Extension of Type 2 Diabetes Genetic Clustering to Populations of non-European Ancestry

将 2 型糖尿病基因聚类扩展到非欧洲血统人群

• 批准号: 10354049
• 负责人: Miriam Sargon Udler
• 金额: $ 12.6万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10354049
• 关键词: African; African American population; Asian ancestry; Asian population; Biological; Biology; Biomedical Research; Body mass index; Characteristics; Clinical; Cluster Analysis; Complications of Diabetes Mellitus; Data; Data Set; Diabetes Mellitus; Disease; Disease Pathway; East Asian; European; Functional disorder; Future; Genetic; Genetic Predisposition to Disease; Genetic Research; Genetic Risk; Genetic Translation; Genetic Variation; Genetic study; Genomics; Goals; Grouping; Health; Healthcare; Heterogeneity; High Prevalence; Hispanic; Individual; Inherited; Insulin Resistance; Insulin deficiency; Latin American; Latino; Latino Population; Medical Records; Medical Research; Medicine; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Participant; Pathogenesis; Pathway interactions; Patient Care; Patients; Phenotype; Physiology; Population; Population Heterogeneity; Prevalence; Research; Research Design; South Asian; System; Time; Translating; United States; Validation; Variant; Visceral; Work; base; biobank; burden of illness; clinical care; clinical heterogeneity; cohort; diabetes management; diabetes mellitus genetics; disorder subtype; drug development; genetic architecture; genetic variant; genome wide association study; genomic locus; improved; novel; polygenic risk score; risk variant; statistics; study population; tool development; trait; translational goal

Abstract In the United States, populations of non-predominantly European ancestry, such as African Americans and Hispanic-Latinos, are disproportionately afflicted with type 2 diabetes (T2D) and T2D-related complications, but are also traditionally under-represented in medical research, particularly genetic studies. There are appreciated, but as yet unexplained, differences in T2D clinical characteristics between populations; for example, at a given body mass index, individuals of Asian ancestry having a higher prevalence of T2D and increased visceral adiposity compared to individuals of European ancestry. Furthermore, several important T2D loci have been identified in non-European populations, such as SLC16A11, which is common in Latin Americans and essentially absent from individuals of European ancestry. We recently performed cluster analysis of T2D-associated genetic variants and T2D-related traits, resulting in five groupings of T2D genetic loci based on the T2D genetic-variant-trait associations (Udler et al, PLoS Medicine 2018). The clusters were readily interpretable: two related to mechanisms of insulin deficiency and three related to mechanisms of insulin resistance. These analyses, however, were restricted to studies in populations of European ancestry due to data availability at the time, but newer genetic studies and datasets are now accessible. We would like to extend the cluster analysis to groups of non-European ancestry in order to elucidate genetic mechanism of disease and generate results that are more widely translatable. In Aim 1 we will perform phenotypically informed cluster analysis of T2D genetic variants using study populations of non- European ancestry (African, East Asian, Hispanic/Latino, and South Asian) to identify T2D mechanistic pathways. In Aim 2, we will utilize the genetic clusters generated in Aim 1 to construct cluster-specific polygenetic scores in individuals of non- European ancestry from validation cohorts (Mass General Brigham Biobank, UK Biobanks, and All of Us) to determine which clinical characteristics are associated with each cluster-specific polygenic score. The goal of Aim 2 is thus to use the genetic clusters to inform T2D subclassification. Finally, in Aim 3, we will investigate whether the relative disease burden conferred by these genetic clusters differs among ancestral populations. The overarching objectives of this R03 are to improve understanding of T2D pathophysiology, translate genomic discoveries to useful applications for patient care, and advance T2D genetics research in populations traditionally under-represented in biomedical research. This proposal will provide necessary preliminary data for a future R01 study aimed at investigating the physiology of individuals with high burden for T2D genetic pathways and support more diverse representation in future research.

抽象的 在美国，非主要欧洲血统的人群，例如非洲裔美国人和 西班牙裔拉丁裔患者罹患 2 型糖尿病 (T2D) 和 T2D 相关并发症的比例不成比例，但是 传统上，医学研究，特别是基因研究中的代表性也不足。有 了解但尚未解释的人群之间 T2D 临床特征的差异；为了 例如，在给定的体重指数下，亚洲血统的个体 T2D 患病率较高，并且 与欧洲血统的人相比，内脏脂肪增多。此外，几个重要的 T2D 基因座已在非欧洲人群中发现，例如拉丁语中常见的 SLC16A11 美国人，基本上不存在欧洲血统的人。我们最近进行了集群 分析 T2D 相关遗传变异和 T2D 相关特征，得出五种 T2D 遗传分组 基于 T2D 遗传变异性状关联的位点（Udler 等人，PLoS Medicine 2018）。这些簇是 易于解释：两个与胰岛素缺乏机制有关，三个与胰岛素缺乏机制有关 胰岛素抵抗。然而，这些分析仅限于对欧洲血统人群的研究 由于当时的数据可用性，但现在可以访问更新的基因研究和数据集。我们想 将聚类分析扩展到非欧洲血统群体，以阐明遗传机制 疾病并产生可更广泛转化的结果。在目标 1 中，我们将表现出表型 使用非欧洲血统的研究人群（非洲、 东亚、西班牙/拉丁裔和南亚）以确定 T2D 机制途径。在目标 2 中，我们将利用 目标 1 中生成的遗传簇，用于在非个体中构建簇特异性多遗传评分 来自验证队列（麻省总医院布里格姆生物银行、英国生物银行和我们所有人）的欧洲血统 确定哪些临床特征与每个簇特异性多基因评分相关。目标是 因此，目标 2 是使用遗传簇来告知 T2D 亚分类。最后，在目标 3 中，我们将调查 这些遗传簇所带来的相对疾病负担在祖先人群中是否有所不同。 R03 的首要目标是提高对 T2D 病理生理学的理解，翻译 将基因组发现转化为患者护理的有用应用，并推进人群中的 T2D 遗传学研究 传统上在生物医学研究中代表性不足。该提案将提供必要的初步数据 未来的 R01 研究旨在调查 T2D 遗传负担高的个体的生理学 途径并支持未来研究中更多样化的代表性。