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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：
10522395
负责人：
Damaskini Valvi
金额：
$ 68.55万
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/10522395
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 Electronic Health Record Endocrine Disruptors Enrollment Enzymes Epidemic Ethnic group Etiology European 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 Health Care Prospective Studies Research Research Personnel Resolution Resources Risk Risk Factors Sampling Seasons Time Unhealthy Diet Walkers adipokines analytical method biobank cohort design diabetes risk diabetogenic early detection biomarkers environmental chemical ethnic diversity ethnic minority experience gene environment interaction genetic epidemiology genetic risk factor high risk innovation metabolome metabolomics modifiable risk multi-ethnic multidisciplinary novel phenotypic data physical inactivity polygenic risk score population based precision medicine prevent prospective racial and ethnic disparities 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.

项目概要 2 型糖尿病 (T2D) 患病率的增加伴随着种族/民族差异，但病因因素促进 T2D 流行和 T2D 差异尚未得到充分理解。越来越多的实验证据表明接触内分泌干扰化学物质（EDC），例如全氟烷基物质和多氟烷基物质（PFAS），促进 T2D 的发展，可能与遗传变异等已知风险因素协同作用。 PFAS 是普遍存在且持久的扰乱新陈代谢的化学物质。然而，很少有前瞻性研究检验 PFAS 与 T2D 风险之间存在关联，而且这些关联几乎全部发生在白人群体中。以前的研究还缺乏临床确定的 T2D 诊断，仅调查了许多潜在的中的少数危险的 PFAS，并且没有检查 PFAS 混合物或基因与 PFAS 相互作用的潜在影响。状态- 最先进的整合组学方法可以克服这些障碍，推动该领域的发展。我们建议第一个综合代谢组-基因组方法 (1) 表征 PFAS 浓度之间的关联诊断前血浆样本中的（单独的 PFAS 和混合物）以及 T2D 事件风险和潜在影响使用多基因风险评分作为研究的创新解决方案，通过 T2D 遗传易感性进行修改相互作用，（2）识别潜在的失调代谢途径，（3）识别代谢特征由 EDC 暴露和与 T2D 相关的内源代谢物定义的诊断前血浆样本风险。我们将利用 BioMe 进行嵌套病例对照研究，BioMe 是一项与电子健康记录相关的持续进行的研究自 2007 年以来，已有超过 55,000 名参与者在西奈山医院（纽约）寻求初级保健时注册。 T2D 病例与 BioMe 无 T2D 对照 (N = 1,700) 匹配 (1:1)，且均为非裔美国人，西班牙裔和白人血统，从抽血到诊断出 T2D 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 PFAS 和代谢途径的诊断前血浆代谢组学 (HRM) 方法。我们将在 T2D 病例和匹配对照中复制研究结果来自洛杉矶和夏威夷基于人群的多种族队列 (MEC) 研究以及现有基因组数据 PFAS 和 HRM 的诊断前血浆浓度与 BioMe 样本在同一实验室测量。在与之前的研究相比，我们纳入了一系列传统的和新兴的 PFAS、暴露混合效应、通过利用最先进的代谢组-基因组方法和在两个独特的、表型良好的多种族队列中进行严格的发现-复制设计，并进行预诊断血浆样本可识别与 T2D 相关的早期生物标志物。这项研究依赖于多学科由经验丰富的研究人员组成的团队，具有环境/遗传流行病学、PFAS 和 T2D 研究方面的专业知识，以及最先进的人力资源管理、基因组学和生物统计暴露混合方法。研究结果将告知精确度 T2D 预防和治疗的医学方法，特别是针对高危多种族人群。