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

Y. Onouchi, Y. Suzuki, H. Suzuki, M. Terai, K. Yasukawa, H. Hamada, T. Suenaga, T. Honda, A. Honda, H. Kobayashi, T. Takeuchi, N. Yoshikawa, J. Sato, S. Shibuta, M. Miyawaki, K. Oishi, H. Yamaga, N. Aoyagi, S. Iwahashi, R. MiyashitaY. Murata, R. Ebata, K. Higashi, K. Ozaki, K. Sasago, T. Tanaka, A. Hata

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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.

Original languageEnglish
Pages (from-to)52-59
Number of pages8
JournalPharmacogenomics Journal
Volume13
Issue number1
DOIs
Publication statusPublished - 2013 Feb 1

Keywords

  • CASP3
  • ITPKC
  • IVIG resistance
  • Kawasaki's disease
  • SNP
  • coronary artery lesion

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Pharmacology

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    Onouchi, Y., Suzuki, Y., Suzuki, H., Terai, M., Yasukawa, K., Hamada, H., Suenaga, T., Honda, T., Honda, A., Kobayashi, H., Takeuchi, T., Yoshikawa, N., Sato, J., Shibuta, S., Miyawaki, M., Oishi, K., Yamaga, H., Aoyagi, N., Iwahashi, S., ... Hata, A. (2013). ITPKC and CASP3 polymorphisms and risks for IVIG unresponsiveness and coronary artery lesion formation in Kawasaki disease. Pharmacogenomics Journal, 13(1), 52-59. https://doi.org/10.1038/tpj.2011.45