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ITPKC and CASP3 polymorphisms and risks for IVIG unresponsiveness and coronary artery lesion formation in Kawasaki disease

The Pharmacogenomics Journal volume 13, pages 52–59 (2013)Cite this article

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Abstract

Functional single-nucleotide polymorphisms (SNPs) in inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) (rs28493229) and caspase-3 (CASP3) (rs113420705; formerly rs72689236) are associated with susceptibility to Kawasaki's disease (KD). To evaluate the involvement of these 2 SNPs in the risk for intravenous immunoglobulin (IVIG) unresponsiveness, we investigated 204 Japanese KD patients who received a single IVIG dose of 2 g kg−1 (n=70) or 1 g kg−1 daily for 2 days (n=134). The susceptibility allele of both SNPs showed a trend of overrepresentation in IVIG non-responders and, in combined analysis of these SNPs, patients with at least 1 susceptible allele at both loci had a higher risk for IVIG unresponsiveness (P=0.0014). In 335 prospectively collected KD patients who were treated with IVIG (2 g kg−1), this 2-locus model showed a more significant association with resistance to initial and additional IVIG (P=0.011) compared with individual SNPs. We observed a significant association when all KD patients with coronary artery lesions were analyzed with the 2-locus model (P=0.0031). Our findings strongly suggest the existence of genetic factors affecting patients’ responses to treatment and the risk for cardiac complications, and provide clues toward understanding the pathophysiology of KD inflammation.

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Acknowledgements

This study was supported by grants from the Millennium Project, Japan Kawasaki Disease Research Center (2009 to YO) and the Ministry of Health, Labour, and Welfare (0401040 to AH).

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Authors and Affiliations

  1. Laboratory for Cardiovascular Diseases, Center for Genomic Medicine RIKEN, Yokohama, Kanagawa, Japan

    Y Onouchi, K Ozaki & T Tanaka

  2. Department of Public Health, Chiba University Graduate School of Medicine, Chiba, Chiba, Japan

    Y Suzuki, K Sasago & A Hata

  3. Department of Pediatrics, Wakayama Medical University, Wakayama, Wakayama, Japan

    H Suzuki, T Suenaga, T Takeuchi & N Yoshikawa

  4. Department of Pediatrics, Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo, Chiba, Japan

    M Terai, H Hamada & T Honda

  5. Department of Pediatrics, Chiba University Graduate School of Medicine, Chiba, Chiba, Japan

    K Yasukawa, R Ebata & K Higashi

  6. Department of Pediatrics, Asahi General Hospital, Asahi, Chiba, Japan

    A Honda & H Kobayashi

  7. Department of Pediatrics, Funabashi Municipal Medical Center, Funabashi, Chiba, Japan

    J Sato

  8. Department of Pediatrics, Social Insurance Kinan Hospital, Tanabe, Wakayama, Japan

    S Shibuta & M Miyawaki

  9. Department of Pediatrics, Hashimoto Municipal Hospital, Hashimoto, Wakayama, Japan

    K Oishi

  10. Department of Pediatrics, Naga Hospital, Kinokawa, Wakayama, Japan

    H Yamaga

  11. Department of Pediatrics, Wakayama Rosai Hospital, Wakayama, Wakayama, Japan

    N Aoyagi

  12. Department of Pediatrics, Hidaka General Hospital, Gobo, Wakayama, Japan

    S Iwahashi

  13. Department of Pediatrics, Izumiotsu Municipal Hospital, Izumiotsu, Osaka, Japan

    R Miyashita

  14. Department of Pediatrics, Sendai City Hospital, Sendai, Miyagi, Japan

    Y Murata

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  1. Y Onouchi
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  2. Y Suzuki
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  3. H Suzuki
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  4. M Terai
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  5. K Yasukawa
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  6. H Hamada
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  7. T Suenaga
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  8. T Honda
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  9. A Honda
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  10. H Kobayashi
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  11. T Takeuchi
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  13. J Sato
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  14. S Shibuta
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  15. M Miyawaki
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  16. K Oishi
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  17. H Yamaga
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  18. N Aoyagi
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  19. S Iwahashi
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  21. Y Murata
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  22. R Ebata
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  23. K Higashi
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  24. K Ozaki
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  25. K Sasago
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  26. T Tanaka
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  27. A Hata
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Correspondence to Y Onouchi.

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Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website

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Onouchi, Y., Suzuki, Y., Suzuki, H. et al. ITPKC and CASP3 polymorphisms and risks for IVIG unresponsiveness and coronary artery lesion formation in Kawasaki disease. Pharmacogenomics J 13, 52–59 (2013). https://doi.org/10.1038/tpj.2011.45

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  • DOI: https://doi.org/10.1038/tpj.2011.45

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