Arsenic Exposure, Genetic Determinants and Diabetes Risk in a Family Study

家庭研究中的砷暴露、遗传决定因素和糖尿病风险

• 批准号: 8266205
• 负责人: Wen Hong Linda Kao
• 金额: $ 68.84万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8266205
• 关键词: Accounting; American Indians; Area; Arizona; Arsenic; Blood specimen; Body fat; Body mass index; Candidate Disease Gene; Carbon; Cardiovascular Diseases; Cell physiology; Cells; Communities; Coupled; DNA; Data; Development; Diabetes Mellitus; Disease; Dose; Enrollment; Epidemiology; Excretory function; Exposure to; Extended Family; Family; Family Study; Family member; Food; Functional disorder; Gene Chips; Genes; Genetic; Genetic Determinism; Genetic Markers; Genetic Polymorphism; Genetic Predisposition to Disease; Genome; Genomics; Glycosylated Hemoglobin; Heart; Heritability; High Pressure Liquid Chromatography; Hip region structure; Human; Hypertension; Incidence; Insulin; Insulin Resistance; Life; Life Style; Lipids; Mass Spectrum Analysis; Measures; Medical; Metabolic; Metabolic syndrome; Metabolism; Methylation; Methyltransferase; Methyltransferase Gene; Modeling; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oklahoma; Outcome; Oxidoreductase; Parents; Participant; Pattern; Phase; Phenotype; Plasma; Population; Predisposition; Prevalence; Prevention; Public Health; Quantitative Trait Loci; Recommendation; Recruitment Activity; Risk; Risk Assessment; Risk Factors; Role; Rural; Rural Community; Sampling; Sampling Studies; Spouses; Stratification; Time; Toxic effect; Urine; Visit; base; cost effective; design; diabetes risk; drinking water; family structure; fasting glucose; follow-up; gene environment interaction; genetic analysis; grandchild; insight; member; offspring; population based; prospective; trait

DESCRIPTION (provided by applicant): Background: Increasing epidemiologic and experimental evidence supports the role of inorganic arsenic in the development of diabetes. Arsenic in drinking water is a major concern for US populations who live in small rural communities. Prospective evidence and mechanisms for arsenic related diabetes must be investigated. Objective: To evaluate the role of inorganic arsenic exposure and metabolism and gene-arsenic interactions in the development of diabetes, insulin resistance, ? cell dysfunction and the metabolic syndrome among 2,717 Strong Heart Family Study (SHFS) participants e18 year old who were free of diabetes at baseline. Preliminary studies: We have identified an association between urine arsenic concentrations and the prevalence of diabetes in American Indians 45-74 year old from Arizona, Oklahoma and the Dakotas who participated in the Strong Heart Study (SHS). Urine arsenic concentrations and methylation excretion patterns remained constant over a 10-year follow-up. The heritability of the proportion of monomethylarsonate (%MMA) in urine was 0.52. In a small linkage study, we detected potential quantitative trait loci associated with %MMA in areas of the genome close to methyltransferase genes. Design and setting: The SHFS is a population- based prospective family study that recruited parents, spouses, offspring, spouses of offspring and grandchildren of SHS participants in 1998-2005. Demographic, lifestyle and medical information and measures of fasting glucose and insulin, lipid profile, hypertension endpoints, body mass index, and waist and hip circumferences are available at baseline and follow-up visits through 2011. Urine samples and blood DNA samples were stored at -70oC. Exposure assessment: We will measure total urine arsenic and urine arsenic species concentrations using inductively coupled plasma-mass spectrometry (ICPMS) and high performance liquid chromatography-ICPMS (HPLC-ICPMS), respectively. Genetic assessment: We will prioritize and measure ~1,500 SNPs in candidate genes related to arsenic metabolism and toxicity using a multiplex panel. We will measure SNPs in candidate genes related to diabetes traits using the Metabo-chip, a highly cost- effective candidate gene chip for diabetes and cardiometabolic traits. Statistical analysis: We will use mixed- effect models for binary and linear outcomes to assess the prospective association of urine arsenic species concentrations at baseline with the incidence of diabetes and the metabolic syndrome and changes in the homeostatic model assessment to quantify insulin resistance (HOMA-IR) and ? cell dysfunction (HOMA-B) over time. Gene-arsenic interaction will be estimated using principle component analysis and accounting for population stratification using genomic control. Significance: By investigating the contribution of inorganic arsenic to diabetes, insulin resistance, ? cell dysfunction and the metabolic syndrome and by identifying genetic susceptibility factors, this study can inform the arsenic-diabetes relationship and impact the prevention and control of arsenic exposure in drinking water and food in the US and abroad. PUBLIC HEALTH RELEVANCE: Increasing evidence supports the role of arsenic exposure in the development of diabetes. This study will evaluate the role of arsenic exposure and metabolism and their interaction with genetic markers in the development of diabetes in American Indian communities. This study can provide insight into the arsenic- diabetes relationship and inform public health recommendations for arsenic levels in drinking water and food.

