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

阐明易患儿童和成人 SLE 的新基因变异

• 批准号: 8034252
• 负责人: CHAIM O. JACOB
• 金额: $ 54.96万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8034252
• 关键词: Adult; Affect; Alternative Splicing; Animal Model; Blood Cells; Candidate Disease Gene; Cells; Childhood; Clinical; DNA Resequencing; Development; Disease; Environmental Risk Factor; Ethnic Origin; Ethnic group; Etiology; Evaluation; Family; Female; Follow-Up Studies; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Goals; Haplotypes; Human; IRAK1 gene; In Vitro; Inflammatory; Knowledge; Lead; Lupus; Maps; Methodology; Modeling; Molecular; Morbidity - disease rate; Mutation; Pathogenesis; Pathology; Pathway interactions; Patients; Phenotype; Population; Population Study; Predisposition; Proteins; Public Health; Research Personnel; Role; Structure; Susceptibility Gene; System; Systemic Lupus Erythematosus; TLR8 gene; TNFSF4 gene; Technology; Testing; Transcript; Variant; base; case control; cell type; cohort; follow-up; genetic association; genetic risk factor; genetic variant; human disease; multidisciplinary; next generation; novel; public health relevance; sle1/sle3 gene; tool

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.

描述(申请人提供)：作为我们之前对儿童期和成年期SLE的遗传学研究的后续行动，我们的目标是识别新基因中的主要遗传风险因素，并表征这些新基因的因果突变和疾病涉及的机制。为了这些研究的目的，我们汇集了一个无与伦比的研究人群，包括6500名成年患者和1100名儿童起病的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，我们开发了一个基因选择工具来增加遗传关联研究的能力，并设计了一个新的微阵列平台来发现与SLE有关的易感基因。我们在儿童期发病的SLE家庭队列中测试了我们的模型，并在第二个更大的儿童期SLE队列和非常大的成人起病SLE队列中重复了结果。我们建议通过对儿童和成人发病队列中四个不同种族的病例对照关联研究中发现的新SNP进行精细定位、重新测序和重新评估，来确定以下新基因：FAIM、IRAK1、KLRG1、TNFSF4、TLR8和SELP中的因果变异。基于发现的变异和原因单倍型块，我们将对SLE的临床亚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亚型中发现并表征的遗传变异可能参与SLE的原因或永久发生的机制。我们预计，这些研究将确定新的基因变异，特别是那些在几个种族群体以及儿童和成人发病的SLE中常见的基因变异。这些关联研究的结果将导致它们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破坏性疾病方面开辟有希望的新方向。 公共卫生相关性：SLE或狼疮是一种破坏性的人类疾病，主要影响女性，并导致美国数十万患者的严重发病率和痛苦。这种疾病是由遗传和环境因素相互作用引起的。这项研究的目标是发现和表征遗传因素，这对于理解疾病的病理机制至关重要，并将为这种毁灭性的疾病带来新的靶点和治疗方法。