Mapping Autoimmune Phenotypes in Multiplex Families

描述（由申请人提供）：自身免疫性疾病构成具有重叠特征和家族聚集倾向的多种表型组。这项提议和其他研究人员最近的数据已经清楚地表明，许多这些疾病都涉及共同的潜在基因。这一建议的基本原理基于这样的假设，即具有自身免疫的多重家族具有多种风险基因，并且通过关注这些家族中的特定表型亚群，将有可能更有效地识别这些基因。我们将采用全面的“全基因组关联”方法来发现这些基因。该提案建立在已经由主要研究者建立的多重自身免疫家族（MADGC集合）的基础上。在具体的目标1中，我们将收集800个多重家庭的登记处，其中两个或更多成员有自身免疫的证据。登记和登记标准将包括要求这些家庭中至少有一名成员患有五种“核心”自身免疫性疾病之一。这五种核心疾病包括类风湿性关节炎（RA）、系统性红斑狼疮（SLE）、自身免疫性甲状腺疾病（AITD， Graves病或桥本甲状腺炎）、多发性硬化症（MS）和1型糖尿病（T1D）。在特定的Aim 2中，我们将使用317,000个snp （Illumina HapMap300）进行全基因组关联筛选。1000名受影响的受试者，每个多重家族的一名成员，将被用于基因发现数据集，并将被单独进行基因分型。我们将从两组中分别研究500名受试者：1)高滴度自身抗体的SLE，或2)存在抗甲状腺球蛋白抗体的桥本甲状腺炎。对照受试者将从18,000名对照受试者中抽取，并根据年龄、性别、种族和祖先信息SNP标记进行匹配。在具体的目标3中，我们将在独立的数据集上重复研究结果，以期精细绘制和明确识别风险等位基因。这些研究将导致鉴定基因，这些基因可能是多种自身免疫表型的基础，具有主要的体液成分。在特定目的1中收集的家庭资源也将允许在临床前自身免疫受试者中对这些遗传风险因素进行未来评估，以及识别与人类自身免疫性疾病有关的基因-环境相互作用。

DESCRIPTION (provided by applicant): Autoimmune disorders constitute a diverse group of phenotypes with overlapping features and a tendency toward familial aggregation. Recent data from the investigators on this proposal and others have now clearly shown that common underlying genes are involved in many of these disorders. The rationale for this proposal rests on the assumption that multiplex families with autoimmunity are enriched for multiple risk genes, and that by focusing on particular phenotypic subgroups in these families, it will be possible to more efficiently identify these genes. We will employ a comprehensive "whole genome association" approach to the discovery of such genes. The proposal builds upon a collection of multiplex autoimmune families (the MADGC collection) that has already been established by the principal investigators. In specific Aim 1 we will assemble a registry of 800 multiplex families in whom two or more members have evidence of autoimmunity. Registry and enrollment criteria will include a requirement that at least one member of these families have one of five "core" autoimmune diseases. The five core diseases will include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Autoimmune thyroid disease (AITD, either Graves disease or Hashimoto's thyroiditis), multiple sclerosis (MS), and type 1 diabetes (T1D). In specific Aim 2 we will carry out a genome wide screen for association using 317,000 SNPs (Illumina HapMap300). One thousand affected subjects, one member from each multiplex family, will be utilized for the gene discovery dataset and will be individually genotyped. We will study 500 subjects from each of two groups: 1) SLE with high titer autoantibodies, or 2) Hashimoto's thyroiditis with the presence of anti-thyroglobulin antibodies. Control subjects will be drawn from a unique collection of 18,000 control subjects and matched by age sex, ethnicity and ancestry informative SNP markers. In specific Aim 3 we will replicate findings on independent datasets with a view to fine mapping and definitive identification of risk alleles. These studies will lead to the identification of genes which may underlie multiple autoimmune phenotypes with a predominant humoral component. The family resources collected in specific aim 1 will also permit the future evaluation of these genetic risk factors in subjects with preclinical autoimmunity, as well as the identification of gene-environment interactions that are involved in human autoimmune disorders.