Susceptibility genes for Kawasaki disease: Toward implementation of personalized medicine

ArticleinJournal of Human Genetics 54(2):67-73 · February 2009with19 Reads
DOI: 10.1038/jhg.2008.9 · Source: PubMed
Kawasaki disease (KD) is an acute systemic vasculitis syndrome, which primarily affects in children under the age of 5 years. In 20-25% of cases, if untreated, coronary artery lesions develop, making KD the leading cause of acquired heart disease in children in both Japan and the United States. Since 1970, 19 nationwide surveys of KD in Japan have been conducted every 2 years and the data are stored in a database. Even though the etiology of KD remains unknown, despite enthusiastic research spanning more than 40 years, we have learnt a great deal about KD from this enormous database. These 19 epidemiologic studies indicate a strong genetic influence on the disease susceptibility, prompting us and other researchers to identify the responsible genes for KD by applying either the candidate gene approach or the genome-wide approach. We have employed a genome-wide linkage study using affected sibling pair data of KD in Japan and have identified several susceptibility loci. Further analysis focusing on a region of chromosome 19, where one of the linked loci was detected, identified a predisposing gene, which codes inositol 1,4,5-trisphosphate 3-kinase C (ITPKC). In this review, we summarize the cumulative knowledge regarding KD, and then outline our hypothesis of the role ITPKC plays in KD susceptibility and our trial that aims toward the implementation of personalized medicine for KD.
    • "The search for the causative agent for Kawasaki disease (KD) has now spanned four decades and the environmental trigger for this self-limited pediatric vasculitis remains elusive [1]. Previous epidemiologic investigations suggest that the agent is widely distributed in the environment, that there is no person-to-person transmission, and that genetic susceptibility explains at least some of the variation in disease incidence among different ethnic and racial groups234. KD was first described by Tomisaku Kawasaki in Japanese children in the early 1960s [5,6]. Since that time KD has been recognized in children of all racial groups from all continents [7]. "
    [Show abstract] [Hide abstract] ABSTRACT: Understanding global seasonal patterns of Kawasaki disease (KD) may provide insight into the etiology of this vasculitis that is now the most common cause of acquired heart disease in children in developed countries worldwide. Data from 1970-2012 from 25 countries distributed over the globe were analyzed for seasonality. The number of KD cases from each location was normalized to minimize the influence of greater numbers from certain locations. The presence of seasonal variation of KD at the individual locations was evaluated using three different tests: time series modeling, spectral analysis, and a Monte Carlo technique. A defined seasonal structure emerged demonstrating broad coherence in fluctuations in KD cases across the Northern Hemisphere extra-tropical latitudes. In the extra-tropical latitudes of the Northern Hemisphere, KD case numbers were highest in January through March and approximately 40% higher than in the months of lowest case numbers from August through October. Datasets were much sparser in the tropics and the Southern Hemisphere extra-tropics and statistical significance of the seasonality tests was weak, but suggested a maximum in May through June, with approximately 30% higher number of cases than in the least active months of February, March and October. The seasonal pattern in the Northern Hemisphere extra-tropics was consistent across the first and second halves of the sample period. Using the first global KD time series, analysis of sites located in the Northern Hemisphere extra-tropics revealed statistically significant and consistent seasonal fluctuations in KD case numbers with high numbers in winter and low numbers in late summer and fall. Neither the tropics nor the Southern Hemisphere extra-tropics registered a statistically significant aggregate seasonal cycle. These data suggest a seasonal exposure to a KD agent that operates over large geographic regions and is concentrated during winter months in the Northern Hemisphere extra-tropics.
    Full-text · Article · Sep 2013
    • "This points towards presence of factors other than the severity of inflammation that play a role in determination of coronary artery involvement. In the recent years a number of genetic markers including certain genetic polymorphisms, specific genes, human lymphocyte antigen types, calcium dependent NFAT signaling, caspase-3, and TGF beta genes have been associated with coronary artery involvement in Kawasaki disease [45][46][47][48][49][50][51][52][53][54][55][56][57]. Yamamura et al. have recently reported higher risk of coronary involvement in BB blood group genotype [58]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Coronary artery involvement is seen in approximately 15-20% of children with Kawasaki disease. There is conflicting literature regarding the clinical and laboratory findings associated with coronary artery involvement. In this retrospective study, we attempt identification of predictive factors for coronary artery involvement at our institute and review the existing literature. Methods and results: A review of 203 patients (65% males) with Kawasaki disease was performed, of whom 33 (16.3%) had coronary artery involvement. High erythrocyte sedimentation rate, high platelet count, low hematocrit, low albumin levels, and refractory Kawasaki disease showed significant association with coronary artery involvement. High erythrocyte sedimentation rate and refractory Kawasaki disease were found to be independent predictors of coronary artery involvement. Review of literature suggested a wide range of coronary involvement (<5% to >60%), and highly conflicting clinical and laboratory associations. Conclusion: It remains difficult to accurately determine risk of coronary artery involvement, although some laboratory markers may provide information that is helpful for parental counseling and clinical follow up. Future identification of novel biomarkers and host predispositions may further our understanding of coronary artery risks and help personalize therapy for Kawasaki disease.
    Full-text · Article · Jun 2013
    • "CONCLUSIONS Finding out the molecular mechanisms of genetic predisposition to the most widespread diseases such as cardioovascular, psychooneurological, and oncology is one of the main problems of modern medical genetics, molecular physiology, and pathology. Within this problem currently all over the world extensive investii gations for detection candidate genes, studying polyy morphisms in nucleotide sequences of these genes, and establishment of relations between one or another studied variant of sequences and studied pathology are conducted (Hata and Onouchi, 2009; Toyoda and Ishh ikawa, 2010; Kingsley, 2011; Chung and Chanock, 2011). However, some concrete polymorphisms in separate genes–candidates are the object of the majorr ity of such works, which do not fully represent the genetically conditioned reasons of the development of multifactor diseases. "
    [Show abstract] [Hide abstract] ABSTRACT: Polymorphisms belonging to the regulatory regions of the APC and MLH1 genes were detected by invoking ChIP-Seq data obtained in the ENCODE project. The significance of these polymorphisms for gene regulation was confirmed by gel retardation of DNA probes by nuclear proteins. More than half of the polymorphisms in the overlapping region of more than eight ChIP-Seq peaks were found to be significant for regulation.
    Full-text · Article · May 2012
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