Kuo Ho-Chang, Chang Jen-Chieh, Guo Mindy Ming-Huey, Hsieh Kai-Sheng, Yeter Deniz, Li Sung-Chou, Yang Kuender D
Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
Chang Gung University College of Medicine, Taoyuan, Taiwan.
PLoS One. 2015 Nov 30;10(11):e0143056. doi: 10.1371/journal.pone.0143056. eCollection 2015.
Kawasaki disease (KD) is a systemic vasculitis primarily affecting children < 5 years old. Genes significantly associated with KD mostly involve cardiovascular, immune, and inflammatory responses. Recent studies have observed stronger associations for KD risk with multiple genes compared to individual genes. Therefore, we investigated whether gene combinations influenced KD susceptibility or coronary artery lesion (CAL) formation. We examined 384 single-nucleotide polymorphisms (SNPs) for 159 immune-related candidate genes in DNA samples from KD patients with CAL (n = 73), KD patients without CAL (n = 153), and cohort controls (n = 575). Individual SNPs were first assessed by univariate analysis (UVA) and multivariate analysis (MVA). We used multifactor dimensionality reduction (MDR) to examine individual SNPs in one-, two-, and three-locus best fit models. UVA identified 53 individual SNPs that were significantly associated with KD risk or CAL formation (p < 0.10), while 35 individual SNPs were significantly associated using MVA (p ≤ 0.05). Significant associations in MDR analysis were only observed for the two-locus models after permutation testing (p ≤ 0.05). In logistic regression, combined possession of PDE2A (rs341058) and CYFIP2 (rs767007) significantly increased KD susceptibility (OR = 3.54; p = 4.14 x 10(-7)), while combinations of LOC100133214 (rs2517892) and IL2RA (rs3118470) significantly increased the risk of CAL in KD patients (OR = 5.35; p = 7.46 x 10(-5)). Our results suggest varying gene-gene associations respectively predispose individuals to KD risk or its complications of CAL.
川崎病（KD）是一种主要影响5岁以下儿童的全身性血管炎。与KD显著相关的基因大多涉及心血管、免疫和炎症反应。最近的研究发现，与单个基因相比，多个基因与KD风险的关联更强。因此，我们研究了基因组合是否会影响KD易感性或冠状动脉病变（CAL）的形成。我们在患有CAL的KD患者（n = 73）、无CAL的KD患者（n = 153）和队列对照（n = 575）的DNA样本中，检测了159个免疫相关候选基因的384个单核苷酸多态性（SNP）。首先通过单变量分析（UVA）和多变量分析（MVA）对单个SNP进行评估。我们使用多因素降维法（MDR）在单基因座、双基因座和三基因座最佳拟合模型中检测单个SNP。UVA确定了53个与KD风险或CAL形成显著相关的单个SNP（p < 0.10），而使用MVA有35个单个SNP显著相关（p≤0.05）。在排列检验后，仅在双基因座模型中观察到MDR分析中的显著关联（p≤0.05）。在逻辑回归中，同时拥有PDE2A（rs341058）和CYFIP2（rs767007）显著增加KD易感性（OR = 3.54；p = 4.14×10⁻⁷），而LOC100133214（rs2517892）和IL2RA（rs3118470）的组合显著增加KD患者发生CAL的风险（OR = 5.35；p = 7.46×10⁻⁵）。我们的结果表明，不同的基因-基因关联分别使个体易患KD风险或其CAL并发症。
