Author:
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.
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.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Genetics(clinical),Cardiology and Cardiovascular Medicine,Genetics