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Genome-wide linkage and association mapping identify susceptibility alleles in ABCC4 for Kawasaki disease
  1. Chiea Chuen Khor1,2,
  2. Sonia Davila1,3,
  3. Chisato Shimizu4,
  4. Stephanie Sheng4,
  5. Tomoyo Matsubara5,
  6. Yasuo Suzuki6,
  7. Jane W Newburger7,
  8. Annette Baker7,
  9. David Burgner8,
  10. Willemijn Breunis9,10,
  11. Taco Kuijpers9,10,
  12. Victoria J Wright11,
  13. Michael Levin11,
  14. Martin L Hibberd1,2,
  15. Jane C Burns4 on behalf of the US and International Kawasaki Disease Genetics Consortia*
  1. 1Division of Infectious Diseases, Genome Institute of Singapore, Singapore
  2. 2Department of Epidemiology and Public Health, Centre for Molecular Epidemiology, National University of Singapore, Singapore
  3. 3Division of Human Genetics, Genome Institute of Singapore, Singapore
  4. 4Department of Pediatrics, University of California San Diego School of Medicine and Rady Children's Hospital, San Diego, California, USA
  5. 5Department of Pediatrics, Juntendo University Graduate School of Medicine, Chiba, Japan
  6. 6Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Ube, Japan
  7. 7Department of Cardiology, Children's Hospital Boston, Boston, Massachusetts, USA
  8. 8Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville Victoria, Australia
  9. 9Department of Paediatric Hematology, Emma Children's Hospital, Academic Medical Center (AMC), Immunology and Infectious Diseases, Amsterdam, The Netherlands
  10. 10Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam, The Netherlands
  11. 11Imperial College London, Department of Pediatrics, Division of Medicine, London, UK
  1. Correspondence to Jane C Burns, Department of Pediatrics, University of California San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0641, USA; jcburns{at}ucsd.edu

Abstract

Background

Background Kawasaki disease (KD) is a self limited vasculitis in which host genetics plays a prominent role. To further the understanding of the role of host genetics in KD, a three-stage genetic study was conducted that began with a family linkage study and ultimately involved more than 3000 individuals to identify new genetic contributions to KD susceptibility.

Methods and results

Methods and results A 26-family linkage study followed by fine mapping was performed in a cohort of 1284 KD subjects and their family members (total 3248 individuals). Suggestive evidence of disease linkage (logarithm of odds (LOD) ≥3.0, p<1.00×10−4) was found for five genomic locations (Chr 3q, 4q, 10p, 13q, 21q). Two of these loci (Chr 4q and Chr 13q) overlapped with validated findings from a recent KD genome-wide association study. Fine mapping analysis revealed three single nucleotide polymorphisms (SNPs) in ATP-binding cassette, subfamily C, member 4 (ABCC4) underlying the Chr 13q linkage peak showing evidence of association to KD (lowest p=8.82×10−5; combined OR 2.00, 95% CI 1.41 to 2.83). ABCC4 is a multifunctional cyclic nucleotide transporter that stimulates the migratory capacity of dendritic cells. It is also a mediator of prostaglandin efflux from human cells and is inhibited by non-steroidal anti-inflammatory medications such as aspirin.

Conclusion

Conclusion These genetic data suggest that ABCC4 could play a fundamental role in KD pathogenesis with effects on immune activation and vascular response to injury.

  • Other cardiovascular medicine

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Footnotes

  • CCK, SD, MLH, and JCB contributed equally to this work.

  • * Members of both consortiums are listed in appendix 1.

  • Competing interests None.

  • Ethics approval Ethical approval was obtained from the appropriate national and regional institutional review boards for each study population.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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