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@article{Shimizu:2016:10.1161/CIRCGENETICS.116.001533,
author = {Shimizu, C and Eleftherohorinou, H and Wright, VJ and Kim, J and Alphonse, MP and Perry, JC and Cimaz, R and Burgner, D and Dahdah, N and Hoang, LT and Khor, CC and Salgado, A and Tremoulet, AH and Davila, S and Kuijpers, TW and Hibberd, ML and Johnson, TA and Takahashi, A and Tsunoda, T and Kubo, M and Tanaka, T and Onouchi, Y and Yeung, RS and Coin, LJ and Levin, M and Burns, JC},
doi = {10.1161/CIRCGENETICS.116.001533},
journal = {Circulation. Cardiovascular Genetics},
pages = {559--568},
title = {Genetic variation in the SLC8A1 calcium signaling pathway is associated with susceptibility to Kawasaki disease and coronary artery abnormalities},
url = {http://dx.doi.org/10.1161/CIRCGENETICS.116.001533},
volume = {9},
year = {2016}
}

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TY  - JOUR
AB  - 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.
AU  - Shimizu,C
AU  - Eleftherohorinou,H
AU  - Wright,VJ
AU  - Kim,J
AU  - Alphonse,MP
AU  - Perry,JC
AU  - Cimaz,R
AU  - Burgner,D
AU  - Dahdah,N
AU  - Hoang,LT
AU  - Khor,CC
AU  - Salgado,A
AU  - Tremoulet,AH
AU  - Davila,S
AU  - Kuijpers,TW
AU  - Hibberd,ML
AU  - Johnson,TA
AU  - Takahashi,A
AU  - Tsunoda,T
AU  - Kubo,M
AU  - Tanaka,T
AU  - Onouchi,Y
AU  - Yeung,RS
AU  - Coin,LJ
AU  - Levin,M
AU  - Burns,JC
DO  - 10.1161/CIRCGENETICS.116.001533
EP  - 568
PY  - 2016///
SN  - 1942-3268
SP  - 559
TI  - Genetic variation in the SLC8A1 calcium signaling pathway is associated with susceptibility to Kawasaki disease and coronary artery abnormalities
T2  - Circulation. Cardiovascular Genetics
UR  - http://dx.doi.org/10.1161/CIRCGENETICS.116.001533
UR  - http://www.ncbi.nlm.nih.gov/pubmed/27879314
UR  - http://hdl.handle.net/10044/1/43316
VL  - 9
ER  -

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