title: Genetic Variation in the SLC8A1 Calcium Signaling Pathway Is Associated With Susceptibility to Kawasaki Disease and Coronary Artery Abnormalities.
abstract: BACKGROUND
  Kawasaki disease (KD) is an acute pediatric vasculitis in which host genetics influence both susceptibility to KD and the formation of coronary artery aneurysms. Variants discovered by genome-wide association studies and linkage studies only partially explain the influence of genetics on KD susceptibility.
  
  
  RESULTS
  To search for additional functional genetic variation, we performed pathway and gene stability analysis on a genome-wide association study data set. Pathway analysis using European genome-wide association study data identified 100 significantly associated pathways (P<5×10-4). Gene stability selection identified 116 single nucleotide polymorphisms in 26 genes that were responsible for driving the pathway associations, and gene ontology analysis demonstrated enrichment for calcium transport (P=1.05×10-4). Three single nucleotide polymorphisms in solute carrier family 8, member 1 (SLC8A1), a sodium/calcium exchanger encoding NCX1, were validated in an independent Japanese genome-wide association study data set (meta-analysis P=0.0001). Patients homozygous for the A (risk) allele of rs13017968 had higher rates of coronary artery abnormalities (P=0.029). NCX1, the protein encoded by SLC8A1, was expressed in spindle-shaped and inflammatory cells in the aneurysm wall. Increased intracellular calcium mobilization was observed in B cell lines from healthy controls carrying the risk allele.
  
  
  CONCLUSIONS
  Pathway-based association analysis followed by gene stability selection proved to be a valuable tool for identifying risk alleles in a rare disease with complex genetics. The role of SLC8A1 polymorphisms in altering calcium flux in cells that mediate coronary artery damage in KD suggests that this pathway may be a therapeutic target and supports the study of calcineurin inhibitors in acute KD.
authors.forename: Chisato
authors.initials: C
authors.lastname: Shimizu
authors.forename: Hariklia
authors.initials: H
authors.lastname: Eleftherohorinou
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Wright
authors.forename: Jihoon
authors.initials: J
authors.lastname: Kim
authors.forename: Martin P
authors.initials: MP
authors.lastname: Alphonse
authors.forename: James C
authors.initials: JC
authors.lastname: Perry
authors.forename: Rolando
authors.initials: R
authors.lastname: Cimaz
authors.forename: David
authors.initials: D
authors.lastname: Burgner
authors.forename: Nagib
authors.initials: N
authors.lastname: Dahdah
authors.forename: Long T
authors.initials: LT
authors.lastname: Hoang
authors.forename: Chiea Chuen
authors.initials: CC
authors.lastname: Khor
authors.forename: Andrea
authors.initials: A
authors.lastname: Salgado
authors.forename: Adriana H
authors.initials: AH
authors.lastname: Tremoulet
authors.forename: Sonia
authors.initials: S
authors.lastname: Davila
authors.forename: Taco W
authors.initials: TW
authors.lastname: Kuijpers
authors.forename: Martin L
authors.initials: ML
authors.lastname: Hibberd
authors.forename: Todd A
authors.initials: TA
authors.lastname: Johnson
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Tsunoda
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Tanaka
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Onouchi
authors.forename: Rae S M
authors.initials: RS
authors.lastname: Yeung
authors.forename: Lachlan J M
authors.initials: LJ
authors.lastname: Coin
authors.forename: Michael
authors.initials: M
authors.lastname: Levin
authors.forename: Jane C
authors.initials: JC
authors.lastname: Burns
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism; D020013:Calcium Signaling / Q000235:genetics*; D002461:Cell Line, Transformed; D002675:Child, Preschool; D019295:Computational Biology; D003323:Coronary Aneurysm / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D030541:Databases, Genetic; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D009080:Mucocutaneous Lymph Node Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012307:Risk Factors; D019831:Sodium-Calcium Exchanger / Q000235:genetics* / Q000378:metabolism
chemical_list: D019831:Sodium-Calcium Exchanger; C110374:sodium-calcium exchanger 1
keywords: Kawasaki disease; aneurysm; calcium channel; coronary artery; quantitative trait loci; sodium–calcium exchanger