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A whole-genome association study of major determinants for allopurinol-related Stevens–Johnson syndrome and toxic epidermal necrolysis in Japanese patients

The Pharmacogenomics Journal volume 13, pages 60–69 (2013)Cite this article

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Abstract

Stevens–Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are severe, cutaneous adverse drug reactions that are rare but life threatening. Genetic biomarkers for allopurinol-related SJS/TEN in Japanese were examined in a genome-wide association study in which Japanese patients (n=14) were compared with ethnically matched healthy controls (n=991). Associations between 890 321 single nucleotide polymorphisms and allopurinol-related SJS/TEN were analyzed by the Fisher's exact test (dominant genotype mode). A total of 21 polymorphisms on chromosome 6 were significantly associated with allopurinol-related SJS/TEN. The strongest association was found at rs2734583 in BAT1, rs3094011 in HCP5 and GA005234 in MICC (P=2.44 × 10−8; odds ratio=66.8; 95% confidence interval, 19.8–225.0). rs9263726 in PSORS1C1, also significantly associated with allopurinol-related SJS/TEN, is in absolute linkage disequilibrium with human leukocyte antigen-B*5801, which is in strong association with allopurinol-induced SJS/TEN. The ease of typing rs9263726 makes it a useful biomarker for allopurinol-related SJS/TEN in Japanese.

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Acknowledgements

We thank all the patients and physicians for their cooperation with this study. We also thank Riken Genesis for the Illumina BeadChip analysis and StaGen for the statistical analysis. This study was supported in part by a Health and Labor Science Research Grant (Research on Advanced Medical Technology) from the Ministry of Health, Labor and Welfare of Japan.

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Author notes

  1. M Tohkin, N Kaniwa, Y Saito, E Sugiyama, K Kurose, J Nishikawa, R Hasegawa, M Aihara, K Matsunaga, M Abe, H Furuya, Y Takahashi, H Ikeda, M Muramatsu, M Ueta, C Sotozono, S Kinoshita and Z Ikezawa: M Tohkin, N Kaniwa, Y Saito, E Sugiyama, K Kurose, J Nishikawa, R Hasegawa, M Aihara, K Matsunaga, M Abe, H Furuya, Y Takahashi, H Ikeda, M Muramatsu, M Ueta, C Sotozono, S Kinoshita and Z Ikezawa: Members of the Japan Severe Adverse Reaction (JSAR) research group.

  2. The members of the Japan Pharmacogenomics Data Science Consortium are listed in the Appendix.

Authors and Affiliations

  1. Department of Medicinal Safety Science, National Institute of Health Sciences, Tokyo, Japan

    M Tohkin, N Kaniwa, Y Saito, E Sugiyama, K Kurose, J Nishikawa & R Hasegawa

  2. Department of Environmental Immunodermatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan

    M Aihara & Z Ikezawa

  3. Department of Dermatology, Fujita Health University School of Medicine, Toyoake, Japan

    K Matsunaga & M Abe

  4. Department of Neurology, Neuro-Muscular Center, National Oomuta Hospital, Oomuta, Japan

    H Furuya

  5. Shizuoka Institute of Epilepsy and Neurological Disorders, National Epilepsy Center, Shizuoka, Japan

    Y Takahashi & H Ikeda

  6. Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan

    M Muramatsu

  7. Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan

    M Ueta, C Sotozono & S Kinoshita

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  1. M Tohkin
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the Japan Pharmacogenomics Data Science Consortium

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Correspondence to M Tohkin.

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The authors declare no conflict of interest except one member of JPDSC, Mitsubishi Tanabe Pharma, which is a distributor of allopurinol in Japan.

Appendix

Japan Pharmacogenomics Data Science Consortium (JPDSC)

The Japan Pharmacogenomics Data Science Consortium is composed of Astellas Pharma, Otsuka Pharmaceutical, Daiichi Sankyo, Taisho Pharmaceutical, Takeda Pharmaceutical and Mitsubishi Tanabe Pharma, and is chaired by Ichiro Nakaoka (Takeda Pharmaceutical).

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Tohkin, M., Kaniwa, N., Saito, Y. et al. A whole-genome association study of major determinants for allopurinol-related Stevens–Johnson syndrome and toxic epidermal necrolysis in Japanese patients. Pharmacogenomics J 13, 60–69 (2013). https://doi.org/10.1038/tpj.2011.41

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