Mapping Autoimmune Diabetes and Thyroiditis Genes

描述（由申请人提供）：自身免疫性（1型）糖尿病（T1 D）和自身免疫性甲状腺疾病（AITD）是最常见的自身免疫性内分泌疾病。T1 D和AITD是密切相关的靶器官自身免疫性疾病，它们彼此强烈相关;即，这两种疾病经常发生在同一个家庭中，而且经常发生在同一个人身上。因此，我们假设T1 D和AITD的联合易感基因在这些疾病的病因学中起主要作用，我们研究的目标是识别和表征这些基因。我们的方法是收集和分析200个家庭的数据集，其中T1 D和AITD聚类在一起（“T1 D-AITD家庭”）。本研究的具体目的是：（1）从分子水平分析HLA Ⅱ类基因在T1 D和AITD联合易感性中的作用。我们将对所有T1 D-AITD家族成员的DR和DQ基因进行测序，并研究特定序列如何影响T1 D、AITD或两者的表达。我们将使用计算机建模研究，以检查确定的肽结合口袋的结构上的序列的影响。(2)通过对200个T1 D-AITD家族进行全基因组扫描，确定T1 D-AITD的非HLA易感位点/基因。将对显示显著LOD评分的基因座进行精细定位，并对位置候选基因进行鉴定和测序。还将分析鉴定的基因座与HLA II类基因的相互作用。(3)通过确定受基因组扫描中确定的每个基因座影响最大的家族子集，解决T1 D-AITD家族的遗传异质性。这将显著增强这些基因座的精细定位和基因鉴定的能力（具体目标2）。我们有能力和专业知识来实现这些目标，专业知识来自我们对AITD遗传学的广泛研究。此外，我们已经访问了100个T1 D-AITD家庭，我们对其中55个家庭进行了初步分析，这证明了我们方法的有效性。为了招募合适的家庭，我们建立了一个由7个中心组成的联盟，通过这个联盟，我们将把数据集扩大到200个家庭。确定T1 D和AITD共同病因的易感基因将使我们能够在最基本的水平上了解导致T1 D和AITD以及可能的其他自身免疫性疾病的共同机制。这将有助于根据引发疾病的机制开发新的治疗和预防方法。

DESCRIPTION (provided by applicant): Autoimmune (Type 1) diabetes (T1D) and autoimmune thyroid diseases (AITD) are the commonest autoimmune endocrine diseases. T1D and AITD are closely related, target-organ autoimmune diseases which are strongly associated with each other; i.e., both diseases frequently occur within the same family, and often in the same individual. Thus, we hypothesize that joint susceptibility genes for T1D and AITD play a major role in the etiology of these diseases, and the goals of our studies are to identify and characterize these genes. Our approach is to assemble and analyze a dataset of 200 families in which both T1D and AITD cluster together ("T1D-AITD families"). Our specific aims are: (1) To analyze, at the molecular level, the contribution of HLA class II genes to the joint susceptibility to T1D and AITD. We will sequence the DR and DQ genes in all T1D-AITD family members and examine how specific sequences affect the expression of T1D, AITD, or both. We will use computer-modeling studies to examine the influence of sequences identified on the structure of the peptide binding pocket. (2) To identify non-HLA susceptibility loci/genes for T1D-AITD by performing a whole genome scan on 200 T1D-AITD families. Loci showing significant LOD scores will be fine-mapped, and positional candidate genes will be identified and sequenced. Identified loci will also be analyzed for interactions with HLA class II genes. (3) To resolve genetic heterogeneity in the T1D-AITD families by identifying subsets of families which are most influenced by each of the loci identified in the genome scan. This will significantly amplify the power of the fine-mapping and gene identification at these loci (Specific Aim 2). We have the capacity and expertise to achieve these goals, expertise gained from our extensive studies on the genetics of AITD. In addition, we already have access to 100 T1D-AITD families, and we have results of preliminary analyses in 55 of them, which prove the efficacy of our approach. For recruiting appropriate families, we have established a consortium of 7 centers through which we will expand our dataset to include 200 families. Identifying susceptibility genes contributing to the common etiology of T1D and AITD will allow us to understand, at the most basic level, the common mechanisms that cause T1D and AITD, and possibly other autoimmune diseases. This will facilitate the development of novel treatment and prevention approaches based on the mechanisms initiating the diseases.