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

项目摘要/摘要 糖尿病传统上分为1型糖尿病(T1D)或2型糖尿病(T2D)。T1D由以下原因引起 自身免疫性破坏β细胞和胰岛素缺乏，而T2D的特征是体重增加 和胰岛素抵抗。然而，一些非典型形式的糖尿病不容易被归类为T1D或T2D，以及 它们在两种情况下都有重叠的特征。 在这个项目中，我们建议使用遗传信息来提高对非典型糖尿病的诊断。在……里面 特别是，我们将使用多基因评分，这是一个很有前途的工具，它结合了多种变异的影响 预测疾病风险的基因组。T1D多基因评分已被证实可以预测T1D的发病 并帮助区分成人的T1D和T2D。在这里，我们将应用T1D多基因评分 在小说的背景下。 在目标1中，我们将检验酮症易患糖尿病，它的表型类似于T2D，但仍涉及 酮症酸中毒。在目标2中，我们将研究成人的潜伏性自身免疫性糖尿病，其表型类似于 T1D，但出现在生命的较晚阶段，与典型的儿童期起病的T1D相比，进展较慢。最后，在 目的3，我们将研究免疫检查点抑制剂诱导的糖尿病，其中个体接受免疫治疗 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，以更好地表征疾病的异质性和 识别具有不同临床结果的糖尿病亚型。通过使用特定于祖先的和多祖先 多基因得分，我们将确保不同的人群得到很好的代表。这一点尤为重要 因为大多数现有的多基因得分都是在具有欧洲血统的人群中产生的，而 某些非典型形式的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。这个 研究环境代表了初级研究人员的理想环境，结合了世界一流的临床 马萨诸塞州总医院的专业知识和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 成为一名独立的内科科学家。

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.