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，非裔美国人和 西班牙裔拉蒂诺斯（Latinos 传统上，医学研究，尤其是遗传研究的代表性不足。有 值得赞赏但尚未解释，人群之间T2D临床特征的差异；为了 例如，在给定的体重指数上，亚洲血统的个体T2D患病率较高 与欧洲血统的个体相比，内脏肥胖增加了。此外，有几个重要 在非欧洲人群中已经确定了T2D基因座，例如SLC16A11，这在拉丁语中很常见 美国人，本质上没有欧洲血统的人。我们最近执行了集群 T2D相关的遗传变异和与T2D相关性状的分析，导致五个T2D遗传 基于T2D遗传变异性特征协会的基因座（Udler等人，PLOS Medicine 2018）。集群是 容易解释：两个与胰岛素缺乏机制有关，三个与机制有关 胰岛素抵抗。但是，这些分析仅限于欧洲血统人群的研究 由于当时的数据可用性，但是现在可以访问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 疾病并产生更广泛翻译的结果。在AIM 1中，我们将以表型进行 使用非欧洲血统的研究人群对T2D遗传变异的知识聚类分析（非洲， 东亚，西班牙裔/拉丁裔和南亚），以识别T2D机械途径。在AIM 2中，我们将使用 AIM 1中产生的遗传簇在非 - 个体中构建集群特异性多基因评分 来自验证队列的欧洲血统（大规模杨百翰生物库，英国生物库以及我们所有人） 确定哪些临床特征与每个群集特异性多基因评分相关。目标 因此，AIM 2是使用遗传簇来告知T2D亚分类。最后，在AIM 3中，我们将调查 这些遗传簇赋予的相对疾病负担是否在祖先种群中有所不同。 该R03的总体目标是提高对T2D病理生理学的理解，翻译 基因组发现对患者护理的有用应用，并推进了人群中的T2D遗传学研究 传统上，生物医学研究中的代表性不足。该建议将提供必要的初步数据 对于未来的R01研究，旨在研究T2D遗传负担很高的个体的生理学 途径和支持未来研究中更多样化的代表。