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, Long T. 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 Levin, Jane C. Burns

Research output: Contribution to journalArticle

11 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 - 01-12-2016

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Mucocutaneous Lymph Node Syndrome
Calcium Signaling
Genome-Wide Association Study
Coronary Vessels
Alleles
Calcium
Genes
Single Nucleotide Polymorphism
Sodium-Calcium Exchanger
Coronary Aneurysm
Gene Ontology
Disease Susceptibility
Acute Disease
Rare Diseases
Vasculitis
Aneurysm
Meta-Analysis
B-Lymphocytes
Pediatrics
Cell Line

All Science Journal Classification (ASJC) codes

  • Genetics
  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)

Cite this

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. / Genetic Variation in the SLC8A1 Calcium Signaling Pathway Is Associated with Susceptibility to Kawasaki Disease and Coronary Artery Abnormalities. In: Circulation: Cardiovascular Genetics. 2016 ; Vol. 9, No. 6. pp. 559-568.
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title = "Genetic Variation in the SLC8A1 Calcium Signaling Pathway Is Associated with Susceptibility to Kawasaki Disease and Coronary Artery Abnormalities",
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.",
author = "Chisato Shimizu and Hariklia Eleftherohorinou and Wright, {Victoria J.} and Jihoon Kim and Alphonse, {Martin P.} and Perry, {James C.} and Rolando Cimaz and David Burgner and Nagib Dahdah and Hoang, {Long T.} and Khor, {Chiea Chuen} and Andrea Salgado and Tremoulet, {Adriana H.} and Sonia Davila and Kuijpers, {Taco W.} and Hibberd, {Martin L.} and Johnson, {Todd A.} and Atsushi Takahashi and Tatsuhiko Tsunoda and Michiaki Kubo and Toshihiro Tanaka and Yoshihiro Onouchi and Yeung, {Rae S.M.} and Coin, {Lachlan J.M.} and Michael Levin and Burns, {Jane C.}",
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language = "English",
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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, RSM, Coin, LJM, Levin, M & Burns, JC 2016, 'Genetic Variation in the SLC8A1 Calcium Signaling Pathway Is Associated with Susceptibility to Kawasaki Disease and Coronary Artery Abnormalities', Circulation: Cardiovascular Genetics, vol. 9, no. 6, pp. 559-568. https://doi.org/10.1161/CIRCGENETICS.116.001533

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

In: Circulation: Cardiovascular Genetics, Vol. 9, No. 6, 01.12.2016, p. 559-568.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genetic Variation in the SLC8A1 Calcium Signaling Pathway Is Associated with Susceptibility to Kawasaki Disease and Coronary Artery Abnormalities

AU - Shimizu, Chisato

AU - Eleftherohorinou, Hariklia

AU - Wright, Victoria J.

AU - Kim, Jihoon

AU - Alphonse, Martin P.

AU - Perry, James C.

AU - Cimaz, Rolando

AU - Burgner, David

AU - Dahdah, Nagib

AU - Hoang, Long T.

AU - Khor, Chiea Chuen

AU - Salgado, Andrea

AU - Tremoulet, Adriana H.

AU - Davila, Sonia

AU - Kuijpers, Taco W.

AU - Hibberd, Martin L.

AU - Johnson, Todd A.

AU - Takahashi, Atsushi

AU - Tsunoda, Tatsuhiko

AU - Kubo, Michiaki

AU - Tanaka, Toshihiro

AU - Onouchi, Yoshihiro

AU - Yeung, Rae S.M.

AU - Coin, Lachlan J.M.

AU - Levin, Michael

AU - Burns, Jane C.

PY - 2016/12/1

Y1 - 2016/12/1

N2 - 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.

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 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.

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U2 - 10.1161/CIRCGENETICS.116.001533

DO - 10.1161/CIRCGENETICS.116.001533

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