Analysis of Type 1 Diabetes Polygenic Scores in Atypical Forms of Diabetes

非典型糖尿病 1 型糖尿病多基因评分分析

基本信息

批准号：
10750644
负责人：
Aaron Jonathan Deutsch
金额：
$ 8.22万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10750644
关键词：
Adult Autoantibodies Autoimmune Diabetes Autoimmunity Beta Cell Body mass index Caring Cell physiology Child Childhood Childhood diabetes Classification Clinical Computational Biology Computing Methodologies Diabetes Mellitus Diagnosis Diagnostic Ensure Environment European ancestry Foundations Functional disorder Funding General Hospitals Genetic Genetic Determinism Genetic Research Genetic Risk Genome Goals Grant Human Genetics Hyperglycemia Immune checkpoint inhibitor Individual Insulin Insulin Resistance Insulin deficiency Insulin-Dependent Diabetes Mellitus K-Series Research Career Programs Life Massachusetts Measures Methods Non-Insulin-Dependent Diabetes Mellitus Outcome Pancreas Phenotype Physicians Population Population Heterogeneity Research Research Personnel Risk Scientist Time Training Uncertainty Variant Work autoimmune pathogenesis checkpoint therapy computing resources diabetes mellitus genetics diabetes risk disease heterogeneity disorder risk early onset genetic architecture genetic information genetic risk factor genetic variant health care disparity improved innovation insulin dependent diabetes mellitus onset insulin secretion novel precision medicine programs risk prediction skills therapy development tool type I and type II diabetes waiver

项目摘要

PROJECT SUMMARY/ABSTRACT Diabetes is traditionally classified as type 1 diabetes (T1D) or type 2 diabetes (T2D). T1D is caused by autoimmune destruction of beta cells and insulin deficiency, while T2D is characterized by increased body mass and insulin resistance. However, some atypical forms of diabetes are not easily classified as T1D or T2D, and they share overlapping features with both conditions. In this project, we propose to use genetic information to enhance the diagnosis of atypical forms of diabetes. In particular, we will use polygenic scores, a promising tool that combines the effects of multiple variants across the genome to predict the risk of disease. T1D polygenic scores have been validated to predict the onset of T1D in children and to help discriminate between T1D and T2D in adults. Here, we will apply T1D polygenic scores in novel contexts. In Aim 1, we will examine ketosis-prone diabetes, which phenotypically resembles T2D but nevertheless involves ketoacidosis. In Aim 2, we will investigate latent autoimmune diabetes in adults, which phenotypically resembles T1D but presents later in life and has slower progression compared to classic, childhood-onset T1D. Finally, in Aim 3, we will study immune checkpoint inhibitor-induced diabetes, in which individuals treated with immune checkpoint inhibitors develop variable phenotypes and may or may not require insulin. In each of these aims, we will implement T1D polygenic scores to better characterize disease heterogeneity and to identify diabetes subtypes with distinct clinical outcomes. By using ancestry-specific and multi-ancestry polygenic scores, we will ensure that diverse populations are well-represented. This is particularly important because most existing polygenic scores have been developed in populations with European ancestry, whereas certain atypical forms of diabetes are more common in other populations. The proposed project will provide advanced training in computational biology and statistical genetics. The research setting represents an ideal environment for junior investigators, combining the world-class clinical expertise of Massachusetts General Hospital with the innovative computational resources of the Broad Institute. This project will provide a foundation for the candidate to apply for a career development award and ultimately to become an independent physician scientist.

项目概要/摘要糖尿病传统上分为 1 型糖尿病 (T1D) 或 2 型糖尿病 (T2D)。 T1D 是由 β 细胞的自身免疫性破坏和胰岛素缺乏，而 T2D 的特点是体重增加和胰岛素抵抗。然而，一些非典型形式的糖尿病不易被归类为 T1D 或 T2D，并且它们与这两种情况都有重叠的特征。在这个项目中，我们建议利用遗传信息来增强非典型糖尿病的诊断。在特别是，我们将使用多基因评分，这是一种很有前途的工具，可以结合多种变异的影响基因组来预测疾病风险。 T1D 多基因评分已被验证可以预测 T1D 的发病帮助区分成人 T1D 和 T2D。在这里，我们将应用 T1D 多基因评分在新颖的背景下。在目标 1 中，我们将检查酮症倾向糖尿病，其表型类似于 T2D，但仍然涉及酮症酸中毒。在目标 2 中，我们将研究成人的潜在自身免疫性糖尿病，其表型类似于但与经典的儿童期发病的 T1D 相比，T1D 发病较晚且进展较慢。最后，在目标 3，我们将研究免疫检查点抑制剂诱发的糖尿病，其中接受免疫治疗的个体检查点抑制剂会产生不同的表型，可能需要也可能不需要胰岛素。在每个目标中，我们将实施 T1D 多基因评分，以更好地表征疾病异质性和识别具有不同临床结果的糖尿病亚型。通过使用特定血统和多血统多基因评分，我们将确保不同人群得到充分代表。这一点尤为重要因为大多数现有的多基因评分是在具有欧洲血统的人群中开发的，而某些非典型糖尿病在其他人群中更为常见。拟议的项目将提供计算生物学和统计遗传学方面的高级培训。这研究环境为初级研究人员提供了一个理想的环境，结合了世界一流的临床麻省总医院的专业知识与布罗德研究所的创新计算资源。该项目将为候选人申请职业发展奖提供基础，并最终成为一名独立的医师科学家。