使用已经存在的生物学标本的病理学风险的个体的亚组。这些研究还将解决一个关键问题，即是否具有更高的甲基化能力为有益的能力。这些研究的结果将为评估高风险群体的干预措施创造机会。它们还将导致生物标志物的鉴定，以促进靶向疗法，以利用易感性涉及的机制，从而产生低风险，低成本的治疗策略，从而有可能降低成千上万人的疾病风险。