A Genome-Wide Association Study Identifies Novel and Functionally Related Susceptibility Loci for Kawasaki Disease

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Abstract
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, pcombined = 1.13×10−6) and ZFHX3 (rs7199343, pcombined = 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.