Shrestha S, Wiener H W, Aissani B, Shendre A, Tang J, Portman M A
Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
Int J Immunogenet. 2015 Jun;42(3):140-6. doi: 10.1111/iji.12190. Epub 2015 Mar 24.
Kawasaki disease (KD) is the leading cause of acquired heart disease in children in most developed countries including the United States. The etiology of KD is not known; however, epidemiological and immunological data suggest infectious or immune-related factors in the manifestation of the disease. Further, KD has several hereditary features that strongly suggest a genetic component to disease pathogenesis. Human leucocyte antigen (HLA) loci have also been reported to be associated with KD, but results have been inconsistent, in part, because of small study samples and varying linkage disequilibrium (LD) patterns observed across different ethnic groups. To maximize the informativeness of single nucleotide polymorphism (SNP) genotypes in the major histocompatibility (MHC) region, we imputed classical HLA I (A, B, C) and HLA II (DRB1, DQA1, DQB1) alleles using SNP2HLA method from genotypes of 6700 SNPs within the extended MHC region contained in the ImmunoChip among 112 White patients with KD and their biological parents from North America and tested their association with KD susceptibility using the transmission disequilibrium test. Mendelian consistency in the trios suggested high accuracy and reliability of the imputed alleles (class I = 97.5%, class II = 96.6%). While several SNPs in the MHC region were individually associated with KD susceptibility, we report over-transmission of HLA-C15 (z = +2.19, P = 0.03) and under-transmission of HLA-B44 (z = -2.49, P = 0.01) alleles from parents to patients with KD. HLA-B44 has been associated with KD in other smaller studies, and both HLA-C15 and HLA-B*44 have biological mechanisms that could potentially be involved in KD pathogenesis. Overall, inferring HLA loci within the same ethnic group, using family-based information is a powerful approach. However, studies with larger sample sizes are warranted to evaluate the correlations of the strength and directions between the SNPs in MHC region and the imputed HLA alleles with KD.
川崎病（KD）是包括美国在内的大多数发达国家儿童获得性心脏病的主要病因。KD的病因尚不清楚；然而，流行病学和免疫学数据表明，疾病表现中存在感染或免疫相关因素。此外，KD有几个遗传特征，强烈提示疾病发病机制中有遗传成分。据报道，人类白细胞抗原（HLA）基因座也与KD有关，但结果并不一致，部分原因是研究样本量小，且不同种族群体中观察到的连锁不平衡（LD）模式不同。为了最大限度地提高主要组织相容性（MHC）区域中单核苷酸多态性（SNP）基因型的信息量，我们使用SNP2HLA方法，从北美112例KD白人患者及其生物学父母的免疫芯片中扩展MHC区域内6700个SNP的基因型中推算出经典HLA I（A、B、C）和HLA II（DRB1、DQA1、DQB1）等位基因，并使用传递不平衡检验测试它们与KD易感性的关联。三联体中的孟德尔一致性表明推算等位基因具有较高的准确性和可靠性（I类=97.5%，II类=96.6%）。虽然MHC区域中的几个SNP分别与KD易感性相关，但我们报告了HLA-C15从父母到KD患者的过度传递（z = +2.19，P = 0.03）和HLA-B44的传递不足（z = -2.49，P = 0.01）。在其他较小的研究中，HLA-B44已与KD相关，并且HLA-C15和HLA-B*44都具有可能参与KD发病机制的生物学机制。总体而言，利用基于家系的信息推断同一种族群体内的HLA基因座是一种有效的方法。然而，需要更大样本量的研究来评估MHC区域中的SNP与推算的HLA等位基因之间的强度和方向与KD的相关性。
