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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL069413-07
Application #
7624192
Study Section
Special Emphasis Panel (ZRG1-CICS (01))
Program Officer
Kaltman, Jonathan R
Project Start
2001-12-01
Project End
2011-01-31
Budget Start
2009-02-01
Budget End
2010-01-31
Support Year
7
Fiscal Year
2009
Total Cost
$731,468
Indirect Cost
Name
University of California San Diego
Department
Pediatrics
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Hao, Shiying; Jin, Bo; Tan, Zhou et al. (2016) A Classification Tool for Differentiation of Kawasaki Disease from Other Febrile Illnesses. J Pediatr 176:114-120.e8
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Rizk, Sherif R Y; El Said, Galal; Daniels, Lori B et al. (2015) Acute myocardial ischemia in adults secondary to missed Kawasaki disease in childhood. Am J Cardiol 115:423-7
Shimizu, Chisato; Sood, Alka; Lau, Hubert D et al. (2015) Cardiovascular pathology in 2 young adults with sudden, unexpected death due to coronary aneurysms from Kawasaki disease in childhood. Cardiovasc Pathol 24:310-6
Lin, Jonathan; Jain, Sonia; Sun, Xiaoying et al. (2014) Lipoprotein particle concentrations in children and adults following Kawasaki disease. J Pediatr 165:727-31

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