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

描述（由申请人提供）：作为我们之前对儿童发病和成人发病的 SLE 进行基因研究的后续行动，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因果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，其中包括 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来提高遗传关联研究的能力，并设计了一种新型微阵列平台来发现导致 SLE 的易感基因。我们在一组儿童期发病的 SLE 家庭中测试了我们的模型，并在第二个更大的儿童期发病 SLE 队列和一个非常大的成人发病 SLE 队列中复制了结果。我们建议通过对在四个不同种族的儿童发病和成人发病队列的病例对照关联研究中测序确定的新 SNP 进行精细定位、重新测序和重新评估，确定以下新基因中的因果变异：FAIM、IRAK1、KLRG1、TNFSF4、TLR8 和 SELP。根据发现的变异和因果单倍型块，我们将对 SLE 的临床亚表型进行基于假设的分析。最后，我们将进行功能研究，以了解在 SLE 亚表型中发现和表征的遗传变异可能与 SLE 的病因或延续有关的机制。我们预计这些研究将鉴定出新的基因变异，尤其是几个种族群体以及儿童和成人发病的系统性红斑狼疮所共有的基因变异。这些关联研究的结果将导致对它们对基因产物的影响进行分子表征，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，并为理解和最终治疗这种破坏性疾病开辟有希望的新方向。 公共卫生相关性：系统性红斑狼疮或狼疮是一种毁灭性的人类疾病，主要影响女性，导致美国数十万患者发病和遭受痛苦。该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，并将为这种破坏性疾病带来新的靶点和治疗方法。

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.