Onouchi Yoshihiro
Laboratory for Cardiovascular disease, Center for Genomic Medicine, RIKEN.
Nihon Rinsho Meneki Gakkai Kaishi. 2010;33(2):73-80. doi: 10.2177/jsci.33.73.
Kawasaki disease is an acute febrile illness of infants and children with unknown etiology. Coronary artery lesions occurring in 20-25% of untreated patients of KD has made KD a leading cause of acquired heart diseases of childhood in developed countries. High prevalence in East Asian countries is one of the epidemiological features of KD and has suggested genetic factors underlying the disease pathogenesis. We tried to identify genetic variants relevant to KD susceptibility by sibpair linkage study and linkage diseuilibrium mapping with SNPs and found that inositol 1,4,5-trisphosphate 3-kianse C gene is a susceptibility gene for KD. We also found the negative regulatory role of ITPKC in TCR signaling and the mechanism by which the responsible SNP in intron 1 of the gene affects transcripts level of ITPKC. Our findings highlighted the importance of Ca(2+)/NFAT pathway in the pathogenesis of KD and shed light on the possibility of immuno-suppressants targeting the pathway as a therapeutic strategy for KD.
川崎病是一种病因不明的婴幼儿急性发热性疾病。在未经治疗的川崎病患者中，20%-25%会出现冠状动脉病变，这使得川崎病成为发达国家儿童后天性心脏病的主要病因。东亚国家的高发病率是川崎病的流行病学特征之一，提示该病发病机制存在遗传因素。我们通过同胞对连锁研究以及利用单核苷酸多态性（SNP）进行连锁不平衡定位，试图确定与川崎病易感性相关的基因变异，发现肌醇1,4,5-三磷酸3-激酶C基因是川崎病的一个易感基因。我们还发现了ITPKC在T细胞受体信号传导中的负调控作用，以及该基因内含子1中相关SNP影响ITPKC转录水平的机制。我们的研究结果突出了Ca(2+)/NFAT途径在川崎病发病机制中的重要性，并为以该途径为靶点的免疫抑制剂作为川崎病治疗策略的可能性提供了线索。
