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

描述（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主要关注点。必须对砷相关糖尿病的前瞻性证据和机制进行调查。目的：探讨无机砷暴露、代谢及基因-砷相互作用在糖尿病、胰岛素抵抗、？在2,717名强心家族研究（SHFS）参与者中，2,717名年龄在18岁以上，基线时无糖尿病的患者的细胞功能障碍和代谢综合征。初步研究：我们在亚利桑那州、俄克拉荷马州和达科他州参加强心研究（SHS）的45-74岁的美国印第安人中发现尿砷浓度与糖尿病患病率之间存在关联。在10年的随访中，尿砷浓度和甲基化排泄模式保持不变。尿中甲基胂酸盐比例的遗传力为0.52。在一个小的连锁研究中，我们检测到潜在的数量性状位点与甲基转移酶基因的基因组区域接近%MMA。设计和设置：SHS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、后代的配偶和孙子。在基线和2011年的随访访视时，可获得人口统计学、生活方式和医学信息以及空腹血糖和胰岛素、血脂、高血压终点、体重指数、腰围和臀围的测量结果。尿样和血液DNA样品储存在-70 ℃下。暴露评估：我们将分别使用电感耦合等离子体质谱（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优先考虑并测量与砷代谢和毒性相关的候选基因中的约1，500个SNP。我们将使用代谢芯片测量与糖尿病性状相关的候选基因中的SNP，代谢芯片是一种用于糖尿病和心脏代谢性状的高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尿砷浓度与糖尿病和代谢综合征发病率的前瞻性相关性，以及稳态模型评估的变化，以量化胰岛素抵抗（HOMA-IR）和？细胞功能障碍（HOMA-B）。基因砷相互作用将估计使用主成分分析和占人口分层使用基因组控制。意义：通过研究无机砷对糖尿病、胰岛素抵抗、？细胞功能障碍和代谢综合征，并通过确定遗传易感因素，这项研究可以告知砷-糖尿病的关系，并影响预防和控制砷暴露在饮用水和食品在美国和国外。

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.