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

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农村社区的美国人最关心的问题。必须对砷相关糖尿病的前瞻性证据和机制进行调查。目的：探讨无机砷暴露与代谢及基因-砷相互作用在糖尿病、胰岛素抵抗、？在2,717名18岁、基线无糖尿病的强心脏家族研究（SHFS）参与者中进行细胞功能障碍和代谢综合征的研究。初步研究：我们已经确定了来自亚利桑那州、俄克拉荷马州和达科他州参加强心脏研究（SHS）的45-74岁美国印第安人尿砷浓度与糖尿病患病率之间的关联。在10年的随访中，尿砷浓度和甲基化排泄模式保持不变。尿中单甲基膦酸盐（%MMA）的遗传率为0.52。在一项小型连锁研究中，我们在基因组靠近甲基转移酶基因的区域检测到与%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，在1998-2005年期间招募了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的测量、血脂、高血压终点、体重指数、腰围和臀围在基线和2011年的随访中都是可用的。尿液样本和血液DNA样本保存在-70℃。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）测量尿总砷和尿砷种浓度。遗传评估：我们将优先考虑并使用多重面板测量与砷代谢和毒性相关的候选基因中的约1500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的snp，代谢芯片是一种高成本效益的糖尿病和心脏代谢性状候选基因芯片。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砷种类浓度与糖尿病和代谢综合征发生率的前瞻性关联，以及在体内平衡模型评估中量化胰岛素抵抗（HOMA-IR）和？细胞功能障碍（HOMA-B）随着时间的推移。基因与砷的相互作用将利用主成分分析进行估计，并利用基因组控制对种群分层进行核算。意义：探讨无机砷对糖尿病、胰岛素抵抗、？本研究可通过确定遗传易感因素，为砷与糖尿病的关系提供信息，并对美国及国外饮用水和食物中砷暴露的预防和控制产生影响。

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.