title: A genome-wide association study identifies novel and functionally related susceptibility Loci for Kawasaki disease.
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, p(combined) = 1.13 x 10(-6)) and ZFHX3 (rs7199343, p(combined) = 2.37 x 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.
authors.affiliation: School of Pediatrics and Child Health, University of Western Australia, Perth, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Burgner
authors.forename: Sonia
authors.initials: S
authors.lastname: Davila
authors.forename: Willemijn B
authors.initials: WB
authors.lastname: Breunis
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Ng
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Carine
authors.initials: C
authors.lastname: Bonnard
authors.forename: Ling
authors.initials: L
authors.lastname: Ling
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Wright
authors.forename: Anbupalam
authors.initials: A
authors.lastname: Thalamuthu
authors.forename: Miranda
authors.initials: M
authors.lastname: Odam
authors.forename: Chisato
authors.initials: C
authors.lastname: Shimizu
authors.forename: Jane C
authors.initials: JC
authors.lastname: Burns
authors.forename: Michael
authors.initials: M
authors.lastname: Levin
authors.forename: Taco W
authors.initials: TW
authors.lastname: Kuijpers
authors.forename: Martin L
authors.initials: ML
authors.lastname: Hibberd
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D002648:Child; D002874:Chromosome Mapping; D030541:Databases, Genetic; D005006:Ethnicity / Q000235:genetics; D015870:Gene Expression; D005787:Gene Frequency; D053263:Gene Regulatory Networks; D005796:Genes; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D009080:Mucocutaneous Lymph Node Syndrome / Q000097:blood / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics