GENETICS OF CHILDHOOD ONSET SLE

描述：（改编自研究者摘要）全身性 红斑狼疮（SLE）包括知之甚少的遗传，环境和 作用于免疫系统的性激素因子。长期目标是 本发明的应用是鉴定涉及人类SLE发病机制的基因 并描述这些基因影响疾病的机制 发展这项申请也将作为一项后续研究， 在小鼠模型和多重家族中进行初步连锁分析。 对于这一阶段的绘图，研究人员建议依赖于关联 （连锁不平衡）研究的核心家庭，因为他们将能够 收集更多的研究人群，而不是依赖于受影响的人群。 同胞配对系谱法。儿童期发作的SLE代表了一种潜在的独特的 亚组的患者，因为其早期发病可能是一个指标， 增加了遗传易感性和遗传易感性， 疾病比成人发病更严重，涉及许多器官，并携带 预后更差因此，研究人员建议研究核心家庭 儿童期SLE受试者。考虑到先证者是儿童， 预计他们的父母和兄弟姐妹将是可用的， 积极参与。具体目标如下。1)招募和 从850个核心家庭收集血液和DNA，其中至少有一个 患有儿童期发作的SLE的受试者。他们将对所有受试者进行临床分类， SLE的实验室证据，其器官受累，疾病的严重程度， 并发症这将通过4个招募研究中心完成， 这将提供大量的儿童狼疮人群。2)测试 与特定候选基因的关联通过连锁、同线性和 使用家庭控制的广义传递的功能相关性 不平衡检验（TDT）方法。3)探索约5个候选区域 连锁不平衡模式的连锁和共线性模式的cM， 检测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为0.5 cM，具有有希望的线索 以0.05cM标记间距进行随访。调查人员指出， 应用程序整合了多学科团队的人才， 临床专业知识与高素质的基础科学家和遗传， 流行病学、分子生物学和遗传分析专业知识。他们 进一步指出，这是一个多中心的应用程序，从一些最大的 儿童狼疮诊所在该国，因此，代表了一个主要的， 儿童期发病SLE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.