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 Kubota; Takemi 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

doi:10.1016/j.biopsych.2015.12.006

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 language	English
Pages (from-to)	636-642
Number of pages	7
Journal	Biological Psychiatry
Volume	80
Issue number	8
DOIs	https://doi.org/10.1016/j.biopsych.2015.12.006
Publication status	Published - 15-10-2016

All Science Journal Classification (ASJC) codes

Biological Psychiatry

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10.1016/j.biopsych.2015.12.006

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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

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title = "Pharmacogenomic Study of Clozapine-Induced Agranulocytosis/Granulocytopenia in a Japanese Population",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2016 Society of Biological Psychiatry",

year = "2016",

month = oct,

day = "15",

doi = "10.1016/j.biopsych.2015.12.006",

language = "English",

volume = "80",

pages = "636--642",

journal = "Biological Psychiatry",

issn = "0006-3223",

publisher = "Elsevier USA",

number = "8",

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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, SI, Makinodan, M, Nishihata, Y, Kubota, M, Kimura, T, Kanahara, N, Hashimoto, N, Fujita, K, Nemoto, K, Fukao, T, Suwa, T, Noda, T, Yada, Y, Takaki, M, Kida, N, Otsuru, T, Murakami, M, Takahashi, A, Kubo, M, Hashimoto, R & Iwata, N 2016, 'Pharmacogenomic Study of Clozapine-Induced Agranulocytosis/Granulocytopenia in a Japanese Population', Biological Psychiatry, vol. 80, no. 8, pp. 636-642. https://doi.org/10.1016/j.biopsych.2015.12.006

TY - JOUR

T1 - Pharmacogenomic Study of Clozapine-Induced Agranulocytosis/Granulocytopenia in a Japanese Population

AU - Saito, Takeo

AU - Ikeda, Masashi

AU - Mushiroda, Taisei

AU - Ozeki, Takeshi

AU - Kondo, Kenji

AU - Shimasaki, Ayu

AU - Kawase, Kohei

AU - Hashimoto, Shuji

AU - Yamamori, Hidenaga

AU - Yasuda, Yuka

AU - Fujimoto, Michiko

AU - Ohi, Kazutaka

AU - Takeda, Masatoshi

AU - Kamatani, Yoichiro

AU - Numata, Shusuke

AU - Ohmori, Tetsuro

AU - Ueno, Shu ichi

AU - Makinodan, Manabu

AU - Nishihata, Yosuke

AU - Kubota, Masaharu

AU - Kimura, Takemi

AU - Kanahara, Nobuhisa

AU - Hashimoto, Naoki

AU - Fujita, Kiyoshi

AU - Nemoto, Kiyotaka

AU - Fukao, Taku

AU - Suwa, Taro

AU - Noda, Tetsuro

AU - Yada, Yuji

AU - Takaki, Manabu

AU - Kida, Naoya

AU - Otsuru, Taku

AU - Murakami, Masaru

AU - Takahashi, Atsushi

AU - Kubo, Michiaki

AU - Hashimoto, Ryota

AU - Iwata, Nakao

PY - 2016/10/15

Y1 - 2016/10/15

N2 - 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.

AB - 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.

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U2 - 10.1016/j.biopsych.2015.12.006

DO - 10.1016/j.biopsych.2015.12.006

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SN - 0006-3223

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JO - Biological Psychiatry

JF - Biological Psychiatry

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ER -

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

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