Genetic Association in Sjogren's Syndrome

描述(由申请者提供)：我们建议识别与干燥综合征风险相关的基因。在过去的十年里，我们一直在利用基因组革命的进步来寻找系统性红斑狼疮的易感基因。在这一点上，我们已经确定了20多种狼疮的遗传效应，并独立证实了其中的6种(见初步数据)。现在，在开始狼疮遗传学研究十年后，我们准备开始研究干燥综合征，这是一种密切相关的疾病。由于现有的基础设施和我们在狼疮方面的经验，我们在干燥综合征方面的进展将会加快。我们计划建立一个科学组织，使我们能够评估300名干燥综合征患者、他们的家人和匹配的对照组中100个候选基因的遗传关联。为了将我们的努力集中在更具遗传同质性的表型上，我们将使用新的欧美共识标准来诊断原发干燥综合征，并增加要求所有受试者都有抗Ro自身抗体沉淀素。我们建议在实验设计中使用遗传关联方法，通过以下实验步骤进行基因鉴定：收集先证者、家庭成员和对照的材料；构建临床和人口学数据库；以及对候选基因及其附近的多态进行基因分型。我们的长期目标是对基因关联进行合理的基因组扫描，但这些技术和方法还没有被证明是可行的。因此，我们设想在未来十年致力于这一科学问题，以实现这一目标，可能需要这样做。另一方面，通过收集所需的材料和寻找候选基因，我们将特别做好准备，一旦可行，就将利用基因组扫描来寻找干燥综合征的基因关联。同时，我们将利用现有的资源和手头的技术和方法，评估尽可能多的候选基因，以阐明干燥综合征病因的遗传成分将为发病机制提供重要的新见解，从而提供新的诊断能力和以前未探索的治疗靶点。

DESCRIPTION (provided by applicant): We propose to identify genes that confer risk for Sjogren's syndrome. For the past ten years, we have been using the advances of the genomic revolution to pursue the genes that predispose to systemic lupus erythematosus. At this juncture, we have established more than 20 genetic effects for lupus and have independently confirmed six of these (see Preliminary Data). Now, a decade after starting the lupus genetics studies, we are ready to begin work with Sjgren's syndrome, a closely-related disorder. Our progress with Sjogren's syndrome will be accelerated because of the infrastructure available and our experience with lupus. We plan to build the scientific organization that will allow us to evaluate 100 candidate genes for genetic association in 300 Sjogren's syndrome patients, their families, and matched controls. In hopes of concentrating our effort on a more genetically homogeneous phenotype, we will use the new European-American consensus criteria for primary Sjogren's syndrome, with the added requirement that all affecteds evaluated have anti-Ro autoantibody precipitins. We propose to use a genetic association approach in an experimental design that will lead to gene identification by the following experimental steps: assembling the materials from probands, family members and controls; constructing the clinical and demographic database; and genotyping polymorphisms in and nearby candidate genes. Our longer term goal is to perform a reasonably powered genome scan for genetic association, but the technologies and methodologies are not yet proven practical. Consequently, we envision a commitment to this scientific problem over the next decade to accomplish this goal, as may be required. On the other hand, by assembling the needed materials and pursuing candidate genes, we will be specifically poised to exploit a genome scan for genetic association in Sjgren's syndrome as soon as it is practical to perform. Meanwhile, we will evaluate as many candidate genes as is practically possible with the resources made available to us and with the technologies and methods in hand to elucidate the genetic component of the etiology of Sjgren's syndrome would provide important new insights into pathogenesis, thereby providing new diagnostic capabilities and previously unexplored therapeutic targets.