Characterizing Immunogenetics in Type 1 Diabetes

1 型糖尿病的免疫遗传学特征

• 批准号: 10585273
• 负责人: DANIEL E. GERAGHTY
• 金额: $ 57.75万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585273
• 关键词: Acceleration; Alleles; Animals; Antigens; Autoantibodies; Autoantigens; Autoimmune Diseases; B-Lymphocytes; Beta Cell; Biological Markers; Birth; C-Peptide; CISH gene; Case/Control Studies; Cell physiology; Cells; Childhood; Clinical; Clinical Research; Collection; DNA; Data; Deceleration; Dependence; Development; Diabetes Mellitus; Diabetes prevention; Diagnosis; Disease; Disease Progression; Elements; Etiology; Funding; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genotype; Glucose; Glycosylated hemoglobin A; Grant; HLA Class I Genes; HLA-DQ Antigens; HLA-DQB1; Haplotypes; Human; Immune; Immunogenetics; Immunoglobulin G; Immunotherapy; Impairment; Incidence; Individual; Infection; Insulin; Insulin-Dependent Diabetes Mellitus; International; Investigation; Islets of Langerhans; Knowledge; Learning; Lymphocytic Infiltrate; MHC Class II Genes; Matched Case-Control Study; Measurement; Measures; Mediating; Methods; Molecular Conformation; National Institute of Diabetes and Digestive and Kidney Diseases; Natural Killer Cells; Nucleic Acid Regulatory Sequences; Nucleotides; OGTT; Oral; Participant; Pathogenesis; Pathway Analysis; Penetrance; Peptide Signal Sequences; Peptides; Pilot Projects; Plasma Cells; Play; Prevalence; Prevention; Prevention Research; Prevention strategy; Prevention trial; Process; Production; Property; Public Health; Regulatory Element; Research; Resolution; Risk; Role; Sampling; T-Lymphocyte; Technology; Testing; Therapeutic; Time; Translational Research; autoreactivity; clinical diagnosis; cohort; cytotoxic CD8 T cells; fighting; genetic association; genome wide association study; glycemic control; hazard; health management; high risk; insight; insulin dependent diabetes mellitus onset; islet cell antibody; molecular modeling; next generation; novel; patient population; prospective; recruit; screening; seroconversion; small molecule; success; targeted sequencing; transcriptome sequencing; transgene expression; translational impact; treatment strategy

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.

项目概要/摘要 我们研究的长期目标是学习和理解启动的遗传机制 1 型糖尿病 (T1DM) 和进展，并制定有效的筛查、诊断、预防、 以及对抗 T1DM 的治疗策略 在这个项目中，我们的重点是与 T1DM 的遗传关联。 从血清转化到 T1DM 的发病，更具体地说，发现新的构象 HLA/KIR/FcGR/IGHG 基因中负责疾病进展的调节片段 (CRS)； CRS指的是调节元件和功能元件，包括肽、核苷酸或其他调节元件。 HLA/KIR/FcGR/IGHG 基因内部或之间的元件具有高度多态性并且下一步。 随着扩展遗传多态性受到关注，一代靶向测序 (NGTS) 将被使用 发现并表征 HLA/KIR/FcGR/IGHG 基因中与进展相关的 CRS。 将有助于我们了解疾病进展的遗传机制，并进一步开发 有效的预防和治疗措施可以减缓甚至恢复临床诊断的进展。 我们获得了 NIDDK 的过桥资金，用于开展 HLA 基因在疾病进展中的试点研究， 基于糖尿病预防试验 1 (DPT-1)，我们的试点研究得出了两个具体的重要发现。 HLA-DQB1 内的残基 β57 和 (-18β)，其中 β57 在结构上已知在 抗原识别和位于信号肽中的残基（-18β） 为了支持这一应用，我们。 获得另一项多中心国际口服胰岛素预防试验（T​​N07）的临床和遗传数据 并能够复制与 β57 的遗传关联 我们能够部分复制这种关联。 带有残基 (-18β)，即使中等分辨率的 DQ 基因分型未覆盖残基 (-18β) 在此初步结果的基础上，该提案有两个具体目标：目标 1 是 估计 DQB1* β57 的外显率，有或没有 (-18β)，从精确的进展 使用年轻糖尿病的环境决定因素确定了 T1DM 发病的血清转化 (TEDDY) 是一个前瞻性出生队列，经常测量自身抗体。 以便能够精确确定血清转化时间。目标2是进行机制研究。 DQB1 CRS 以及 HLA/KIR/FcGR/IGHG 基因中的其他 CRS，利用广泛的功能数据 具体来说，我们将评估发现的 CRS 与纵向测量的关联。 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，并将利用纵向研究 CRS 如何与顺式和转基因表达相关联 TEDDY 病例对照研究中的 RNAseq 数据将获得对遗传的重要见解。 疾病进展的机制，并将影响预防和治疗的转化研究 针对 T1DM 的治疗方法/策略。