Elucidation of novel gene variants predisposing to childhood and adult-onset SLE

描述（由申请人提供）：作为我们先前在儿童期发作和成人期发作SLE中进行的遗传研究的后续研究，我们的目标是确定新基因中的主要遗传风险因素，并描述这些新基因的致病突变和疾病参与机制。为了这些研究的目的，我们组建了一个无与伦比的研究人群，包括6,500例成人发病和1,100例儿童发病的SLE病例，以及一个大型的多学科合作研究团队。基于贝叶斯方法，我们开发了一种基因选择工具，以增加遗传关联研究的能力，我们设计了一种新的微阵列平台，以发现导致SLE的易感基因。我们在儿童期发病的SLE家族队列中测试了我们的模型，并在第二个更大的儿童期发病的SLE队列和一个非常大的成人发病的SLE队列中复制了结果。我们建议通过在儿童期发病和成人期发病队列中的四个不同种族的病例对照关联研究中通过测序确定的新SNP的精细定位、重新测序和重新评估来确定以下新基因中的因果变异：FAIM、IRAK 1、KLRG 1、TNFSF 4、TLR 8和SELP。基于发现的变异和因果单倍型块，我们将在SLE的临床亚表型中进行基于假设的分析。最后，我们将进行功能性研究，以了解在SLE亚表型中发现和表征的遗传变异可能参与SLE的病因或延续的机制。我们预计这些研究将确定新的基因变异，特别是那些常见的几个种族群体和儿童和成人发病的SLE。这些关联研究的结果将导致其对基因产物的影响的分子表征，并了解这些基因在SLE发病机制中的作用。从这些研究中获得的知识将揭示新的范式，并在理解和最终治疗这种毁灭性疾病方面开辟有希望的新方向。 公共卫生相关性：SLE或狼疮是一种主要影响女性的毁灭性人类疾病，并导致美国数十万患者的显著发病率和痛苦。这种疾病是由遗传和环境因素相互作用引起的。作为本研究目标的遗传因素的发现和表征对于理解该疾病的病理学至关重要，并将为这种毁灭性疾病带来新的靶点和疗法。

DESCRIPTION (provided by applicant): As a follow up to our previous genetic studies both in childhood-onset and adult-onset SLE, our goal is to identify major genetic risk factors in novel genes and characterize the causal mutations and the mechanisms of disease involvement of these new genes. For the purpose of these studies we have assembled an unparalleled study population of 6,500 adult-onsets and 1,100 childhood-onset cases of SLE and a large multidisciplinary collaborative team of investigators. Based on Bayesian methodology, we developed a gene selection tool to increase the power of genetic association studies, and we devised a novel microarray platform to discover susceptibility genes contributing to SLE. We tested our model in a cohort of childhood-onset SLE families and replicated the results in a second much larger childhood-onset SLE cohort and a very large cohort of adult onset SLE. We propose to identify the causal variants in the following new genes: FAIM, IRAK1, KLRG1, TNFSF4, TLR8 and SELP by fine mapping, re-sequencing and re-evaluation of the new SNPs identified through sequencing in case-control association studies in four different ethnicities in both childhood-onset and adult-onset cohorts. Based on the variants and causal haplotype blocks found, we will conduct hypothesis-based analyses in clinical sub-phenotypes of SLE. Finally we will conduct functional studies toward understanding the mechanisms through which the genetic variants discovered and characterized in sub-phenotypes of SLE may be involved in the causation or perpetuation of SLE. We anticipate that these studies will identify novel gene variants, especially those that are common to several ethnic groups and to both childhood- and adult-onset SLE. Results of these association studies will lead to the molecular characterization of their effects on the gene products and an understanding of the role of these genes in the pathogenesis of SLE. Knowledge gained from these studies will reveal new paradigms and open promising new directions in the understanding and ultimately the treatment of this devastating disorder. PUBLIC HEALTH RELEVANCE: SLE or lupus is a devastating human disease affecting mainly females and is responsible for significant morbidity and suffering to hundreds of thousands of patients within USA. The disease is caused by interacting genetic and environmental factors. The discovery and characterization of the genetic factors which are the goals of this study are crucial for the understanding of the pathology of the disease and will result in novel targets and therapies for this devastating condition.