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: 10542762
• 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/10542762
• 关键词: African; African American population; Applied Genetics; Asian ancestry; Asian population; Biological; Biology; Biomedical Research; Body mass index; Characteristics; Classification; Clinical; Cluster Analysis; Complications of Diabetes Mellitus; Data; Data Set; Diabetes Mellitus; Disease; Disease Pathway; Disparity; East Asian; Electronic Health Record; European; European ancestry; Functional disorder; Future; Genetic; Genetic Predisposition to Disease; Genetic Research; Genetic Risk; Genetic Variation; Genetic study; Genomics; Goals; Grouping; Healthcare; Heterogeneity; High Prevalence; Hispanic; Individual; Inherited; Insulin Resistance; Insulin deficiency; Latin American; Latino; Latino Population; 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; 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 genetics; 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.

摘要 在美国，非主要欧洲血统的人口，如非洲裔美国人和 西班牙裔拉丁美洲人，不成比例地患有2型糖尿病（T2 D）和T2 D相关并发症，但 在医学研究中，特别是遗传学研究中，传统上也代表性不足。有 认识到，但尚未解释的T2 D临床特征在人群之间的差异; 例如，在给定的体重指数下，具有较高T2 D患病率的亚洲血统的个体， 与欧洲血统的个体相比，内脏肥胖增加。此外，一些重要的 已经在非欧洲人群中鉴定了T2 D基因座，例如SLC 16 A11，其在拉丁美洲人群中很常见。 美国人，基本上没有欧洲血统的人。我们最近进行了集群 分析T2 D相关的遗传变异和T2 D相关性状，产生五组T2 D遗传变异。 基于T2 D遗传变异性状关联的基因座（Udler et al，PLoS Medicine 2018）。这些集群是 容易解释：两个与胰岛素缺乏的机制有关，三个与胰岛素缺乏的机制有关。 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，但现在可以获得更新的遗传研究和数据集。我们想 将聚类分析扩展到非欧洲血统的群体，以阐明 疾病并产生更广泛可翻译的结果。在目标1中，我们将表现出 使用非欧洲血统的研究人群（非洲人， 东亚人、西班牙裔/拉丁裔和南亚人），以确定T2 D机制途径。在目标2中，我们将利用 目的1中生成的遗传簇，以构建非遗传性个体的簇特异性多遗传评分， 来自验证队列（Mass General Brigham Biobank、UK Biobank和All of Us）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。的目标 因此，目的2是使用遗传聚类来告知T2 D子分类。最后，在目标3中，我们将研究 这些遗传簇所带来的相对疾病负担在祖先群体中是否不同。 本R 03的总体目标是提高对T2 D病理生理学的理解， 基因组发现对患者护理的有用应用，并推进T2 D人群遗传学研究 传统上在生物医学研究中代表性不足。本提案将提供必要的初步数据 未来的R 01研究旨在研究T2 D遗传高负担个体的生理学， 途径，并支持在未来的研究更多样化的代表性。