GENETICS OF CHILDHOOD ONSET SLE

描述：(改编自《调查者摘要》)系统性肺炎的病因学 红斑狼疮(SLE)包括鲜为人知的遗传、环境和 作用于免疫系统的性激素因素。这样做的长期目标是 应用于识别与人类系统性红斑狼疮发病机制有关的基因 并描述这些基因影响疾病的机制 发展。这项申请也将作为对 在小鼠模型和多基因家族中进行的初步连锁分析。 对于这一阶段的映射，研究人员建议依赖于关联 (连锁不平衡)研究核心家庭，因为他们将能够 收集的研究人群比依赖受影响的人多得多 SIB-配对系谱方法。儿童期发病的系统性红斑狼疮是一种潜在的独特的 患者的亚群，因为其早期发病可能是 遗传易感性和外显性增加，而且因为儿童期发病 这种疾病比成人发病更严重，涉及许多器官，并带有 预后更差。因此，研究人员建议研究核心家庭。 儿童期起病的系统性红斑狼疮患者。鉴于先驱者将是孩子，他们 期待他们的父母和兄弟姐妹可以随时与他们在一起 有参与的动力。具体目标如下。1)招聘和 从850个核心家庭采集血液和DNA，其中至少有一个 患有儿童期系统性红斑狼疮的受试者。他们将对所有的临床研究对象进行分类 系统性红斑狼疮的实验室证据，其器官受累，疾病的严重性和 并发症。这将使用四个招聘研究网站来完成， 这将提供大量的儿科狼疮患者。2)测试 与特定候选基因的关联由连锁、共性和 使用家族控制的广义传输的功能关联性 不平衡检验(TDT)方法。3)探索约5个候选区域 连锁性和同时性提示的连锁不平衡模式 测试标记关联和单倍型共享。最初，他们将使用 每个区域的标记间隔约0.5厘米，并有前景看好的线索 以0.05 cm的标记间距进行随访。调查人员指出，这一点 应用程序集成了多学科团队的人才，结合了 临床专业知识，具有高资质的基础科学家和基因， 流行病学、分子生物学和遗传分析方面的专业知识。他们 进一步声明这是一个多中心应用程序，来自一些最大的 全国的儿童狼疮诊所，因此，代表着一个主要的和 儿童期系统性红斑狼疮遗传学研究的独特资源。

DESCRIPTION: (Adapted from Investigator's Abstract) The etiology of systemic lupus erythematosus (SLE) includes poorly understood genetic, environmental and sex-hormone factors acting on the immune system. The long term goal of this application is to identify genes involved in the etiopathogenesis of human SLE and to characterize the mechanisms by which these genes influence disease development. This application will also serve as a follow-up study of the initial linkage analyses performed in mouse models and in multiplex families. For this stage of mapping, the investigators propose to rely on association (linkage disequilibrium) studies in nuclear families as they will be able to collect a much larger study population than if they relied on the affected sib-pair pedigree approach. Childhood-onset SLE represents a potentially unique subgroup of patients because its early disease onset may be an indicator of increased genetic predisposition and penetrance, and because childhood-onset disease is more severe than adult-onset involving many organs and carrying a worse prognosis. The investigators therefore propose to study nuclear families of childhood-onset SLE subjects. Given that probands will be children, they anticipate that their parents and siblings will be available and strongly motivated to participate. The specific aims are as follow. 1) Recruitment and blood and DNA collection from 850 nuclear families containing at least one subject with childhood-onset SLE. They will classify all subjects for clinical and laboratory evidence of SLE, its organ involvement, severity of disease and complications. This will be accomplished using four recruitment study sites, which will provide large pediatric lupus populations. 2) Testing for association with specific candidate genes suggested by linkage, synteny and functional relevance using the family-controlled generalized transmission disequilibrium test (TDT) approach. 3) Exploring candidate regions of about 5 cM suggested by linkage and synteny for patterns of linkage disequilibrium by testing for marker associations and haplotype sharing. Initially, they will use markers spaced roughly 0.5 cM apart in each region, with promising leads followed up at a 0.05 cM marker spacing. The investigators point out that this application integrates the talent of a multidisciplinary team, combining clinical expertise with highly qualified basic scientists and with genetic, epidemiological, molecular biological and genetic analytic expertise. They further state that this is a multi-center application from some of the largest pediatric lupus clinics in the country and, therefore, represents a major and unique resource for the study of the genetics of childhood-onset SLE.