Laboratory for Cardiovascular Diseases, Center for Genomic Medicine RIKEN, Yokohama, Kanagawa, Japan.
Pharmacogenomics J. 2013 Feb;13(1):52-9. doi: 10.1038/tpj.2011.45. Epub 2011 Oct 11.
Functional single-nucleotide polymorphisms (SNPs) in inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) (rs28493229) and caspase-3 (CASP3) (rs113420705; formerly rs72689236) are associated with susceptibility to Kawasaki's disease (KD). To evaluate the involvement of these 2 SNPs in the risk for intravenous immunoglobulin (IVIG) unresponsiveness, we investigated 204 Japanese KD patients who received a single IVIG dose of 2 g kg(-1) (n=70) or 1 g kg(-1) daily for 2 days (n=134). The susceptibility allele of both SNPs showed a trend of overrepresentation in IVIG non-responders and, in combined analysis of these SNPs, patients with at least 1 susceptible allele at both loci had a higher risk for IVIG unresponsiveness (P=0.0014). In 335 prospectively collected KD patients who were treated with IVIG (2 g kg(-1)), this 2-locus model showed a more significant association with resistance to initial and additional IVIG (P=0.011) compared with individual SNPs. We observed a significant association when all KD patients with coronary artery lesions were analyzed with the 2-locus model (P=0.0031). Our findings strongly suggest the existence of genetic factors affecting patients' responses to treatment and the risk for cardiac complications, and provide clues toward understanding the pathophysiology of KD inflammation.
功能性单核苷酸多态性（SNPs）在肌醇 1,4,5-三磷酸 3-激酶 C（ITPKC）（rs28493229）和半胱氨酸蛋白酶-3（CASP3）（rs113420705；以前称为 rs72689236）与川崎病（KD）的易感性有关。为了评估这两个 SNPs 是否与静脉注射免疫球蛋白（IVIG）无反应有关，我们研究了 204 名接受单次 2g/kg（n=70）或 1g/kg 每日 2 天（n=134）IVIG 剂量的日本 KD 患者。两个 SNP 的易感等位基因在 IVIG 无反应者中表现出过度表达的趋势，并且在这些 SNP 的联合分析中，两个位点至少有一个易感等位基因的患者 IVIG 无反应的风险更高（P=0.0014）。在 335 名接受 IVIG（2g/kg）治疗的前瞻性 KD 患者中，与个体 SNP 相比，该 2 个基因座模型与初始和额外 IVIG 的耐药性具有更显著的相关性（P=0.011）。当所有伴有冠状动脉病变的 KD 患者均采用 2 个基因座模型进行分析时，我们观察到了显著的相关性（P=0.0031）。我们的研究结果强烈表明存在影响患者对治疗反应和心脏并发症风险的遗传因素，并为理解 KD 炎症的病理生理学提供了线索。
