Identification of the Early Onset SLE Gene on 17p13

描述(由申请人提供)： OMRF正在进行的研究招募了160多个系统性红斑狼疮(SLE)多发性家系，并对其进行了基因分型。对至少有一名发病年龄小于16岁的系统性红斑狼疮患者的家庭进行的亚组分析显示，17p13的Lod评分为3.0的可能是早发性狼疮的易感基因。使用主成分方法对160个家系中受影响的亲属对进行独立分析，证实发病年龄是一个主要的协变量，在同一位点D17s1298产生的LOD值为4.4。我们将这个可能的易感基因命名为SLE儿科1(SLEP1)，本应用的目的是寻找和鉴定该基因。首先，我们预计，通过在OMRF招募多个家系的持续努力，将有另外30-45个家庭至少包含一名儿童起病SLE成员，我们将在第二个队列中寻求确认D17s1298的效果。如果成功，我们将使用精细作图技术，首先使用额外的微卫星标记，然后使用SNPs，将感兴趣的区域缩小到2-3厘米。接下来，我们将评估缩小易感区域的潜在候选基因，方法是对该区域已知基因的SNP标记进行基因分型，并用连锁不平衡方法进行分析。在这一阶段，将优先考虑该区域内任何在自身免疫发病机制中可能起作用的基因。最后，如果选择通过与SLE连锁不平衡来识别基因的SNP被证明不是致病突变，我们将对可能的易感基因进行测序，并试图发现导致SLEP1的功能突变。 该项目是为了支持K08临床科学家导师发展奖而提出的。它与首席研究员的职业目标有关，既是作为儿科流变学家，也是作为一名新的科学调查员。这个项目有可能增加我们对早发性SLE和狼疮发病机制的遗传因素的理解。它将使首席研究人员能够与一些合作者互动，并更熟悉OMRF狼疮遗传学项目目前使用的最先进的基因分型和生物统计分析技术。此外，该项目有可能产生分子生物学方面的相关项目，使首席研究人员完全独立。

DESCRIPTION (provided by applicant): Ongoing studies at the OMRF have recruited and genotyped over 160 families multiplex for systemic lupus erythernatosus (SLE). Subgroup analysis of those families containing at least one SLE patient with age of onset less than 16 has revealed a putative susceptibility gene for early onset lupus with a lod score of 3.0 at 17p13. Independent analysis of affected relative pairs in the 160 family collection, using a principal component approach, confirms that age of onset is a major covariate, producing a lod of 4.4 at the same site, D17s1298. We have designated this putative susceptibility gene SLE pediatric 1 (SLEP1), and the goal of this application is to find and characterize this gene. First, we expect that an additional 30-45 families containing at least one member with pediatric onset SLE will become available from ongoing efforts to recruit multiplex pedigrees at OMRF, and we will seek to confirm the effect at D17s1298 in a second cohort. If successful, we will use fine mapping techniques, first with additional microsatellite markers and later with SNPs, to narrow the region of interest to 2-3 cM. Next, we will evaluate potential candidate genes in the narrowed susceptibility region by genotyping at SNP markers in known genes in the region and analyzing these by linkage disequilibrium methods. At this stage, priority will be given to any genes in the region with a plausible role in autoimmune pathogenesis. Finally, if the SNP selected to identify the gene through linkage disequilibrium to SLE does not prove to be the causative mutation, we will sequence the putative susceptibility gene and attempt to discover the functional mutations leading to SLEP1. This project is proposed in support of a K08 Mentored Clinical Scientist Development Award. It is relevant to the career goals of the principal investigator, both as a pediatric rheurnatologist and as a new scientific investigator. This project has the potential to increase our understanding of the genetic factors contributing to the pathogenesis of early onset SLE, as well as lupus in general. It will allow the principal investigator to interact with a number of collaborators and to become more familiar with the state of the art genotyping and biostatistical analysis techniques currently used in the OMRF lupus genetics project. In addition, this project has the potential to generate related projects in molecular biology that would allow the principal investigator to become fully independent.