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Family-based association analysis implicates IL-4 in susceptibility to Kawasaki disease

Genes & Immunity volume 6, pages 438–444 (2005)Cite this article

Abstract

Several compelling lines of evidence suggest an important influence of genetic variation in susceptibility to Kawasaki disease (KD), an acute vasculitis that causes coronary artery aneurysms in children. We performed a family-based genotyping study to test for association between KD and 58 genes involved in cardiovascular disease and inflammation. By analysis of a cohort of 209 KD trios using the transmission disequilibrium test, we documented the asymmetric transmission of five alleles including the interleukin-4 (IL-4) C(−589)T allele (P=0.03). Asymmetric transmission of the IL-4 C(−589)T was replicated in a second, independent cohort of 60 trios (P=0.05, combined P=0.002). Haplotypes of alleles in IL-4, colony-stimulating factor 2 (CSF2), IL-13, and transcription factor 7 (TCF7), all located in the interleukin gene cluster on 5q31, were also asymmetrically transmitted. The reported associations of KD with atopic dermatitis and allergy, elevated serum IgE levels, eosinophilia, and increased circulating numbers of monocyte/macrophages expressing the low-affinity IgE receptor (FCɛR2) may be related to effects of IL-4. Thus, the largest family-based genotyping study of KD patients to date suggests that genetic variation in the IL-4 gene, or regions linked to IL-4, plays an important role in KD pathogenesis and disease susceptibility.

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Acknowledgements

This work was supported by grants from the National Institutes of Health, NIH-RO1HL69413 and K24HL074864 (awarded to JCB) and by a Grant-in-Aid from the American Heart Association, Western Affiliate #035061Y (awarded to JCB). Some of the results of this paper were obtained by using the program package SAGE which is supported by a US Public Health Service Resource Grant (RR03655) from the National Center for Research Resources. We thank John F Bastian for patient referral and collection of DNA samples. We also thank our clinical nurses Ellen McGrath, and Jennifer Foley, and the army of students including David Bronstein, Jennie Buchanan, Marina Dergun, Christina Lin, Erin Miller, and Mathew Leach without whose help we could never have collected all the DNA samples required for this study. We also thank Calvin Mano, Tracy Nguyen, and Nang Tan (RMS) for their support in producing the genotyping reagents, and Jeff Post (RMS) for the strip interpretation software used for this work.

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Authors and Affiliations

  1. Department of Pediatrics-0830, University of California San Diego, School of Medicine, La Jolla, CA, USA

    J C Burns, C Shimizu & H Shike

  2. Departments of Cardiology and Pediatrics, Boston Children's Hospital, Boston, MA, USA

    J W Newburger, R P Sundel & A L Baker

  3. Department of Pediatrics, Yamaguchi University, Yamaguchi, Japan

    T Matsubara & Y Ishikawa

  4. Department of Human Genetics, Roche Molecular Systems, Alameda, CA, USA

    V A Brophy, S Cheng, M A Grow & L L Steiner

  5. Departments of Human Genetics and Pediatrics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA

    N Kono & R M Cantor

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Burns, J., Shimizu, C., Shike, H. et al. Family-based association analysis implicates IL-4 in susceptibility to Kawasaki disease. Genes Immun 6, 438–444 (2005). https://doi.org/10.1038/sj.gene.6364225

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