Identification of the Early Onset SLE Gene on 17p13

17p13 上早发 SLE 基因的鉴定

• 批准号: 6797285
• 负责人: ANDREA L SESTAK
• 金额: $ 12.69万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6797285
• 关键词: clinical research; disease /disorder onset; family genetics; gene expression; gene mutation; genetic mapping; genetic markers; genetic susceptibility; genotype; human genetic material tag; human tissue; linkage disequilibriums; pediatrics; single nucleotide polymorphism; systemic lupus erythematosus

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.

描述（由申请人提供）： OMRF正在进行的研究已经招募了160多个系统性红斑狼疮（SLE）家族并进行了基因分型。亚组分析显示，在17 p13的LOD值为3.0的早发性狼疮的易感基因，这些家庭中至少有一个SLE患者发病年龄小于16岁。在160个家庭收集的受影响的相对对的独立分析，使用主成分法，证实发病年龄是一个主要的协变量，在同一网站，D17 s1298产生的LOD为4.4。我们已经指定这个假定的易感基因SLE pediatric 1（SLEP 1），本申请的目标是找到和表征这个基因。首先，我们预计，通过在OMRF招募多重家系的持续努力，将有另外30-45个家庭（其中至少有一名儿童期SLE患者）可供选择，我们将在第二个队列中确认D17 s1298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SNP，将感兴趣的区域缩小到2-3 cM。接下来，我们将通过对该区域已知基因的SNP标记进行基因分型，并通过连锁不平衡方法分析这些标记，来评估缩小的易感区域中的潜在候选基因。在这个阶段，优先考虑该区域中在自身免疫发病机制中具有合理作用的任何基因。最后，如果通过与SLE的连锁不平衡来鉴定基因的SNP没有被证明是致病突变，我们将对推定的易感基因进行测序，并试图发现导致SLEP 1的功能突变。 该项目旨在支持K 08指导临床科学家发展奖。它与主要研究者的职业目标有关，无论是作为儿科风湿病学家还是作为新的科学研究者。该项目有可能增加我们对早发性SLE以及一般狼疮发病机制的遗传因素的理解。它将允许主要研究者与一些合作者互动，并更加熟悉OMRF狼疮遗传学项目中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，使主要研究者能够完全独立。