Center for Identification and Study of Individuals with Atypical Diabetes Mellitus (U54)

非典型糖尿病个体识别和研究中心 (U54)

• 批准号: 9597055
• 负责人: ASHOK BALASUBRAMANYAM
• 金额: $ 250万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-10 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9597055
• 关键词: Adult; Affect; Ancillary Study; Autoantibodies; Autoimmune Diabetes; Autoimmune Process; Biological Markers; C-Peptide; Categories; Characteristics; Classification; Clinic; Clinical; Clinical Protocols; Cluster Analysis; Collaborations; Collection; Colorado; Communication; Complex; Complex Mixtures; Complication; Core Facility; DNA; DNA Sequencing Facility; Data; Data Analyses; Data Storage and Retrieval; Databases; Development; Diabetes Mellitus; Diagnosis; Disease; Enrollment; Environmental Risk Factor; Epigenetic Process; Etiology; Evaluation; Family Study; Florida; Foundations; Functional disorder; Future; Genetic; Genome; Genotype; Goals; Heterogeneity; Immunology; Indiana; Individual; Insulin; Insulin-Dependent Diabetes Mellitus; International; Investigation; Longitudinal Studies; Medical Genetics; Medicine; Metabolic; Mining; Mission; Mitochondria; Molecular; Molecular Diagnosis; Multicenter Trials; National Institute of Diabetes and Digestive and Kidney Diseases; Natural History; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Participant; Pathogenesis; Pathologic; Patient Recruitments; Patients; Phenotype; Physiology; Population; Proinsulin; Registries; Research; Research Personnel; Resources; Sampling; Scientist; Secure; Serum; Single Nucleotide Polymorphism; Subgroup; Surface; Symptoms; Syndrome; System; Therapeutic; Universities; Variant; Washington; Work; Youth; adiponectin; base; biobank; cohort; college; data sharing; database of Genotypes and Phenotypes; design; diabetes mellitus genetics; exome; follow-up; genetic analysis; genetic information; genetic registry; genetic variant; improved; insight; islet; learning strategy; metabolomics; mitochondrial genome; novel; novel diagnostics; novel therapeutics; outreach; patient registry; phenotypic data; polypeptide C; prospective; recruit; repository; treatment response; unsupervised learning; web site

Diabetes is traditionally classified in two broad categories: autoimmune Type 1 and obesity-related Type 2. Numerous phenotypically and etiologically distinct forms exist and are emerging, collectively termed “atypical diabetes” (AD), that do not fit into either category. We hypothesize that AD comprises a spectrum that includes numerous forms, both known (e.g, MODY/monogenic, Latent Autoimmune Diabetes of Adults, Ketosis-Prone Diabetes) and unknown. We propose to establish the Center for Atypical Diabetes Research and Evaluation (CADRE). The goals of CADRE are to (1) identify and define comprehensively the forms of AD; and (2) establish an extensive database and repository of biosamples from AD patients. Defining the forms of AD is challenging because the etiology of AD can range from a single gene variant to a highly complex mixture of genetics, epigenetics and environmental factors. To identify patients with AD, and then to define the forms, we will use a two-pronged approach. Approach (a) will use clustering analysis of genotypic and phenotypic data from diverse groups of patients with diabetes. We have recruited 15 domestic and international population cohorts with data on more than 33,000 patients with diabetes. Further, we have recruited six diabetes study clinics (Baylor College of Medicine [BCM], University of Washington [UW], Indiana University [IU], Emory University, University of Colorado, and SUNY Downstate) who will prospectively recruit patients. The Juvenile Diabetes Research Foundation will facilitate recruitment from patient groups. The Administrative Core at BCM will work with cohorts and clinics to obtain data. The University of South Florida (USF) will filter data for AD and separate patients into phenotypically homogenous clusters that can be diagnosed based on genetic and clinical features unique to the cluster. Approach (b) will identify monogenic, oligogenic and mitochondrial forms of AD from patients enrolled in genetics registries (BCM) and a family study with genetic data (Botnia). The BCM registries include patients referred to the Undiagnosed Disease Network. All patients will undergo whole-exome and mitochondrial genome sequencing (Cores at BCM), single-nucleotide polymorphism variant analysis (Oxford), metabolomic analysis (Duke) and phenotypic analysis of C-peptide, adiponectin, proinsulin, islet autoantibodies, and serum insulin DNA levels (Cores at UW and IU). To establish the database and biorepository, we will invite patients with AD to participate in sample donation and longitudinal follow-up via the cohorts and clinics. Data and samples will be transferred to the Database and Biorepository Core at USF, with input and tracking implemented using the successful framework developed by USF for large multicenter trials. Data will be made available through the NIDDK and a CADRE website and samples will be made available through ancillary study application. Ongoing patient recruitment to expand the database and biorepository will occur through the study clinics and clinician referral through the CADRE website. Overall, CADRE will be built on a foundation of existing, successful core facilities and computational systems to create a lasting resource that will substantially advance AD research.

糖尿病传统上分为两大类：自身免疫1型和肥胖相关2型。 许多表型和病因学上不同的形式存在并正在出现，统称为“非典型 糖尿病（AD），不属于任何一类。我们假设AD包括一个谱， 多种形式，既有已知的（例如，MODY/单基因，成人潜伏性自身免疫性糖尿病，酮症倾向 糖尿病，未知。我们建议建立非典型糖尿病研究和评估中心 （CADRE）. CADRE的目标是（1）全面识别和定义AD的形式;（2）建立 一个广泛的数据库和储存库的生物样本从AD患者。定义AD的形式具有挑战性 因为AD的病因可以从单一基因变异到高度复杂的遗传学混合物， 表观遗传学和环境因素。为了识别AD患者，然后定义表格，我们将使用 双管齐下方法（a）将使用来自不同的基因型和表型数据的聚类分析， 糖尿病患者群体。我们招募了15个国内和国际人群队列， 超过33，000名糖尿病患者。此外，我们还招募了六个糖尿病研究诊所（贝勒学院 医学[美]、华盛顿大学[美]、印第安纳州大学[美]、埃默里大学、 科罗拉多和SUNY Downstate），他们将前瞻性招募患者。青少年糖尿病研究 基金会将促进从患者群体中招募。联合国难民事务高级专员办事处的行政核心将与 和诊所获取数据。南佛罗里达大学（USF）将筛选AD数据，并将患者分为 表型上同质的集群，可以诊断的基础上独特的遗传和临床特征， 集群方法（B）将鉴定来自入组研究的患者的AD的单基因、寡基因和线粒体形式。 遗传学登记处（Genetics Registry）和一项具有遗传数据的家族研究（Botnia）。这些登记处包括患者 未确诊疾病网络所有患者将接受全外显子组和线粒体基因组 测序（Cores at Geneva）、单核苷酸多态性变体分析（Oxford）、代谢组学分析 （杜克）和C肽、脂联素、胰岛素原、胰岛自身抗体和血清胰岛素的表型分析 DNA水平（UW和IU的核心）。为了建立数据库和生物库，我们将邀请AD患者 通过队列和诊所参与样本捐赠和纵向随访。数据和样本将 转移到USF的数据库和生物储存核心，使用 USF为大型多中心试验开发的成功框架。数据将通过 NIDDK和CADRE网站和样本将通过辅助研究申请提供。正在进行 将通过研究诊所和临床医生招募患者以扩大数据库和生物储存库 通过CADRE网站推荐。总的来说，CADRE将建立在现有的，成功的核心 设施和计算系统，以创造一个持久的资源，将大大推进AD研究。