Characterizing Immunogenetics in Type 1 Diabetes

项目摘要/摘要 我们研究的长期目标是学习和理解潜在的遗传机制。 和1型糖尿病(T1 DM)的进展，并开发有效的筛查、诊断、预防和 以及与T1 DM作斗争的治疗策略。在这个项目中，我们的重点是基因与 从血清转换到T1 DM的进展，更具体地说，发现新的构象 负责疾病进展的HLA/KIR/FcGR/IGHG基因的调节片段(CRS)； CRS是指调节元件和功能元件，包括肽、核苷酸或其他调节元件 基因内部或基因之间的元素。人类白细胞抗原/KIR/FcGR/IGHG基因高度多态，其次是 世代靶向测序(NGTS)将被用于扩展遗传多态的雷达下 GWA型的。人类白细胞抗原/KIR/FcGR/IGHG基因中与进展相关的CRS的发现和特征 将有助于我们了解疾病进展的遗传机制，并进一步发展 有效的预防和治疗措施，以减缓甚至恢复临床诊断的进展。2018年， 我们从NIDDK获得了过渡性资金，用于开展一项关于人类白细胞抗原基因在疾病进展中的初步研究， 基于糖尿病预防试验1(DPT-1)。我们的初步研究产生了两个具体的重要发现 HLADQB1中的残基β57和(-18β)，其中β57在结构上起重要作用 抗原识别和位于信号肽中的残基(-18β)。为了支持这一应用程序，我们 从另一项多中心国际口服胰岛素预防试验(TN07)获得临床和遗传学数据 并能够复制与β57的遗传关联。我们能够部分复制这种关联 使用残基(-18β)，即使中等分辨率的DQ基因分型不包括残基(-18β) 位于信号肽中。为了在这一初步成果的基础上再接再厉，该提案有两个具体目标：目标1是 估计DQB1*β57在有或没有(-18β)的情况下的外显率，从精确到 利用青年糖尿病的环境决定因素确定血清转换为T1糖尿病的发病 (泰迪)Teddy是一个前瞻性的出生队列，经常测量自身抗体。 从而可以准确地确定血清转换时间。目标二是开展机械调查 DQB1 CRS以及其他在HLA/KIR/FcGR/IGHG基因中的CRS，利用了广泛的功能数据 在泰迪身上收集的。具体来说，我们将评估已发现CRS如何与纵向测量的CRS相关联 自身抗体水平(GADA、IAA、IA-2A、ZnT8A)、β细胞功能(葡萄糖、C肽、OGTT)和HbA1c 水平，并将研究CRS如何使用纵向的 Teddy病例对照研究中的RNAseq数据。该项目的结果将获得对基因的重要见解 疾病进展的机制，并将影响预防性和 针对T1 DM的治疗方法/策略。

PROJECT SUMMARY/ABSTRACT The long-term objective of our research is to learn and understand genetic mechanisms underlying initiation and progression of type 1 diabetes mellitus (T1DM), and to develop effective screening, diagnosis, preventive, and treatment strategies in the fight against T1DM. In this project, our focus is on genetic associations with the progression from seroconversion to the onset of T1DM, more specifically, discovering novel Conformational Regulatory Segments (CRS) in HLA/KIR/FcGR/IGHG genes that are responsible for the disease progression; CRS refer to both regulatory and functional elements, including peptides, nucleotides or other regulatory elements within or between genes. The HLA/KIR/FcGR/IGHG genes are highly polymorphic and Next Generation Targeted Sequencing (NGTS) will be used as extended genetic polymorphisms go under the radar of GWAS. Discovering and characterizing progression-associated CRS within HLA/KIR/FcGR/IGHG genes would help us to understand the genetic mechanism of the disease progression, and further to develop effective prevention and treatment remedies to slow or even revert progression to clinical diagnosis. In 2018, we received a bridge funding from NIDDK to carry out a pilot study of HLA genes in the disease progression, based on Diabetes Prevention Trial-1 (DPT-1). Our pilot study produced an important finding of two specific residues β57 and (-18β), within HLA-DQB1, in which β57 was structurally known to play an important role in antigen recognition and the residue (-18β) located in the signal peptide. In support of this application, we obtained clinical and genetic data from another multi-center international Oral Insulin Prevention Trial (TN07) and were able to replicate the genetic association with β57. We were able to partially replicate the association with the residue (-18β), even though DQ genotyping at intermediate resolution did not cover the residue (-18β) located in the signal peptide. To build on this preliminary result, this proposal has two specific aims: Aim 1 is to estimate the penetrance of DQB1* β57, with or without (-18β), to the progression from the precisely determined seroconversion to T1DM onset, using The Environmental Determinants of Diabetes in the Young (TEDDY). TEDDY is a prospectively conducted birth cohort and has frequent measurements of autoantibodies so that seroconversion time can be precisely determined. Aim 2 is to carry out mechanistic investigation of DQB1 CRS as well as additional CRS in HLA/KIR/ FcGR/IGHG genes, leveraging extensive functional data collected in TEDDY. Specifically, we will assess how discovered CRS associate with longitudinally measured autoantibody levels (GADA, IAA, IA-2A, ZnT8A), the β-cell function (glucose, C-peptide, OGTT) and HbA1c levels, and will investigate how CRS associate with cis- and trans-gene expressions using the longitudinal RNAseq data in a TEDDY case-control study. Results from this project will gain significant insights into genetic mechanism underlying the disease progression and will impact the translational research of preventative and therapeutic methods/strategies against T1DM.