Mapping Autoimmune Diabetes and Thyroiditis Genes

描述(申请人提供)：自身免疫性(1型)糖尿病(T1D)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。T1D和AITD是密切相关的靶器官自身免疫性疾病，彼此之间有很强的相关性；即这两种疾病经常发生在同一个家庭内，往往发生在同一个人身上。因此，我们假设T1D和AITD的联合易感基因在这些疾病的病因中起主要作用，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一个包含200个家族的数据集，其中T1D和AITD聚在一起(“T1D-AITD家族”)。我们的具体目标是：(1)从分子水平分析人类白细胞抗原II类基因在T1D和AITD联合易感性中的作用。我们将对所有T1D-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T1D和/或AITD的表达。我们将使用计算机模拟研究来检查识别的序列对肽结合口袋结构的影响。(2)对200个T1D-AITD家系进行全基因组扫描，寻找T1D-AITD的非人类白细胞抗原易感基因。显示显著LOD分数的基因座将被精细绘制，位置候选基因将被识别和测序。已识别的基因座也将被分析与人类白细胞抗原II类基因的相互作用。(3)通过确定受基因组扫描中每个基因座影响最大的家系子集来解决T1D-AITD家系的遗传异质性。这将极大地增强这些基因座精细定位和基因识别的能力(具体目标2)。我们有能力和专业知识来实现这些目标，这是从我们对AITD遗传学的广泛研究中获得的专业知识。此外，我们已经获得了100个T1D-AITD家系，并对其中55个家系进行了初步分析，证明了我们方法的有效性。为了招募合适的家庭，我们已经建立了一个由7个中心组成的联盟，通过这个联盟，我们将把我们的数据集扩大到包括200个家庭。识别导致T1D和AITD常见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T1D和AITD以及可能导致其他自身免疫性疾病的常见机制。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.