Identification of Rheumatic Disease Genes

描述(由申请人提供)：在免疫学、遗传学和医学领域，确定引发和促进风湿性和自身免疫性疾病永久存在的机制是一个令人信服的目标。疾病的重要因素显然包括遗传因素、环境诱因以及通过淋巴细胞和炎症细胞功能改变而表现出来的随机或偶然事件。发现疾病基因的广泛努力遇到了挫折，尽管有大量数据确定了统计上与疾病相关的基因组位点。对狼疮易感基因的初步分析，以及基因组中假定的风湿性疾病基因阴性的区域，证明了全长基因组元素的频繁存在，其中一些是多态的，接近与疾病相关的微卫星标记。这些重复元件中的一些被称为长散布核元件(LINE；L1)，位于宿主基因的内含子片段中，包括一些以前与复杂疾病的发病相关的片段。这些初步数据刺激了以下假设的阐述：L1元件全长拷贝的多态存在识别候选疾病基因，并可能通过改变这些宿主基因的表达、功能或免疫原性而导致疾病。这项拟议的研究将通过识别与整个人类基因组中的全长L1元件相关的基因，并通过测试与系统性自身免疫病患者和对照受试者的免疫系统基因相关的几个多态全长L1元件的流行率，来推进这一新概念。其具体目的是1)鉴定含有全长L1元件的人类基因，以及2)评估CD38和BRD7基因中全长L1元件的多态在风湿病患者和对照组中的发生率。虽然风险很高，但对这一创新概念的研究可能会对确定风湿病的遗传贡献产生重要影响，并对所有复杂疾病产生额外的诊断和治疗意义。

DESCRIPTION (provided by applicant): Defining the mechanisms that initiate and promote perpetuation of rheumatic and autoimmune diseases is a compelling goal within the fields of immunology, genetics, and medicine. The important contributors to disease clearly include genetic factors, environmental triggers, and stochastic or chance events that are played out through altered function of lymphocytes and inflammatory cells. Extensive efforts to uncover disease genes have met with frustration, in spite of abundant data that identify genomic loci that are statistically associated with disease. A pilot analysis of lupus susceptibility loci, along with regions of the genome negative for putative rheumatic disease genes, demonstrated the frequent presence of full-length genomic elements, some of which are polymorphic, near microsatellite markers associated with disease. Some of these repeat elements, termed long interspersed nuclear elements (LINEs; L1), are located within intronic segments of host genes, including some that have previously been associated with the pathogenesis of complex diseases. These preliminary data stimulated elaboration of the following hypothesis: the presence of polymorphic full-length copies of L1 elements identifies candidate disease genes and may contribute to disease by modifying expression, function, or immunogenicity of those host genes. The proposed research will advance this novel concept by identifying the genes associated with full-length L1 elements throughout the human genome and by testing the prevalence of several polymorphic full-length L1 elements associated with immune system genes in patients with systemic autoimmune disease and control subjects. The specific aims are 1) to identify the human genes harboring full-length L1 elements, and 2) to assess the prevalence of polymorphic full-length L1 elements in the CD38 and BRD7 genes among rheumatic disease patients and controls. While high risk, investigation of this innovative concept may have an important impact on defining the genetic contributions to rheumatic diseases, with additional diagnostic and therapeutic implications for all complex diseases.