Genetic Markers and gene expression in Kawasaki Disease

川崎病的遗传标记和基因表达

基本信息

批准号：
7763774
负责人：
JANE C BURNS
金额：
$ 73.51万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-12-01 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7763774
关键词：
ADRB2 gene Abdominal Aortic Aneurysm Acute Adherence Adjuvant Therapy Adrenergic Receptor Affect Age American Aneurysm Antigens Atherosclerosis Atopic Dermatitis Autopsy B-Lymphocytes Basophils Biological Blood Cells Blood Vessels Burn injury CCL3L1 gene CCL4 gene CD4 Positive T Lymphocytes CD8B1 gene CXCR4 gene Candidate Disease Gene Cardiovascular Diseases Case-Control Studies Cells Cessation of life Child Childhood Clinical Clinical Trials Coagulation Process Cohort Analysis Communicable Diseases Complex Complication Coronary artery Cytokine Gene Data Development Disease Disease Outcome Disease susceptibility Dose Early treatment Educational process of instructing Eosinophilia Epidemiology Etiology Extracellular Matrix Failure Family Fathers Fever Functional disorder Funding Gamma globulin Gene Dosage Gene Expression Genes Genetic Genetic Markers Genetic Polymorphism Genetic Transcription Genetic Variation Genotype HIV HIV-1 Haplotypes Heart Diseases Helper-Inducer T-Lymphocyte Human Human Genome Humoral Immunities Hypersensitivity IL4 Signaling Pathway IL4 gene IgE Immune Immune Response Genes Immune response Immunity Immunologics Incidence Individual Infection Inflammation Inflammatory Injury Integration Host Factors Interleukin 4 Receptor Interleukin-10 Interleukin-13 Interleukin-4 Interleukin-5 Interleukin-6 International Intravenous Intravenous Immunoglobulins Laboratories Lead Leukocytes Ligands Link Literature Low affinity IgE receptor Lymphocyte MME gene Macrophage Inflammatory Protein-1 Malaria Mediating Microarray Analysis Molecular Monocyte Chemoattractant Protein-1 Mononuclear Monozygotic twins Mothers Mucocutaneous Lymph Node Syndrome Myocardial Infarction Myocardial Ischemia National Heart, Lung, and Blood Institute Neprilysin Outcome PTPRC gene Parents Pathogenesis Pathway interactions Patients Phase Phenotype Phosphoric Monoester Hydrolases Plasma Platelet Glycoproteins Play Pneumonia Population Predisposition Principal Investigator Process Protein Isoforms Protein Tyrosine Phosphatase Proteins Public Health RNA Reaction Receptor Gene Recording of previous events Recovery Recruitment Activity Regulation Research Research Personnel Resistance Resources Risk Role STAT6 Transcription Factor Sample Size Sampling Scientist Serum Signal Pathway Signal Transduction Single Nucleotide Polymorphism Specimen Symptoms System T-Lymphocyte Testing Therapeutic Transcript Translating Treatment outcome United States Universities Upper respiratory tract Variant Vascular Diseases Vascular Endothelium Vasculitis Whole Blood Work base bench to bedside blood pressure regulation chemokine chemokine receptor clinical phenotype cohort cytokine disorder prevention disorder risk gene discovery gene interaction genetic analysis high risk human coronavirus innovation insight lipid metabolism mRNA Stability mast cell member monocyte novel novel therapeutics prevent protective effect receptor response tool transmission process treatment response vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): Kawasaki disease (KD) is the most common cause of acquired cardiovascular disease in childhood in the United States. This acute vasculitis primarily affects children under the age of 5 yrs. who present with fever and mucocutaneous signs of inflammation. The cause of KD remains uncertain, although recent data have implicated a new human coronavirus that causes pneumonia and upper respiratory tract symptoms in children but may cause vasculitis in genetically susceptible hosts. There is currently no specific laboratory test to identify children with KD. Without treatment, one in four children will develop permanent damage to the coronary arteries that may lead to ischemic heart disease, myocardial infarction, and death. High dose intravenous gamma globulin administered within the first 10 days of fever significantly reduces the risk of coronary artery damage by unknown mechanisms. Understanding the process of acute vascular wall damage and recovery in KD will teach us about cellular pathways that are likely to be important in other inflammatory vascular diseases including atherosclerosis and abdominal aortic aneurysms. Long-term objective and specific aims: At the beginning of this project 3 years ago, essentially nothing was known about the genetic influences in KD and no systematic examination of gene transcription in blood cells had been performed. We have now identified candidate genes that may influence disease susceptibility, response to treatment, and outcome. Our exciting finding of a protective effect of a deletion in the chemokine receptor 5 gene (CCR5) suggests an important role of this chemokine receptor in KD and will lead to new insight into KD pathogenesis. An important role for T helper cell-2 signaling pathways was suggested by work implicating the IL-4 gene in disease susceptibility. Gene-gene interactions in the IL-4 pathway will be explored in the current proposal. Other genes implicated in our preliminary studies will be tested in new cohorts of KD patients and include platelet glycoprotein receptor genes and genes involved in lipid metabolism, regulation of blood pressure, extracellular matrix remodeling, and coagulation. The B2- adrenergic receptor was implicated in the development of coronary artery aneurysms. The current proposal focuses on genetic approaches that can identify pathways important in KD pathogenesis and brings together an international team of clinicians with expertise in KD, molecular biologists, a statistical genetics team expert in evaluating genetic influences on disease, and experts in chemokine signaling. Relevance to public health: Each year over 4,000 American children suffer from KD. There is currently no way to predict their response to treatment (15% fail) or outcome (5% develop coronary artery aneurysms). This project will build on previous work to understand the genetic basis for susceptibility to KD and its complications, which will lead to new insights into therapeutics and disease prevention.

