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Characterizing the Takayasu arteritis genetic risk in RPS9/LILRB3

RPS9/LILRB3 中大动脉炎遗传风险的表征

基本信息

批准号：
10017651
负责人：
Amr H Sawalha
金额：
$ 33.96万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-12 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10017651
关键词：
19q13 Address Affect Age Antigen-Presenting Cells Aortitis Appearance Applications Grants Architecture Arteries Arthralgia Blood Vessels Body Weight decreased Characteristics Chromatin Chromosome 19 Chromosomes Chronic Collaborations Complex Custom Data Dilatation - action Disease Disease Pathway Disease susceptibility Enhancers Ethnic Origin Etiology Fatigue Female Fever Fibrosis Gene Cluster Genes Genetic Genetic Predisposition to Disease Genetic Risk Genetic study Genomic Segment Genomics Geographic Locations Granulomatous HLA-B Antigens Human Immunoglobulins Infiltration Inflammatory Interleukin-6 International Ischemia Leukocytes Limb structure Link Locus Control Region Macrophage Activation Molecular Conformation Myalgia Night Sweating Nucleic Acid Regulatory Sequences Organ Pathogenesis Pathogenicity Pathologic Patients Pattern Phenotype Physiologic pulse Prevalence Process Role Serum Signal Transduction Structure Susceptibility Gene Symptoms Takayasu&apos s Arteritis Transcript Uncertainty Untranslated RNA Variant Vasculitis Woman Work causal variant cohort design disorder risk epigenomics ethnic difference functional genomics genetic association genetic variant genome wide association study immunoregulation innovation killer immunoglobulin-like receptor mRNA Expression male monocyte novel receptor risk variant targeted treatment transcriptome sequencing transcriptomics

项目摘要

Abstract Takayasu arteritis is a systemic inflammatory disease of the large arteries and their major branches. The etiology and pathogenesis of Takayasu arteritis are poorly understood, however, a genetic contribution to the disease has been suggested by the established genetic association with HLA-B*52. Our recent work identified and confirmed multiple genetic susceptibility loci for Takayasu arteritis outside of the HLA region. These include a genetic risk locus on the leukocyte receptor complex (LRC) region on chromosome 19q13.4. We localized the genetic signal in this region to RPS9/LILRB3, and the causal variant(s) in this locus is tagged by the SNP rs11666543 which influences the expression levels of multiple transcripts within this region suggesting that the causal variant is located within a regulatory genetic element. Indeed, rs11666543 is located within an active enhancer region in primary monocytes, and the disease risk variant is associated with significant reduction of LILRB3 mRNA expression. LILRB3 is an inhibitory immunoregulatory receptor expressed on antigen presenting cells, and its deficiency has been linked to monocyte/macrophage activation. We propose to use innovative state-of-the-art genomic and epigenomic approaches, followed by functional studies to identify and characterize the causal genetic variants in this locus, and their functional pathogenic effect upon disease susceptibility.

抽象的大动脉炎是大动脉及其主要分支的全身性炎症性疾病。这人们对大动脉炎的病因和发病机制知之甚少，然而，遗传因素对大动脉炎的影响已确定的与 HLA-B*52 的遗传关联表明该疾病。我们最近的工作确定并确认了 HLA 区域之外的多个大动脉炎遗传易感位点。这些包括染色体 19q13.4 上白细胞受体复合物 (LRC) 区域的遗传风险位点。我们将该区域的遗传信号定位于 RPS9/LILRB3，并且该基因座中的因果变异被标记为 SNP rs11666543 影响该区域内多个转录本的表达水平，表明因果变异位于调控遗传元件内。事实上，rs11666543 位于原代单核细胞中的活性增强子区域，并且疾病风险变异与显着相关 LILRB3 mRNA 表达减少。 LILRB3 是一种抑制性免疫调节受体，表达于抗原呈递细胞，其缺陷与单核细胞/巨噬细胞活化有关。我们建议使用创新的最先进的基因组和表观基因组方法，然后进行功能研究识别和表征该位点的因果遗传变异，及其功能性致病作用疾病易感性。