Genetic Variation in the SLC8A1 Calcium Signaling Pathway Is Associated with Susceptibility to Kawasaki Disease and Coronary Artery Abnormalities

Chisato Shimizu, Hariklia Eleftherohorinou, Victoria J. Wright, Jihoon Kim, Martin P. Alphonse, James C. Perry, Rolando Cimaz, David Burgner, Nagib Dahdah, Thuy Long Hoang, Chiea Chuen Khor, Andrea Salgado, Adriana H. Tremoulet, Sonia Davila, Taco W. Kuijpers, Martin L. Hibberd, Todd A. Johnson, Atsushi Takahashi, Tatsuhiko Tsunoda, Michiaki KuboToshihiro Tanaka, Yoshihiro Onouchi, Rae S M Yeung, Lachlan J M Coin, Michael E Levin, Jane C. Burns

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17 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)559-568
Number of pages10
JournalCirculation: Cardiovascular Genetics
Volume9
Issue number6
DOIs
Publication statusPublished - 1 Dec 2016

Keywords

  • aneurysm
  • calcium channel
  • coronary artery
  • Kawasaki disease
  • quantitative trait loci
  • sodium-calcium exchanger

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