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。饮用水中的砷是居住在小型农村社区的美国人的主要担忧。必须调查与砷相关的糖尿病的前瞻性证据和发病机制。目的：探讨无机砷暴露和代谢及基因-砷相互作用在糖尿病、胰岛素抵抗、糖尿病、胰岛素抵抗、糖尿病、胰岛素抵抗等疾病发生发展中的作用。2,717名强心家族研究(SHFS)参与者中的细胞功能障碍和代谢综合征，E18岁，基线无糖尿病。初步研究：我们已经确定了来自亚利桑那州、俄克拉何马州和达科他州的45-74岁的美国印第安人的尿砷浓度与糖尿病患病率之间的关系，他们参加了强心脏研究(SHS)。经过10年的随访，尿砷浓度和甲基化排泄模式保持不变。尿中亚甲基硫酸酯(%MMA)的遗传度为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检测到了与%MMA相关的潜在数量性状基因座。设计和环境：SHFS是一项以人群为基础的前瞻性家庭研究，在1998-2005年间招募了SHS参与者的父母、配偶、子女、子女的配偶和孙子。人口、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、腰围和臀围的测量在基线和2011年前的后续访问中可用。尿样和血DNA样本保存在-70oC。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)测量尿总砷和尿砷形态浓度。遗传评估：我们将使用多重小组对与砷代谢和毒性相关的候选基因中的约1500个SNPs进行优先排序和测量。我们将使用代谢芯片测量与糖尿病特征相关的候选基因中的SNPs，这是一种针对糖尿病和心脏代谢特征的高性价比候选基因芯片。统计分析：我们将使用混合效应模型对二元和线性结果进行评估，以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？随着时间推移，细胞功能障碍(HOMA-B)。基因-砷的相互作用将使用主成分分析进行估计，并使用基因组控制来考虑种群分层。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，通过识别遗传易感因素，这项研究可以为砷与糖尿病的关系提供信息，并影响美国和国外饮用水和食物中砷暴露的预防和控制。

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.