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

David Burgner, S. Davila, W.B. Breunis, S.B. Ng, Y. Li, C. Bonnard, L. Ling, V.J. Wright, A. Thalamuthu, M. Odam, C. Shimizu, J.C. Burns, M. Levin, T.W. Kuijpers, M.L. Hibberd

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    190 Citations (Scopus)

    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 susceptiblechildren. 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 byreplication in an independent cohort and subsequent fine-mapping, for a total of 893 KD cases plus population and familycontrols. Significant associations of 40 SNPs and six haplotypes, identifying 31 genes, were replicated in an independentcohort of 583 predominantly Caucasian KD families, with NAALADL2 (rs17531088, pcombined = 1.1361026) and ZFHX3(rs7199343, pcombined = 2.3761026) 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 590from 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, andTCP1), the neighboring markers were more significantly associated than the originally associated variants. Investigation offunctional relationships between the eight fine-mapped genes using Ingenuity Pathway Analysis identified a singlefunctional network (p=10213) containing five fine-mapped genes—LNX1, CAMK2D, ZFHX3, CSMD1, and TCP1—withfunctional relationships potentially related to inflammation, apoptosis, and cardiovascular pathology. Pair-wise bloodtranscript levels were measured during acute and convalescent KD for all fine-mapped genes, revealing a consistent trend ofsignificantly reduced transcript levels prior to treatment. This is one of the first GWAS in an infectious disease. We haveidentified novel, plausible, and functionally related variants associated with KD susceptibility that may also be relevant toother cardiovascular diseases.
    Original languageEnglish
    Pages (from-to)1-15
    JournalPLoS Genetics
    Volume5
    Issue number1
    DOIs
    Publication statusPublished - 2009

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