Analyzing The Joint Susceptibility Genes for Autoimmune Thyroiditis and Diabetes

自身免疫性甲状腺炎和糖尿病的联合易感基因分析

• 批准号: 7739237
• 负责人: YARON TOMER
• 金额: $ 37.25万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7739237
• 关键词: 3' Untranslated Regions; Alternative Splicing; Amino Acids; Autoimmune thyroiditis; Autoimmunity; Binding; Biochemical; Bioinformatics; Biological; Candidate Disease Gene; Chromosome Mapping; Chromosomes; Collaborations; Complex; Data; Data Set; Development; Diabetes Mellitus; Disease; Etiology; Family; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genome Scan; Genotype; Goals; Grant; Graves' Disease; HLA-DR Antigens; Haplotypes; Hashimoto Disease; Individual; Insulin; Insulin-Dependent Diabetes Mellitus; Introns; Islet Cell; Joints; Knowledge; Lead; Link; Logistic Regressions; Maps; Mass Spectrum Analysis; Microsatellite Repeats; Minisatellite Repeats; Minor; Modality; Modeling; Molecular; Molecular Models; PTPN22 gene; Pathway interactions; Patients; Peptides; Phenotype; Prevention strategy; Reporting; Research; Risk; Structure; Susceptibility Gene; Syndrome; T-Lymphocyte; TNFRSF5 gene; Testing; Thyroglobulin; Thyroid Gland; Thyrotropin Receptor; Translational Research; Variant; Work; autoimmune thyroid disease; base; disease phenotype; experience; gene function; gene interaction; high risk; mRNA Stability; molecular modeling; novel; public health relevance; research study; risk sharing; three dimensional structure; tool

DESCRIPTION (provided by applicant): Autoimmune thyroid diseases (AITD) and type 1 diabetes (T1D) frequently occur within the same family and in the same individual. When AITD+T1D occur in the same individual, the phenotype is considered a variant of the polyglandular syndrome type 3 (APS3 variant [APS3v]). Our goals are: (1) to identify and characterize the joint susceptibility genes for AITD and T1D, and (2) to dissect the mechanisms by which they cause disease. During the last grant period, we have made substantial progress toward these goals, including: (1) We completed the first reported genome scan in families with AITD & T1D, mapped new loci common to AITD & T1D, and identified 3 joint genes for AITD & T1D in linked loci; (2)Determined thatCTLA-4, PTPN22, Insulin VNTR are susceptibility genes for the APS3v (AITD+T1D) phenotype; (3) Discovered a unique HLA-DR pocket amino acid signature that was critical for the development of APS3v and determined the 3-D structure of that pocket; (4) Assembled a dataset of ~ 700 individuals with AITD+T1D (APS3v), giving us power for large scale association studies in this subset; and (5) Dissected mechanisms by which variants in AITD genes (Tg, CD40, & TSHR) predispose to disease. We propose to build on these findings to pursue our hypothesis that the joint etiology of AITD & T1D depends on genetic and biological interactions between several genes. Our specific aims are: Specific Aim 1: To identify & characterize thyroglobulin (Tg), TPO, insulin, and GAD65 peptides that bind to the unique HLA-DR pocket that we found to be critical for the development of APS3v. We will use: (1) molecular modeling and bioinformatics studies to predict peptides that best fit the structure of the APS3v-associated pocket; and (2) biochemical and mass spectrometry experiments to identify peptides that bind to the pocket. Specific Aim 2: To dissect the mechanisms by which CTLA-4 & FOXP3 variants predispose to APS3v: (1) CTLA-4: we will test whether a 3'UTR microsatellite predisposes to APS3v by lowering CTLA-4 mRNA stability. (2) FOXP3: we will examine whether an intron 5 (TC)n microsatellite repeat confers risk for APS3v by altering the alternative splicing of FOXP3. Specific Aim 3: To fine map and identify new susceptibility genes for APS3v (AITD+T1D): (1) Fine mapping: A major locus on 2p will be fine mapped using densely spaced SNPs & the gene identified. (2) Subset analysis: We will perform a comprehensive association study on the subset of APS3v patients, using our large dataset of APS3v patients and available genotypes on 4000 ethnically matched controls. (3) Gene-gene interaction: genes identified will be analyzed for gene-gene interaction. The current proposal builds directly on the knowledge gained in the previous grant period, and aims to dissect the molecular pathways causing the strong association between AITD and T1D. This will lead to better understanding of the common etiology of both AITD & T1D, as well as APS3v, and may facilitate the development of mechanism- based treatment modalities, such as HLA-DR pocket blockade, or CTLA-4 activation. PUBLIC HEALTH RELEVANCE: Autoimmune thyroid diseases, including Hashimoto's thyroiditis and Graves' disease commonly occur together with type 1 (Juvenile) diabetes in the same families and in the same individual, most likely due to shared genetic susceptibility. The goal of our studies is to identify and characterize the joint susceptibility genes for autoimmune thyroid diseases and type 1 diabetes, and to study the mechanisms by which they cause these two diseases. Understanding the mechanisms causing the strong association between thyroid autoimmunity and type1 diabetes will allow us not only disease predictions within families, but also to develop rational, mechanism-based, treatment and prevention strategies

