Identification of Rheumatic Disease Genes

描述（由申请人提供）：定义引发和促进风湿性和自身免疫性疾病的机制是免疫学、遗传学和医学领域的一个引人注目的目标。造成疾病的重要因素显然包括遗传因素、环境触发因素以及随机或偶然事件，这些事件通过淋巴细胞和炎症细胞的功能改变而发挥作用。尽管有大量的数据可以确定与疾病相关的基因组位点，但发现疾病基因的广泛努力却遇到了挫折。对狼疮易感位点以及假定的风湿病基因阴性的基因组区域的初步分析表明，在与疾病相关的微卫星标记附近，经常存在全长基因组元件，其中一些是多态的。这些重复元件中的一些，被称为长穿插核元件（LINEs; L1），位于宿主基因的内含子片段中，包括一些先前与复杂疾病的发病机制相关的元件。这些初步数据促进了以下假设的阐述：L1元件的多态性全长拷贝的存在确定了候选疾病基因，并可能通过改变这些宿主基因的表达、功能或免疫原性来促进疾病。该研究将通过在人类基因组中鉴定与全长L1元件相关的基因，以及在系统性自身免疫性疾病患者和对照受试者中检测与免疫系统基因相关的几种多态性全长L1元件的患病率，来推进这一新概念。具体目的是1)鉴定含有全长L1元件的人类基因，2)评估风湿性疾病患者和对照组中CD38和BRD7基因中多态性全长L1元件的患病率。虽然风险很高，但对这一创新概念的研究可能对确定风湿性疾病的遗传因素产生重要影响，并对所有复杂疾病具有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.