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ID 115021
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Phamacogenomics of Clozapine-Induced Agranulocytosis
Saito, Takeo Fujita Health University
Ikeda, Masashi Fujita Health University
Mushiroda, Taisei RIKEN Center for Integrative Medical Sciences
Ozeki, Takeshi RIKEN Center for Integrative Medical Sciences
Kondo, Kenji Fujita Health University
Shimasaki, Ayu Fujita Health University
Kawase, Kohei Fujita Health University
Hashimoto, Shuji Fujita Health University
Yamamori, Hidenaga Osaka University
Yasuda, Yuka Osaka University
Fujimoto, Michiko Osaka University
Ohi, Kazutaka Osaka University
Takeda, Masatoshi Osaka University
Kamatani, Yoichiro RIKEN Center for Integrative Medical Sciences
Ueno, Shu-ichi Ehime University
Makinodan, Manabu Nara Medical University
Nishihata, Yosuke Nara Medical University
Kubota, Masaharu Kusakabe Memorial Hospital
Kimura, Takemi National Hospital Organization Kikuchi Hospital
Kanahara, Nobuhisa Chiba University
Hashimoto, Naoki Hokkaido University
Fujita, Kiyoshi Okehazama Hospital
Nemoto, Kiyotaka University of Tsukuba
Fukao, Taku Gifu University
Suwa, Taro Kyoto University
Noda, Tetsuro Osaka Psychiatric Medical Center
Yada, Yuji Okayama Psychiatric Medical Center
Takaki, Manabu Okayama University
Kida, Naoya National Hospital Organization Ryukyu Hospital
Otsuru, Taku National Hospital Organization Ryukyu Hospital
Murakami, Masaru National Hospital Organization Ryukyu Hospital
Takahashi, Atsushi RIKEN Center for Integrative Medical Sciences|National Cerebral and Cardiovascular Center
Kubo, Michiaki RIKEN Center for Integrative Medical Sciences
Hashimoto, Ryota Osaka University
Iwata, Nakao Fujita Health University
Genome-wide association study
Human leukocyte antigen
Side effect
Single nucleotide polymorphism
Content Type
Journal Article
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.
Journal Title
Biological Psychiatry
Society of Biological Psychiatry|Elsevier
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© 2016 Society of Biological Psychiatry. This is an open access article under the CC BY-NC-ND license (
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Medical Sciences