Genetic Prediction for Treatment Resistance in Kawasaki Disease

川崎病治疗耐药性的基因预测

• 批准号: 10065014
• 负责人: Michael A Portman
• 金额: $ 84.7万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-15 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10065014
• 关键词: Acute; African American; Age; American; American Heart Association; Aneurysm; Anti-Inflammatory Agents; Anticoagulation; Asia; Aspirin; Biological Markers; Candidate Disease Gene; Cardiovascular system; Case-Control Studies; Catheters; Child; Clinical; Clinical Data; Clinical Trials; Coronary; Coronary Aneurysm; Coronary Arteriosclerosis; Coronary artery; Coronary heart disease; DNA; Data; Detection; Development; Disease; Disease susceptibility; Echocardiography; Enrollment; Foundations; Frequencies; Funding; Future; Gamma globulin; Gender; Genes; Genetic; Genetic Markers; Genetic Variation; Guidelines; Impairment; Incidence; Individual; Infant; Inflammation; Inflammatory; Institutes; Intercistronic Region; Intravenous; Intravenous Immunoglobulins; Japan; Japanese Population; Laboratories; Life; Linkage Disequilibrium; Medical; Methodology; Methods; Modification; Morbidity - disease rate; Mucocutaneous Lymph Node Syndrome; Myocardial Infarction; Natural History; North America; Operative Surgical Procedures; Pacific Northwest; Parents; Patients; Pharmacogenomics; Phase; Phenotype; Population; Prediction of Response to Therapy; Principal Component Analysis; Privatization; Race; Research; Research Personnel; Resistance; Resources; Risk; Sampling; Stenosis; Structure; Techniques; Therapy trial; Thrombosis; Time; Transcriptional Regulation; Update; Variant; Vasculitis; base; biobank; clinical biomarkers; exome sequencing; genetic approach; genetic information; genetic variant; genome analysis; genome sequencing; genome wide association study; high risk; improved; improved outcome; individual patient; insertion/deletion mutation; novel; predicting response; prediction algorithm; prevent; rare variant; recruit; repository; research clinical testing; response; therapy development; therapy resistant; treatment response; whole genome

PROJECT SUMMARY/ABSTRACT Kawasaki Disease (KD) is a major contributor to cardiovascular morbidity in children. Poor response to IVIG remains one of the critical determinants of coronary artery risk in KD. The inability to predict this response and the potential for developing persistent coronary artery aneurysms serves as a major impediment to progress and development of intensified therapy. Currently available data indicate that KD susceptibility and treatment response, as well as the propensity for coronary artery disease, depend on an individual patient's genetic background. Studies directed at identifying appropriate genetic biomarkers have been impaired by: 1) phenotyping lacking rigor, 2) use of genome wide association studies often employing chips or arrays for detection of common variants rather than low frequency or rare variants, 3) lack of clarity for the mechanisms of IVIG anti-inflammation in KD (necessary for guiding most pharmacogenomics studies) 4) focus on gene candidates, which are impractical for clinical testing, and 5) vague racial assignment methodology confounding pharmacogenomics. Furthermore, exome sequencing and analyses likely would miss potential important variants as IVIG anti-inflammatory mechanism includes transcriptional regulation at intergenic regions. We hypothesize that, by using improved and rigorous phenotyping techniques in combination with whole genome sequencing (WGS) and analyses, we will be able to identify select biomarkers for accurate prediction of KD treatment response and development of coronary aneurysms. The Pacific Northwest Kawasaki Disease Data-Biobank, established mainly through funding via PI Portman, R21HL090558, Thrasher Research Foundation; and PI, Shrestha, Southeastern AHA has accumulated DNA and clinical data from over 800 KD patients, eligible for pharmacogenomics analyses. We will leverage this wealth of DNA and clinical data along with recently updated AHA clinical KD criteria in order to identify rare and common variants, which determine IVIG treatment response. WGS will also allow a) identification of individual private SNPs (rare variants), b) identification of population-specific private SNPs, c) building a complete picture of genetic variations including structural variants (CNVs and insertion/deletions), d) gene- based analysis of both common and rare variants, and e) identification of actual functional SNPs as opposed to common imputed or SNPs in linkage disequilibrium (LD). Additionally, we will account for race, an important variant in KD, by rigorous racial assignment using ancestry information markers and principal component analyses. We will use rigorous methodology to achieve the following specific aims 1) Perform whole genome sequencing to identify genetic variations, which could serve as clinical biomarkers for IVIG resistance in KD patients. 2) Determine novel genomic variants associated with giant coronary artery aneurysms (GCA) among children with KD. 3) Prepare to assess if IVIG resistance is greater among African Americans and if this response depends on racial based differences in the frequency of genetic variations.

项目摘要/摘要 川崎病（KD）是儿童心血管发病率的主要因素。对IVIG的反应不佳 仍然是KD冠状动脉风险的关键决定因素之一。无法预测这种反应 发展持续性冠状动脉动脉瘤的潜力是对 加强治疗的进展和发展。当前可用的数据表明KD易感性和 治疗反应以及冠状动脉疾病的倾向取决于个体患者的 遗传背景。针对识别适当遗传生物标志物的研究受到了以下损害：1） 表型缺乏严格，2）使用基因组广泛的关联研究通常使用芯片或阵列进行 检测常见变体，而不是低频或稀有变体，3）缺乏对机制的清晰度 KD中的IVIG抗炎（指导大多数药物基因组学所必需）4）专注于基因 候选人，对于临床测试是不切实际的，5）模糊的种族分配方法 混淆药物基因组学。此外，外显子组测序和分析可能会错过潜力 重要变体作为IVIG抗炎机制包括基因间的转录调节 地区。我们假设，通过使用改进和严格的表型技术与 整个基因组测序（WGS）和分析，我们将能够识别精确的生物标志物以准确 KD治疗反应和冠状动脉瘤的发育的预测。太平洋西北 川崎疾病数据库，主要是通过Pi Portman的资金建立的，R21HL090558， Thrasher Research Foundation；和PI，Shrestha，AHA东南AHA积累了DNA和临床 来自800多名患者的数据，有资格进行药物基因组学分析。我们将利用这种财富 DNA和临床数据以及最近更新的AHA临床KD标准，以确定稀有和 常见变体，确定IVIG治疗反应。 WGS还将允许a）识别 单个私人SNP（稀有变体），b）识别特定人群的私人SNP，c）建造A 遗传变异的完整图片，包括结构变异（CNV和插入/缺失），d）基因 基于共同变体和稀有变体的分析，以及e）识别实际功能SNP 在连锁不平衡（LD）中进行的普通估算或SNP。此外，我们将考虑种族 KD中的重要变体，通过使用祖先信息标记和校长进行严格的种族分配 组件分析。我们将使用严格的方法来实现以下特定目的1）执行 整个基因组测序以鉴定遗传变异，可以用作IVIG的临床生物标志物 KD患者的抗药性。 2）确定与巨型冠状动脉相关的新型基因组变异 KD儿童中的动脉瘤（GCA）。 3）准备评估非洲IVIG抵抗是否更大 美国人以及这种反应取决于基于种族的遗传变异频率的差异。