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dc.titleA genome-wide association study identifies novel and functionally related susceptibility loci for Kawasaki disease
dc.contributor.authorBurgner D.
dc.contributor.authorDavila S.
dc.contributor.authorBreunis W.B.
dc.contributor.authorNg S.B.
dc.contributor.authorLi Y.
dc.contributor.authorBonnard C.
dc.contributor.authorLing L.
dc.contributor.authorWright V.J.
dc.contributor.authorThalamuthu A.
dc.contributor.authorOdam M.
dc.contributor.authorShimizu C.
dc.contributor.authorBurns J.C.
dc.contributor.authorLevin M.
dc.contributor.authorKuijpers T.W.
dc.contributor.authorHibberd M.L.
dc.contributor.authorChristiansen F.
dc.contributor.authorWitt C.
dc.contributor.authorGoldwater P.
dc.contributor.authorCurtis N.
dc.contributor.authorPalasanthiran P.
dc.contributor.authorZiegler J.
dc.contributor.authorNissan M.
dc.contributor.authorNourse C.
dc.contributor.authorKuipers I.M.
dc.contributor.authorOttenkamp J.J.
dc.contributor.authorGeissler J.
dc.contributor.authorBiezeveld M.
dc.contributor.authorFilippini L.
dc.contributor.authorBrogan P.
dc.contributor.authorKlein N.
dc.contributor.authorShah V.
dc.contributor.authorDillon M.
dc.contributor.authorBooy R.
dc.contributor.authorShingadia D.
dc.contributor.authorBose A.
dc.contributor.authorMukasa T.
dc.contributor.authorTulloh R.
dc.contributor.authorMichie C.
dc.contributor.authorShike H.
dc.contributor.authorNievergelt C.M.
dc.contributor.authorSchork N.J.
dc.contributor.authorNewburger J.W.
dc.contributor.authorBaker A.L.
dc.contributor.authorSundel R.P.
dc.contributor.authorRowley A.H.
dc.contributor.authorShulman S.T.
dc.identifier.citationBurgner D., Davila S., Breunis W.B., Ng S.B., Li Y., Bonnard C., Ling L., Wright V.J., Thalamuthu A., Odam M., Shimizu C., Burns J.C., Levin M., Kuijpers T.W., Hibberd M.L., Christiansen F., Witt C., Goldwater P., Curtis N., Palasanthiran P., Ziegler J., Nissan M., Nourse C., Kuipers I.M., Ottenkamp J.J., Geissler J., Biezeveld M., Filippini L., Brogan P., Klein N., Shah V., Dillon M., Booy R., Shingadia D., Bose A., Mukasa T., Tulloh R., Michie C., Shike H., Nievergelt C.M., Schork N.J., Newburger J.W., Baker A.L., Sundel R.P., Rowley A.H., Shulman S.T. (2009). A genome-wide association study identifies novel and functionally related susceptibility loci for Kawasaki disease. PLoS Genetics 5 (1) : e1000319. ScholarBank@NUS Repository.
dc.description.abstractKawasaki 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. © 2009 Burgner et al.
dc.rightsAttribution 4.0 International
dc.sourceUnpaywall 20191101
dc.subjectcamk2d gene
dc.subjectcohort analysis
dc.subjectcontrolled study
dc.subjectcsmd1 gene
dc.subjectgene expression
dc.subjectgene frequency
dc.subjectgene function
dc.subjectgene identification
dc.subjectgene locus
dc.subjectgene mapping
dc.subjectgene replication
dc.subjectgenetic transcription
dc.subjectlnx1 gene
dc.subjectmajor clinical study
dc.subjectmucocutaneous lymph node syndrome
dc.subjectnaaladl2 gene
dc.subjectnucleotide sequence
dc.subjectppp1r14c gene
dc.subjectsingle nucleotide polymorphism
dc.subjectzfhx3 gene
dc.subjectcase control study
dc.subjectchi square distribution
dc.subjectchromosome map
dc.subjectDNA microarray
dc.subjectethnic group
dc.subjectgene linkage disequilibrium
dc.subjectgene regulatory network
dc.subjectgenetic association
dc.subjectgenetic database
dc.subjectgenetic predisposition
dc.subjectsingle nucleotide polymorphism
dc.subjectCase-Control Studies
dc.subjectChi-Square Distribution
dc.subjectChromosome Mapping
dc.subjectDatabases, Genetic
dc.subjectEthnic Groups
dc.subjectGene Expression
dc.subjectGene Frequency
dc.subjectGene Regulatory Networks
dc.subjectGenetic Predisposition to Disease
dc.subjectGenome-Wide Association Study
dc.subjectLinkage Disequilibrium
dc.subjectMucocutaneous Lymph Node Syndrome
dc.subjectOligonucleotide Array Sequence Analysis
dc.subjectPolymorphism, Single Nucleotide
dc.contributor.departmentSAW SWEE HOCK SCHOOL OF PUBLIC HEALTH
dc.description.sourcetitlePLoS Genetics
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