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Biol Psychiatry. 2016 Oct 15;80(8):636-42. doi: 10.1016/j.biopsych.2015.12.006. Epub 2016 Feb 11.

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

Author information

1
Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi.
2
Research Group for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama.
3
Department of Hygiene, Fujita Health University School of Medicine, Toyoake, Aichi.
4
Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka.
5
Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka; Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Suita, Osaka.
6
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama.
7
Department of Psychiatry, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima.
8
Department of Neuropsychiatry, Ehime University Graduate School of Medicine, Shitsukawa.
9
Department of Psychiatry, Faculty of Medicine, Nara Medical University, Kashihara, Nara.
10
Kusakabe Memorial Hospital, Yamanasi, Yamanasi; RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
11
Division of Clinical Research, National Hospital Organization Kikuchi Hospital, Koshi, Kumamoto.
12
Chiba University Center for Forensic Mental Health, Chiba, Chiba.
13
Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido.
14
Department of Psychiatry, Okehazama Hospital, Toyoake, Aichi.
15
Department of Psychiatry, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki.
16
Department of Psychiatry, Gifu University Graduate School of Medicine, Gifu.
17
Department of Psychiatry, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto.
18
Osaka Psychiatric Medical Center, Hirakata, Osaka.
19
Okayama Psychiatric Medical Center, Kita-ku, Okayama.
20
Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama City, Okayama.
21
National Hospital Organization Ryukyu Hospital, Kunigami-gun, Okinawa.
22
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama; Laboratory for Omics Informatics, Omics Research Center, National Cerebral and Cardiovascular Center, Osaka.
23
RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
24
Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka; Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Suita, Osaka. Electronic address: hashimor@psy.med.osaka-u.ac.jp.

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.

KEYWORDS:

Genome-wide association study; Human leukocyte antigen; Pharmacogenomics; Schizophrenia; Side effect; Single nucleotide polymorphism

Comment in

PMID:
26876947
DOI:
10.1016/j.biopsych.2015.12.006
[Indexed for MEDLINE]
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