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.

项目总结/摘要 我们研究的长期目标是学习和理解启动的遗传机制 和1型糖尿病（T1 DM）的进展，并制定有效的筛查，诊断，预防， 和治疗策略在与T1 DM的斗争。在这个项目中，我们的重点是遗传协会与 从血清转换到T1 DM发作的进展，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是指调控元件和功能元件，包括肽、核苷酸或其他调控元件。 基因内或基因间的元素。HLA/KIR/FcGR/IGHG基因具有高度多态性， 世代靶向测序（NGTS）将被用于扩展遗传多态性， 的GWAS。发现和表征HLA/KIR/FcGR/IGHG基因内的进展相关CRS 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，以减缓或甚至恢复临床诊断的进展。在2018年， 我们从NIDDK获得了一笔桥梁资金，用于开展HLA基因在疾病进展中的试点研究， 根据糖尿病预防试验-1（DPT-1）。我们的试点研究产生了两个具体的重要发现， HLA-DQB 1中的β57和（-18β）残基，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）。为支持这项申请，我们 从另一项多中心国际口服胰岛素预防试验（TN 07）中获得临床和遗传数据 并且能够复制与β57的遗传关联。我们能够部分复制出 与残基（-18β），即使中间分辨率的DQ基因分型未覆盖残基（-18β） 位于信号肽中。在这一初步成果的基础上，本提案有两个具体目标：目标1是 估计DQB 1 * β57的突变率，有或没有（-18β），从精确的 使用年轻人糖尿病的环境决定因素确定T1 DM发病的血清转换 （泰迪）。TEDDY是一项前瞻性的出生队列研究， 从而可以精确地确定血清转化时间。目的二是进行机理研究， DQB 1 CRS以及HLA/KIR/ FcGR/IGHG基因中的其他CRS，利用广泛的功能数据 收藏于TEDDY具体来说，我们将评估发现的CRS如何与纵向测量的 自身抗体水平（GADA、IAA、IA-2A、ZnT 8A）、β细胞功能（葡萄糖、C肽、OGTT）和HbA 1c 水平，并将研究如何CRS与顺式和反式基因表达使用纵向 TEDDY病例对照研究中的RNAseq数据。该项目的结果将获得对遗传学的重要见解。 疾病进展的潜在机制，并将影响预防和治疗的转化研究。 针对T1 DM的治疗方法/策略。