A genome-wide association study identifies novel and functionally related susceptibility Loci for Kawasaki disease.
A genome-wide association study identifies novel and functionally related susceptibility Loci for Kawasaki disease.
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DOI：
10.1371/journal.pgen.1000319
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发表时间：
2009-01
期刊：
影响因子：
4.5
通讯作者：
International Kawasaki Disease Genetics Consortium
中科院分区：
文献类型：
--
作者：
Burgner D;Davila S;Breunis WB;Ng SB;Li Y;Bonnard C;Ling L;Wright VJ;Thalamuthu A;Odam M;Shimizu C;Burns JC;Levin M;Kuijpers TW;Hibberd ML;International Kawasaki Disease Genetics Consortium
川崎（KD）是一种儿科血管炎，在25%的未治疗儿童和大约5%的治疗儿童中损害冠状动脉。流行病学数据表明，KD是由遗传易感儿童中的不明感染引发的。为了研究KD易感性的遗传决定因素，我们在119例高加索KD病例和135例匹配对照中进行了全基因组关联研究（GWAS），对可能的混合物进行了严格校正，然后在一个独立队列中重复，随后进行精细定位，共893例KD病例加上人群和家族对照。在一个由583个主要为高加索人的KD家族组成的独立队列中，40个SNP和6个单倍型（鉴定出31个基因）的显著相关性被重复，其中NAALADL 2（rs 17531088，p组合= 1.13×10−6）和ZFHX 3（rs7199343，p组合= 2.37×10−6）的相关性最显著。 在781个KD病例中，包括来自发现和复制阶段的590个病例，用HapMap标记SNP对位于已知基因内或接近已知基因的次要等位基因频率>0.05的16个相关变异进行精细定位。其中8个基因的原始或标记SNP复制了原始发现，其中7个基因在相邻区域具有进一步的显著标记。在四个基因（ZFHX 3，NAALADL 2，PPP 1 R14 C和TCP 1）中，相邻标记的相关性比最初相关的变体更显著。使用Inflamity Pathway Analysis对8个精细定位基因之间的功能关系进行研究，发现了一个单一的功能网络（p = 10−13），其中包含5个精细定位基因-LNX 1，CAMK 2D，ZFHX 3，CSMD 1和TCP 1-与炎症，凋亡和心血管病理学可能相关的功能关系。 在急性和恢复期KD期间测量所有精细定位基因的成对血液转录物水平，揭示了治疗前转录物水平显著降低的一致趋势。这是传染病中最早的GWAS之一。我们已经确定了与KD易感性相关的新的、合理的和功能相关的变体，这些变体也可能与其他心血管疾病相关。川崎是一种炎症性儿科疾病，在四分之一未经治疗的患者中会损害冠状动脉，并且是发达国家儿童获得性心脏病的最常见原因。虽然感染触发因素仍不清楚，但流行病学证据表明，人类遗传变异是易感性的基础。为了确定可能导致这种疾病的新机制，我们进行了全基因组关联研究，该研究在没有预先假设感兴趣的基因座的情况下调查遗传决定因素。这是以这种方式研究的第一批复杂传染病之一，也是最大的川崎遗传研究之一，有893例。我们在一个国际高加索患者队列中鉴定并确认了40个SNP和6个单倍型，确定了31个基因。我们追踪了16个SNP，其中相关的遗传变异更常见，并且位于基因内，通过在整个基因上进行精细定位确认了8个SNP。在这8个基因中，7个在血液中表达，5个在急性期和恢复期川崎患者样本中显示出显著不同的基因表达。八个基因中的五个似乎也参与了一个相互作用基因的单一假定功能网络。这些新的基因和途径可能最终导致新的诊断和治疗川崎。
Kawasaki disease (KD) is a pediatric vasculitis that damages the coronary arteries in 25% of untreated and approximately 5% of treated children. Epidemiologic data suggest that KD is triggered by unidentified infection(s) in genetically susceptible children. To investigate genetic determinants of KD susceptibility, we performed a genome-wide association study (GWAS) in 119 Caucasian KD cases and 135 matched controls with stringent correction for possible admixture, followed by replication in an independent cohort and subsequent fine-mapping, for a total of 893 KD cases plus population and family controls. Significant associations of 40 SNPs and six haplotypes, identifying 31 genes, were replicated in an independent cohort of 583 predominantly Caucasian KD families, with NAALADL2 (rs17531088, p combined = 1.13×10−6) and ZFHX3 (rs7199343, p combined = 2.37×10−6) most significantly associated. Sixteen associated variants with a minor allele frequency of >0.05 that lay within or close to known genes were fine-mapped with HapMap tagging SNPs in 781 KD cases, including 590 from the discovery and replication stages. Original or tagging SNPs in eight of these genes replicated the original findings, with seven genes having further significant markers in adjacent regions. In four genes (ZFHX3, NAALADL2, PPP1R14C, and TCP1), the neighboring markers were more significantly associated than the originally associated variants. Investigation of functional relationships between the eight fine-mapped genes using Ingenuity Pathway Analysis identified a single functional network (p = 10−13) containing five fine-mapped genes—LNX1, CAMK2D, ZFHX3, CSMD1, and TCP1—with functional relationships potentially related to inflammation, apoptosis, and cardiovascular pathology. Pair-wise blood transcript levels were measured during acute and convalescent KD for all fine-mapped genes, revealing a consistent trend of significantly reduced transcript levels prior to treatment. This is one of the first GWAS in an infectious disease. We have identified novel, plausible, and functionally related variants associated with KD susceptibility that may also be relevant to other cardiovascular diseases. Kawasaki disease is an inflammatory pediatric condition that damages the coronary arteries in a quarter of untreated patients and is the commonest cause of childhood acquired heart disease in developed countries. While the infectious trigger(s) remain unknown, epidemiologic evidence suggests that human genetic variation underlies the susceptibility. In order to identify novel mechanisms that may predispose to this disease, we undertook a genome-wide association study, which investigates genetic determinants without prior supposition regarding the loci of interest. This was amongst the first complex infectious diseases to be studied in this way and one of the largest genetic studies of Kawasaki disease with 893 cases. We identified and confirmed 40 SNPs and six haplotypes, identifying 31 genes, in an international cohort of Caucasian patients. We followed up 16 SNPs where the associated genetic variant was more common and was situated within a gene, confirming eight SNPs by fine-mapping across the entire gene. Of these eight genes, seven were expressed in blood and five showed significantly different gene expression in paired patient samples taken during acute and convalescent Kawasaki disease. Five of the eight genes also appear to be involved in a single putative functional network of interacting genes. These novel genes and pathways may ultimately lead to novel diagnostics and treatment for Kawasaki disease.
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