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

摘要 在美国，非主要是欧洲血统的人口，如非裔美国人和 西班牙裔拉丁裔，患有2型糖尿病(T2D)和T2D相关并发症的比例不成比例，但 在医学研究中，特别是在基因研究中，传统上也是代表不足。确实有 认识到，但尚未解释，T2D临床特征在人群之间的差异； 例如，在给定的体重指数下，亚洲血统的人有更高的T2D和 与欧洲血统的人相比，内脏肥胖症增加。此外，几个重要的 已在非欧洲人群中发现了T2D基因座，例如在拉丁语中常见的SLC16A11 美国人，基本上没有欧洲血统的人。我们最近执行了群集 对T2D相关遗传变异和T2D相关性状的分析，得出了T2D遗传的五类 基于T2D遗传-变异-性状关联的基因座(Udler等人，2018年PLoS Medicine)。这些星团是 容易理解：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，但更新的基因研究和数据集现在可以访问。我们想要 将聚类分析推广到非欧洲血统群体，以阐明遗传机制。 并产生更广泛可翻译的结果。在目标1中，我们将执行表型 使用非欧洲血统(非洲， 东亚人、西班牙裔/拉丁裔和南亚人)，以识别T2D机械路径。在目标2中，我们将利用 在目标1中产生的遗传簇用于构建非遗传病患者个体的簇特异性多基因得分 欧洲血统从验证队列(麻省总医院生物银行、英国生物银行和我们所有人)到 确定哪些临床特征与每个特定于簇的多基因评分相关。的目标是 因此，目标2是使用遗传聚类来告知T2D亚分类。最后，在目标3中，我们将调查 这些基因簇带来的相对疾病负担是否在祖先群体中有所不同。 本R03的主要目标是提高对T2D病理生理学的理解，翻译 基因组发现在患者护理中的有用应用，并在人群中推进T2D遗传学研究 传统上在生物医学研究中的代表性不足。该提案将提供必要的初步数据 对于未来的R01研究，旨在调查T2D基因高负担个体的生理 并在未来的研究中支持更多样化的代表性。

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.