Susceptibility genes for Kawasaki disease: Toward implementation of personalized medicine

Department of Public Health, Graduate School of Medicine, Chiba University, Chiba, Japan.
Journal of Human Genetics (Impact Factor: 2.46). 02/2009; 54(2):67-73. 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.

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    • "ITPKC is an important molecule in the regulation of T cell activation, and it may function as a calcium channel modulator21. In 2008, Onouchi and colleagues first identified the functional polymorphism of ITPKC (rs28493229) that is significantly associated with the susceptibility to KD and coronary artery lesions in both Japanese and US children21, 61. Using cell-based functional studies, Onouchi et al further indicated that the risk allele (C allele) of ITPKC reduces the splicing efficiency of the ITPKC mRNA that, in turn, may contribute to the hyperactivation of Ca2+-dependent NFAT pathways in T cells21. "
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    ABSTRACT: Kawasaki disease (KD) is an acute febrile systemic vasculitis, and the cause of KD is not well understood. It is likely due to multiple interactions between genes and environmental factors. The development of genetic association and genome-wide association studies (GWAS) has opened an avenue to better understanding the molecular mechanisms underlying KD. A novel ITPKC signaling pathway was recently found to be responsible for the susceptibility to KD. Furthermore, the GWAS demonstrated the functionally related susceptibility loci for KD in the Caucasian population. In the last decade, the identification of several genomic regions linked to the pathogenesis of KD has made a major breakthrough in understanding the genetics of KD. This review will focus on genetic polymorphisms associated with KD and describe some of the possible clinical implications and molecular mechanisms that can be used to explain how genetic variants regulate the pathogenesis in KD.
    Acta Pharmacologica Sinica 09/2011; 32(10):1193-8. DOI:10.1038/aps.2011.93 · 2.91 Impact Factor
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    • "In recent years, it has been well demonstrated that inflammatory molecules, as well as single nucleotide polymorphisms of genes encoding inflammatory mediators, may contribute to the development and progression of a large number of pathologic conditions including cardiovascular disease.18-21) "
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    ABSTRACT: Kawasaki disease (KD) is a multi-systemic vasculitis with coronary artery involvement. Serum interleukin (IL)-6 levels during acute phase showed a significant correlation with the duration of fever in patients with KD who were not treated with intravenous immunoglobulin (IVIG), suggesting that the regulation of IL-6 expression in KD patients may differ from that in normal children. However, there are controversies surrounding the association between IL-6 (-636 C/G) gene polymorphism and development of KD. One hundred and nine children with KD and 191 children with congenital heart disease were included in this study. Echocardiography was performed to examine cardiac involvement in patients with KD. Genotyping of the IL-6 (-636 C/G) gene polymorphism was performed using the single-base extension method, and serum IL-6 concentrations were estimated using the sandwich enzyme immunoassay method. Neutrophil, platelet count, liver function test, total protein and albumin concentrations were significantly different in the KD group and the serum IL-6 concentration was significantly higher in the KD group than the control group. There was no difference between the patients with coronary arterial dilatation (CAD) and those without CAD in the IL-6 (-636 C/G) polymorphism. The serum albumin concentration was significantly lower in patients with KD who had the -636 C/G or GG genotype compared with the control group. The serum IL-6 concentration was significantly higher in patients with KD who had the -636 C/G or GG genotype. There was no association between the IL-6 (-636 C/G) gene polymorphism and development of coronary arterial lesions in KD. Further multicenter studies are required to establish the relationship between the IL-6 (-636 C/G) gene polymorphism and development of KD.
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    ABSTRACT: Systemic vasculitis is a group of disorders with multiorgan involvement. These disorders have diverse clinical manifestations associated with significant morbidity and mortality. The most common vasculitides in children--Henoch-Schönlein purpura and Kawasaki disease--are self-limiting conditions. The lifelong and chronic vasculitides (eg, giant cell arteritis, Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, polyarteritis nodosa, and Takayasu arteritis) are rarely seen in children. Therefore, the outcome in general is more favorable in children. This article offers an overview of the epidemiologic, etiologic, pathophysiologic, and clinical features of vasculitis in children, with emphasis on common conditions.
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