Genetic Variation in the SLC8A1 Calcium Signaling Pathway Is Associated With Susceptibility to Kawasaki Disease and Coronary Artery Abnormalities. (December 2016)

• Record Type: Journal Article
• Authors: Shimizu, Chisato; Eleftherohorinou, Hariklia; Wright, Victoria J.; Kim, Jihoon; Alphonse, Martin P.; Perry, James C.; Cimaz, Rolando; Burgner, David; Dahdah, Nagib; Hoang, Long T.; Khor, Chiea Chuen; Salgado, Andrea; Tremoulet, Adriana H.; Davila, Sonia; Kuijpers, Taco W.; Hibberd, Martin L.; Johnson, Todd A.; Takahashi, Atsushi; Tsunoda, Tatsuhiko; Kubo, Michiaki; Tanaka, Toshihiro; Onouchi, Yoshihiro; Yeung, Rae S.M.; Coin, Lachlan J.M.; Levin, Michael; Burns, Jane C.
• Is Part Of: Circulation. Volume 9:Number 6(2016)
• Publication Date: 2016-12
• Subjects: aneurysm -- calcium channel -- coronary artery -- Kawasaki disease -- quantitative trait loci -- sodium–calcium exchanger; Arrhythmia -- Periodicals; Heart -- Electric properties -- Periodicals; 616.1042
• DOI: 10.1161/CIRCGENETICS.116.001533
• Languages: English
• ISSNs: 1942-325X

Abstract

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. Methods and 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. Abstract : Supplemental Digital Content is available in the text.