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Genetic variation in the SLC8A1 calcium signaling pathway is associated with susceptibility to Kawasaki disease and coronary artery abnormalities

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Title: Genetic variation in the SLC8A1 calcium signaling pathway is associated with susceptibility to Kawasaki disease and coronary artery abnormalities
Authors: Shimizu, C
Eleftherohorinou, H
Wright, VJ
Kim, J
Alphonse, MP
Perry, JC
Cimaz, R
Burgner, D
Dahdah, N
Hoang, LT
Khor, CC
Salgado, A
Tremoulet, AH
Davila, S
Kuijpers, TW
Hibberd, ML
Johnson, TA
Takahashi, A
Tsunoda, T
Kubo, M
Tanaka, T
Onouchi, Y
Yeung, RS
Coin, LJ
Levin, M
Burns, JC
Item Type: Journal Article
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 (GWAS) and linkage studies only partially explain the influence of genetics on KD susceptibility. METHODS AND RESULTS: -To search for additional functional genetic variation, we performed pathway and gene stability analysis on a GWAS dataset. Pathway analysis using European GWAS data identified 100 significantly associated pathways (p< 5 ×10(-4)). Gene stability selection identified 116 single nucleotide polymorphisms (SNPs) 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 SNPs in solute carrier family 8 member 1 (SLC8A1), a sodium/calcium exchanger encoding NCX1, were validated in an independent Japanese GWAS dataset (metaanalysis 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.
Issue Date: 21-Nov-2016
Date of Acceptance: 2-Nov-2016
URI: http://hdl.handle.net/10044/1/43316
DOI: http://dx.doi.org/10.1161/CIRCGENETICS.116.001533
ISSN: 1942-3268
Publisher: American Heart Association
Start Page: 559
End Page: 568
Journal / Book Title: Circulation. Cardiovascular Genetics
Volume: 9
Copyright Statement: © 2016 American Heart Association, Inc.
Keywords: Gene stability selection
Kawasaki disease
Pathway analysis
aneurysm
calcium channel
coronary artery
eQTL
genome-wide analysis
sodium calcium exchanger
0604 Genetics
1102 Cardiovascular Medicine And Haematology
Publication Status: Published
Conference Place: United States
Appears in Collections:Department of Medicine
Faculty of Medicine



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