描述（由申请人提供）： 背景：越来越多的流行病学和实验证据支持无机砷在糖尿病发展中的作用。饮用水中的砷是生活在小型农村社区的美国人口的一个主要担忧。必须研究砷相关糖尿病的前瞻性证据和机制。目的：评估无机砷暴露和代谢以及基因砷相互作用在糖尿病、胰岛素抵抗、糖尿病、胰岛素抵抗等疾病发展中的作用。 2,717 名 18 岁强心家族研究 (SHFS) 参与者的细胞功能障碍和代谢综合征在基线时没有糖尿病。初步研究：我们已经确定参加强心研究 (SHS) 的来自亚利桑那州、俄克拉荷马州和达科他州的 45-74 岁美国印第安人的尿砷浓度与糖尿病患病率之间存在关联。在 10 年的随访中，尿液砷浓度和甲基化排泄模式保持恒定。尿液中胂酸单甲酯(%MMA)比例的遗传力为0.52。在一项小型连锁研究中，我们在靠近甲基转移酶基因的基因组区域中检测到与 %MMA 相关的潜在数量性状位点。设计和背景：SHFS 是一项基于人群的前瞻性家庭研究，招募了 1998-2005 年 SHS 参与者的父母、配偶、后代、后代的配偶和孙辈。人口统计、生活方式和医疗信息以及空腹血糖和胰岛素、血脂、高血压终点、体重指数以及腰围和臀围的测量数据可在 2011 年的基线和随访中获得。尿液样本和血液 DNA 样本储存在 -70oC。暴露评估：我们将分别使用电感耦合等离子体质谱法 (ICPMS) 和高效液相色谱-ICPMS (HPLC-ICPMS) 测量尿总砷和尿砷物质浓度。遗传评估：我们将使用多重面板对与砷代谢和毒性相关的候选基因中约 1,500 个 SNP 进行优先排序和测量。我们将使用Metabo-chip测量与糖尿病性状相关的候选基因中的SNP，Metabo-chip是一种针对糖尿病和心脏代谢性状的极具成本效益的候选基因芯片。统计分析：我们将使用二元和线性结果的混合效应模型来评估基线时尿液砷物质浓度与糖尿病和代谢综合征发病率的前瞻性关联，以及稳态模型评估的变化以量化胰岛素抵抗（HOMA-IR）和？随着时间的推移，细胞功能障碍（HOMA-B）。将使用主成分分析来估计基因-砷相互作用，并使用基因组控制来解释群体分层。意义：通过研究无机砷对糖尿病、胰岛素抵抗的影响，？这项研究可以了解砷与糖尿病的关系，并影响美国和国外饮用水和食品中砷暴露的预防和控制。 公共卫生相关性：越来越多的证据支持砷暴露在糖尿病发展中的作用。这项研究将评估砷暴露和代谢的作用及其与遗传标记在美洲印第安人社区糖尿病发展中的相互作用。这项研究可以深入了解砷与糖尿病的关系，并为饮用水和食品中砷含量的公共卫生建议提供参考。