OK COBRE: GENETIC ASSOCIATION IN PEDIATRIC SLE PATIENTS

系统性红斑狼疮(SLE)是一种复杂的自身免疫性疾病，具有多种临床表现，影响所有种族、性别和年龄组。在儿童时期起病的SLE往往更严重，临床病程更具侵略性。虽然已经进行了许多关于SLE的遗传学特征的研究，但没有一项研究集中在儿童发病的亚群上。我们先前收集了三组儿童系统性红斑狼疮患者和匹配的对照组。目前可以获得大多数受试者的临床数据、血清样本和DNA，但到目前为止还没有完成对这些受试者的遗传学研究。目前，据报道，有超过50种不同的基因与成人人群中的系统性红斑狼疮有关，还有数百种以上。 代表优秀的候选基因，基于它们的生理功能。我们计划使用Affymetrix基因芯片简化我们在儿童发病的SLE队列中对易感基因的搜索，该芯片允许在10,000个座位上同时进行基因分型，不久将扩大到在100,000个座位上进行测试。在数据分析核心的帮助下，基因芯片的结果将与文献中报道的候选Gone基因座以及与成人系统性红斑狼疮的已知关联和联系的数据库相关联。根据关联的重要性和作为SLE候选基因的强度的加权，排名前300的影响将在第二个儿科发病的SLE病例和对照队列中表现出来。预计 只有这些效应的一部分将被证实，但那些可复制的效应很可能代表真实的SLE易感基因。最后，将在每个确认的区域中对更多的SNPs进行分型，以确定最相关的单倍型块，该单倍型块应该包含疾病易感性突变本身。发现这种易感性突变可能有助于预测儿童系统性红斑狼疮的疾病风险或临床进展，也可能适用于成人疾病。追踪儿童狼疮易感基因的生物学功能和导致SLE发病机制的功能变化将为进一步适合我作为分子背景的工作提供一个极好的跳板 生物学家和我作为一名儿科风湿病专家对系统性红斑狼疮的兴趣。

Systemic lupus erythematosus (SLE) is a complex autoimmune disease that presents with a variety of clinical manifestations and affects all races, genders, and age groups. SLE that has onset in childhood tends to be more severe and to have a more aggressive clinical course. Although numerous studies have been performed characterizing the genetics of SLE, none of them have focused on the pediatric-onset subgroup. We have previously collected three cohorts of pediatric SLE patients and matched controls. Clinical data, serum samples, and DNA on most of these subjects are currently available, but no genetic studies on these subjects have been completed to date. At present, over 50 different genes are reported to be associated with SLE in adult populations, and hundreds more represent excellent candidate genes, based on their physiologic functions. We plan to streamline our search for susceptibility genes in pediatric-onset SLE cohorts using the Affymetrix GeneChip, which allows simultaneous genotyping at 10,000 loci and is soon to be expanded to test at 100,000 loci. With assistance from the Data Analysis Core, results from the GeneChip will be correlated with a database of candidate gone loci and known associations and linkages to SLE in adults, as reported in the literature. The top 300 effects, based on a weighting of the significance of the association and the strength of the gene as a candidate for SLE, will be characterized in a second cohort of pediatric-onset SLE cases and controls. It is expected that only a subset of these effects will be confirmed, but those effects that can be replicated are likely to represent true SLE susceptibility loci. Finally, additional SNPs will be typed in each confirmed region to determine the most closely associated haplotype block, which should contain the disease susceptibility mutation itself. Finding such a susceptibility mutation could be useful in predicting disease risk or clinical progression in children with SLE and might be applicable to adult disease, as well. Tracing the biological function of pediatric lupus susceptibility genes and the changes in function that lead to SLE pathogenesis would present an excellent springboard for further work well suited to my background as a molecular biologist and my interest in SLE as a pediatric rheumatologist.