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, rash, conjunctival injection, red mucosal membranes, cervical lymphadenopathy, and swollen extremities. The cause of KD remains unknown and there is no specific laboratory test to identify affected children. Nonetheless, high dose intravenous gamma globulin administered within the first 10 days of fever significantly reduces the risk of coronary artery damage by unknown mechanisms. 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. KD thus presents a unique dilemma: the disease may be difficult to recognize, there is no diagnostic laboratory test, there is an extremely effective therapy, and there is a 25 percent chance of serious cardiovascular damage or death if the therapy is not administered. Recent advances in the field of functional genomics allow the analysis of gene expression in complex biologic events such as the response to infection or vascular injury. These advances coincide with the emerging recognition that the hosts innate immune system responds to pathogen-associated molecular patterns with stereotypic patterns of gene expression. Thus, a survey of the transcriptional response can yield clues about the nature of the stimulus. This proposal brings together clinicians with expertise in KD, molecular biologists skilled in the application of these new genomic tools, and a statistical genetics team expert in evaluating genetic influences on disease susceptibility and outcome. This interdisciplinary team will discover the pattern of gene expression in acute KD and in patients with similar appearing, non-KD illness using DNA microarray techniques and mRNA quantitation by kinetic reverse transcriptase-polymerase chain reaction. Unique features of the transcriptional response in KD children will be used to develop a diagnostic test for KD. The role that genetic polymorphisms play in these gene expression patterns and their influence on disease susceptibility, response to therapy, and outcome will also be examined.
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