Perfluoroalkyl substances and incident type 2 diabetes in a multi-ethnic population: A metabolome-genome investigation

全氟烷基物质与多种族人群中 2 型糖尿病的发生：代谢组-基因组研究

基本信息

批准号：
10696215
负责人：
Damaskini Valvi
金额：
$ 67.35万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-02 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10696215
关键词：
Adult Affect African American African American population Age American Amino Acids Beta Cell Biometry Blood Carbohydrate Metabolism Pathway Chemical Exposure Chemicals Clinical Cohort Studies Data Development Diabetes prevention Diagnosis Diagnostic Disparity Early identification Electronic Health Record Endocrine Disruptors Enzymes Epidemic Ethnic Population Etiology European European ancestry Exposure to Functional disorder Genes Genetic Genetic Predisposition to Disease Genetic Variation Genome Genomic approach Genomics Glucose Goals Hawaii Health Hispanic Hispanic Populations Hospitals Impairment Individual Insulin Resistance Investigation Life Style Link Lipids Liver Longevity Longitudinal cohort Los Angeles Low Birth Weight Infant Measures Metabolic Metabolic Pathway Metabolism Methods Modification Nested Case-Control Study Non-Insulin-Dependent Diabetes Mellitus Obesity Outcome Participant Patient Self-Report Phenotype Plasma Poly-fluoroalkyl substances Population Population Control Population Heterogeneity Prediabetes syndrome Prevalence Prevention approach Primary Care Prospective Studies Research Research Personnel Resolution Resources Risk Risk Factors Sampling Seasons Time Unhealthy Diet adipokines analytical method biobank cohort data integration design diabetes risk diabetogenic early detection biomarkers environmental chemical ethnic disparity ethnic diversity ethnic minority experience gene environment interaction genetic epidemiology genetic risk factor high risk innovation metabolome metabolomics modifiable risk multi-ethnic multidisciplinary novel participant enrollment phenotypic data physical inactivity polygenic risk score population based precision medicine prevent prospective racial disparity sex synergism

项目摘要

PROJECT SUMMARY Increasing prevalence of type 2 diabetes (T2D) is accompanied by racial/ethnic disparities, but etiological factors promoting the T2D epidemic and T2D disparities are not fully understood. Growing experimental evidence shows that exposures to endocrine-disrupting chemicals (EDCs), such as per- and polyfluoroalkyl substances (PFAS), promote T2D development, likely in synergy with known risk factors such as genetic variations. PFAS are ubiquitous and persistent chemicals that perturb metabolism. However, few prospective studies examined the association between PFAS and T2D risk, and those were almost exclusively in White populations. Previous studies also lacked clinically ascertained T2D diagnosis, investigated only a few of the many potentially hazardous PFAS, and did not examine potential effects of PFAS mixtures or gene–PFAS interactions. State-of- the-art integrated omics approaches can overcome these barriers to advance the field. We propose the first integrated metabolome–genome approach to (1) characterize the associations between PFAS concentrations (individual PFAS and mixtures) in prediagnostic plasma samples and incident T2D risk and potential effect modification by genetic predisposition to T2D using polygenic risk scores as an innovative solution for studying interactions, (2) identify underlying dysregulated metabolic pathways, and (3) identify metabolic signatures in prediagnostic plasma samples defined by EDC exposures and endogenous metabolites associated with T2D risk. We will perform a nested case–control study leveraging BioMe, an ongoing electronic health record-linked biobank with >55,000 participants enrolled while seeking primary care at Mount Sinai Hospital (NY) since 2007. Incident T2D cases are matched (1:1) to BioMe T2D-free controls (N = 1,700) and are of African American, Hispanic and White ancestry, with ~6 years average time between blood draw and T2D diagnosis. We will use prediagnostic plasma to measure PFAS and metabolic pathways using state-of-the-art high-resolution metabolomics (HRM) approaches. We will replicate findings among incident T2D cases and matched controls from the population-based Multiethnic Cohort (MEC) study in Los Angeles and Hawaii with extant genome data and prediagnostic plasma concentrations of PFAS and HRM measured at the same lab as BioMe samples. In contrast to prior studies, we incorporate a wide suite of legacy and emerging PFAS, exposure-mixture effects, and gene–environment interactions by leveraging state-of-the-art metabolome–genome approaches and a rigorous discovery–replication design in two unique, well-phenotyped multiethnic cohorts with prediagnostic plasma samples to identify early biomarkers associated with T2D. This research relies on a multidisciplinary team of seasoned investigators with expertise in environmental/genetic epidemiology, PFAS and T2D research, and state-of-the-art HRM, genomics, and biostatistical exposure–mixture methods. Findings will inform precision medicine approaches for T2D prevention and treatment, particularly for high-risk multiethnic populations.

项目摘要种族/族裔差异可以实现2型糖尿病（T2D）的患病率的增加，但病因因素促进T2D流行病和T2D差异尚不完全了解。越来越多的实验证据表明暴露于内分泌干扰化学物质（EDC），例如per和多氟烷基物质（PFA），促进T2D发展，可能与已知危险因素（例如遗传变异）的协同作用。 PFA是无处不在和持续的化学物质，这些化学物质会扰动代谢。但是，很少有前瞻性研究检查 PFA和T2D风险之间的关联以及这些风险几乎完全在白人人群中。以前的研究还缺乏临床确定的T2D诊断，仅研究了许多潜在的少数危险的PFA，没有检查PFA混合物或基因– PFA相互作用的潜在影响。最新 ART综合的OMIC方法可以克服这些障碍以推进该领域。我们提出了第一个集成代谢组 - 基因组方法（1）表征PFAS浓度之间的关联（单个PFA和混合物）在诊断血浆样品和入射T2D风险和潜在效果中使用多基因风险评分作为研究的创新解决方案，通过遗传易感T2D修饰T2D 相互作用，（2）识别潜在的失调代谢途径，（3）确定代谢特征由EDC暴露和内源性代谢物定义的与T2D相关的内源性代谢产物定义的诊断性血浆样品风险。我们将进行嵌套的情况 - 对照研究利用Biome，这是一种正在进行的电子健康记录链接自2007年以来，在纽约州西奈山医院（纽约）寻求初级保健时，拥有> 55,000名参与者的生物库。事件T2D病例（1：1）与Biome T2D无T2D对照（n = 1,700）匹配，并且是非裔美国人，西班牙裔和白人血统，抽血和T2D诊断之间的平均时间约为6年。我们将使用使用最先进的高分辨率测量PFA和代谢途径的诊断性血浆代谢组学（HRM）方法。我们将在事件T2D案例和匹配的控件中复制发现来自洛杉矶和夏威夷的基于人群的多民族队列（MEC）研究 PFA和HRM的诊断性血浆浓度与Biome样品在同一实验室中测得。在与先前的研究形成鲜明对比的是，我们结合了一系列遗产和新兴的PFA，暴露混合效应，通过利用最新代谢组 - 基因组方法和一个基因 - 环境相互作用严格的发现 - 两种独特的，良好的多种族同类群体的复制设计，血浆样品鉴定与T2D相关的早期生物标志物。这项研究依赖于多学科经验丰富的调查员团队在环境/遗传流行病学，PFA和T2D研究方面具有专业知识，以及最先进的HRM，基因组学和生物统计暴露 - 混合方法。调查结果将为精度提供信息 T2D预防和治疗的医学方法，特别是对于高风险的多种族人群。