描述（由申请人提供）：自身免疫性甲状腺疾病（AITD）和 1 型糖尿病（T1D）经常发生在同一家庭和同一个人中。当 AITD+T1D 发生在同一个体时，该表型被认为是 3 型多腺体综合征的变异体（APS3 变异体 [APS3v]）。我们的目标是：(1) 识别和表征 AITD 和 T1D 的联合易感基因，(2) 剖析它们引起疾病的机制。在上一资助期内，我们在实现这些目标方面取得了实质性进展，包括：（1）我们完成了首次报告的 AITD 和 T1D 家族基因组扫描，绘制了 AITD 和 T1D 共有的新位点，并在连锁位点中鉴定了 AITD 和 T1D 的 3 个联合基因； (2)确定CTLA-4、PTPN22、胰岛素VNTR为APS3v(AITD+T1D)表型的易感基因； (3) 发现了对 APS3v 发育至关重要的独特 HLA-DR 口袋氨基酸特征，并确定了该口袋的 3-D 结构； (4) 收集了约 700 名 AITD+T1D (APS3v) 患者的数据集，为我们在该子集中进行大规模关联研究提供了动力； (5) 剖析 AITD 基因变异（Tg、CD40 和 TSHR）诱发疾病的机制。我们建议在这些发现的基础上继续我们的假设，即 AITD 和 T1D 的共同病因取决于多个基因之间的遗传和生物相互作用。我们的具体目标是： 具体目标 1：识别和表征与独特的 HLA-DR 口袋结合的甲状腺球蛋白 (Tg)、TPO、胰岛素和 GAD65 肽，我们发现该口袋对于 APS3v 的发展至关重要。我们将使用：（1）分子建模和生物信息学研究来预测最适合APS3v相关口袋结构的肽； (2) 生化和质谱实验来鉴定与口袋结合的肽。具体目标2：剖析CTLA-4和FOXP3变体易患APS3v的机制：（1）CTLA-4：我们将测试3'UTR微卫星是否通过降低CTLA-4 mRNA稳定性而易患APS3v。 (2) FOXP3：我们将通过改变 FOXP3 的选择性剪接来检查内含子 5 (TC)n 微卫星重复是否会带来 APS3v 的风险。具体目标 3：精细定位并鉴定 APS3v (AITD+T1D) 的新易感基因： (1) 精细定位：将使用密集间隔的 SNP 和已识别的基因对 2p 上的主要基因座进行精细定位。 (2) 子集分析：我们将使用我们的 APS3v 患者大型数据集和 4000 名种族匹配对照的可用基因型，对 APS3v 患者子集进行全面的关联研究。 (3)基因-基因相互作用：对识别出的基因进行基因-基因相互作用分析。当前的提案直接建立在之前资助期间获得的知识的基础上，旨在剖析导致 AITD 和 T1D 之间密切关联的分子途径。这将有助于更好地了解 AITD 和 T1D 以及 APS3v 的常见病因，并可能促进基于机制的治疗方式的开发，例如 HLA-DR 口袋阻断或 CTLA-4 激活。公共卫生相关性：自身免疫性甲状腺疾病，包括桥本甲状腺炎和格雷夫斯病，通常与 1 型（青少年）糖尿病一起发生在同一家庭和同一个体中，最有可能是由于共同的遗传易感性。我们研究的目标是识别和表征自身免疫性甲状腺疾病和 1 型糖尿病的联合易感基因，并研究它们引起这两种疾病的机制。了解甲状腺自身免疫与 1 型糖尿病之间密切相关的机制将使我们不仅能够预测家庭内的疾病，而且能够制定合理的、基于机制的治疗和预防策略