描述（由申请人提供）：川崎疾病（KD）是美国儿童时期获得性心血管疾病的最常见原因。这种急性血管炎主要影响5岁以下的儿童。他们出现发烧和炎症的粘膜迹象。 KD的原因仍然不确定，尽管最近的数据暗示了一种新的人类冠状病毒，该冠状病毒导致儿童的肺炎和上呼吸道症状，但可能导致遗传易感宿主的血管炎。目前尚无特定的实验室测试来识别KD儿童。没有治疗，四分之一的孩子将对冠状动脉造成永久性损害，这可能导致缺血性心脏病，心肌梗死和死亡。在发烧的前10天内给药的高剂量静脉γ球蛋白显着降低了未知机制的冠状动脉损伤风险。了解KD中急性血管壁损伤和恢复的过程将教会我们有关其他在包括动脉粥样硬化和腹部主动脉瘤在内的其他炎症性血管疾病中可能很重要的细胞途径。长期客观和具体目标：在3年前该项目的开始，基本上，对KD的遗传影响尚无了解，并且没有对血细胞中基因转录进行系统的检查。现在，我们已经确定了可能影响疾病易感性，对治疗和结果的候选基因。我们在趋化因子受体5基因（CCR5）中对缺失的保护作用的令人兴奋的发现表明，该趋化因子受体在KD中的重要作用，并将导致对KD发病机理的新见解。 T辅助细胞2信号通路的一个重要作用是通过在疾病易感性中暗示IL-4基因的工作提出的。当前建议将探讨IL-4途径中的基因基因相互作用。与我们的初步研究有关的其他基因将在新的KD患者中进行测试，包括血小板糖蛋白受体基因以及涉及脂质代谢的基因，血压调节，细胞外基质重塑和凝结。 B2-肾上腺素受体与冠状动脉动脉瘤的发展有关。当前的建议着重于遗传方法，这些方法可以识别可以在KD发病机理中重要的途径，并汇集了一个具有KD专业知识的临床医生，分子生物学家，分子生物学家，统计遗传学团队在评估遗传影响疾病的统计遗传学专家以及趋化因子信号方面的专家。与公共卫生有关：每年有4,000多名美国儿童患有KD。目前无法预测其对治疗的反应（失败15％）或结果（5％发展冠状动脉瘤）。该项目将以先前的工作为基础，以了解对KD易感性及其并发症的遗传基础，这将导致对预防治疗和疾病的新见解。

项目成果

期刊论文数量（44）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A diagnostic algorithm combining clinical and molecular data distinguishes Kawasaki disease from other febrile illnesses.

DOI：
10.1186/1741-7015-9-130
发表时间：
2011-12-06
期刊：
BMC medicine
影响因子：
9.3
作者：
Ling XB;Lau K;Kanegaye JT;Pan Z;Peng S;Ji J;Liu G;Sato Y;Yu TT;Whitin JC;Schilling J;Burns JC;Cohen HJ
通讯作者：
Cohen HJ

Gene-expression patterns reveal underlying biological processes in Kawasaki disease.

DOI：
10.1186/gb-2007-8-12-r261
发表时间：
2007
期刊：
Genome biology
影响因子：
12.3
作者：
Popper SJ;Shimizu C;Shike H;Kanegaye JT;Newburger JW;Sundel RP;Brown PO;Burns JC;Relman DA
通讯作者：
Relman DA

Transforming growth factor-beta signaling pathway in patients with Kawasaki disease.

DOI：
10.1161/circgenetics.110.940858
发表时间：
2011-02
期刊：
Circulation. Cardiovascular genetics
影响因子：
0
作者：
Shimizu C;Jain S;Davila S;Hibberd ML;Lin KO;Molkara D;Frazer JR;Sun S;Baker AL;Newburger JW;Rowley AH;Shulman ST;Burgner D;Breunis WB;Kuijpers TW;Wright VJ;Levin M;Eleftherohorinou H;Coin L;Popper SJ;Relman DA;Fury W;Lin C;Mellis S;Tremoulet AH;Burns JC
通讯作者：
Burns JC

Transcript abundance patterns in Kawasaki disease patients with intravenous immunoglobulin resistance.

DOI：
10.1016/j.humimm.2010.06.008
发表时间：
2010-09
期刊：
HUMAN IMMUNOLOGY
影响因子：
2.7
作者：
Fury, Wen;Tremoulet, Adriana H.;Watson, Virginia E.;Best, Brookie M.;Shimizu, Chisato;Hamilton, Jennifer;Kanegaye, John T.;Wei, Yi;Kao, Chiayi;Mellis, Scott;Lin, Calvin;Burns, Jane C.
通讯作者：
Burns, Jane C.

Calcium scoring in patients with a history of Kawasaki disease.

DOI：
10.1016/j.jcmg.2011.12.010
发表时间：
2012-03
期刊：
JACC-CARDIOVASCULAR IMAGING
影响因子：
14
作者：
Kahn, Andrew M.;Budoff, Matthew J.;Daniels, Lori B.;Jimenez-Fernandez, Susan;Cox, Amber S.;Gordon, John B.;Burns, Jane C.
通讯作者：
Burns, Jane C.