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Title: A genome-wide association study identifies novel and functionally related susceptibility loci for Kawasaki disease
Authors: Burgner 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.
Keywords: allele
camk2d gene
cohort analysis
controlled study
csmd1 gene
gene expression
gene frequency
gene function
gene identification
gene locus
gene mapping
gene replication
genetic transcription
lnx1 gene
major clinical study
mucocutaneous lymph node syndrome
naaladl2 gene
nucleotide sequence
ppp1r14c gene
single nucleotide polymorphism
zfhx3 gene
case control study
chi square distribution
chromosome map
DNA microarray
ethnic group
gene linkage disequilibrium
gene regulatory network
genetic association
genetic database
genetic predisposition
single nucleotide polymorphism
Case-Control Studies
Chi-Square Distribution
Chromosome Mapping
Databases, Genetic
Ethnic Groups
Gene Expression
Gene Frequency
Gene Regulatory Networks
Genetic Predisposition to Disease
Genome-Wide Association Study
Linkage Disequilibrium
Mucocutaneous Lymph Node Syndrome
Oligonucleotide Array Sequence Analysis
Polymorphism, Single Nucleotide
Issue Date: 2009
Citation: Burgner 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.
Rights: Attribution 4.0 International
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. © 2009 Burgner et al.
Source Title: PLoS Genetics
ISSN: 15537390
DOI: 10.1371/journal.pgen.1000319
Rights: Attribution 4.0 International
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