Pharmacogenomic Study of Clozapine-Induced Agranulocytosis/Granulocytopenia in a Japanese Population

Takeo Saito, Masashi Ikeda, Taisei Mushiroda, Takeshi Ozeki, Kenji Kondo, Ayu Shimasaki, Kohei Kawase, Shuji Hashimoto, Hidenaga Yamamori, Yuka Yasuda, Michiko Fujimoto, Kazutaka Ohi, Masatoshi Takeda, Yoichiro Kamatani, Shusuke Numata, Tetsuro Ohmori, Shu ichi Ueno, Manabu Makinodan, Yosuke Nishihata, Masaharu KubotaTakemi Kimura, Nobuhisa Kanahara, Naoki Hashimoto, Kiyoshi Fujita, Kiyotaka Nemoto, Taku Fukao, Taro Suwa, Tetsuro Noda, Yuji Yada, Manabu Takaki, Naoya Kida, Taku Otsuru, Masaru Murakami, Atsushi Takahashi, Michiaki Kubo, Ryota Hashimoto, Nakao Iwata

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Abstract

Background Clozapine-induced agranulocytosis (CIA)/clozapine-induced granulocytopenia (CIG) (CIAG) is a life-threatening event for schizophrenic subjects treated with clozapine. Methods To examine the genetic factor for CIAG, a genome-wide pharmacogenomic analysis was conducted using 50 subjects with CIAG and 2905 control subjects. Results We identified a significant association in the human leukocyte antigen (HLA) region (rs1800625, p = 3.46 × 10−9, odds ratio [OR] = 3.8); therefore, subsequent HLA typing was performed. We detected a significant association of HLA-B*59:01 with CIAG (p = 3.81 × 10−8, OR = 10.7) and confirmed this association by comparing with an independent clozapine-tolerant control group (n = 380, p = 2.97 × 10−5, OR = 6.3). As we observed that the OR of CIA (OR: 9.3~15.8) was approximately double that in CIG (OR: 4.4~7.4), we hypothesized that the CIG subjects were a mixed population of those who potentially would develop CIA and those who would not develop CIA (non-CIA). This hypothesis allowed the proportion of the CIG who were non-CIA to be calculated, enabling us to estimate the positive predictive value of the nonrisk allele on non-CIA in CIG subjects. Assuming this model, we estimated that 1) ~50% of CIG subjects would be non-CIA; and 2) ~60% of the CIG subjects without the risk allele would be non-CIA and therefore not expected to develop CIA. Conclusions Our results suggest that HLA-B*59:01 is a risk factor for CIAG in the Japanese population. Furthermore, if our model is true, the results suggest that rechallenging certain CIG subjects with clozapine may not be always contraindicated.

Original languageEnglish
Pages (from-to)636-642
Number of pages7
JournalBiological Psychiatry
Volume80
Issue number8
DOIs
Publication statusPublished - 15-10-2016

All Science Journal Classification (ASJC) codes

  • Biological Psychiatry

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    Saito, T., Ikeda, M., Mushiroda, T., Ozeki, T., Kondo, K., Shimasaki, A., Kawase, K., Hashimoto, S., Yamamori, H., Yasuda, Y., Fujimoto, M., Ohi, K., Takeda, M., Kamatani, Y., Numata, S., Ohmori, T., Ueno, S. I., Makinodan, M., Nishihata, Y., ... Iwata, N. (2016). Pharmacogenomic Study of Clozapine-Induced Agranulocytosis/Granulocytopenia in a Japanese Population. Biological Psychiatry, 80(8), 636-642. https://doi.org/10.1016/j.biopsych.2015.12.006