PMID- 26876947
OWN - NLM
STAT- MEDLINE
DCOM- 20170807
LR  - 20221207
IS  - 1873-2402 (Electronic)
IS  - 0006-3223 (Linking)
VI  - 80
IP  - 8
DP  - 2016 Oct 15
TI  - Pharmacogenomic Study of Clozapine-Induced Agranulocytosis/Granulocytopenia in a 
      Japanese Population.
PG  - 636-42
LID - S0006-3223(15)01041-0 [pii]
LID - 10.1016/j.biopsych.2015.12.006 [doi]
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 x 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 x 10(-8), OR = 10.7) 
      and confirmed this association by comparing with an independent 
      clozapine-tolerant control group (n = 380, p = 2.97 x 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.
CI  - Copyright (c) 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All 
      rights reserved.
FAU - Saito, Takeo
AU  - Saito T
AD  - Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, 
      Aichi.
FAU - Ikeda, Masashi
AU  - Ikeda M
AD  - Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, 
      Aichi.
FAU - Mushiroda, Taisei
AU  - Mushiroda T
AD  - Research Group for Pharmacogenomics, RIKEN Center for Integrative Medical 
      Sciences, Yokohama.
FAU - Ozeki, Takeshi
AU  - Ozeki T
AD  - Research Group for Pharmacogenomics, RIKEN Center for Integrative Medical 
      Sciences, Yokohama.
FAU - Kondo, Kenji
AU  - Kondo K
AD  - Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, 
      Aichi.
FAU - Shimasaki, Ayu
AU  - Shimasaki A
AD  - Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, 
      Aichi.
FAU - Kawase, Kohei
AU  - Kawase K
AD  - Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, 
      Aichi.
FAU - Hashimoto, Shuji
AU  - Hashimoto S
AD  - Department of Hygiene, Fujita Health University School of Medicine, Toyoake, 
      Aichi.
FAU - Yamamori, Hidenaga
AU  - Yamamori H
AD  - Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, 
      Osaka.
FAU - Yasuda, Yuka
AU  - Yasuda Y
AD  - Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, 
      Osaka.
FAU - Fujimoto, Michiko
AU  - Fujimoto M
AD  - Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, 
      Osaka.
FAU - Ohi, Kazutaka
AU  - Ohi K
AD  - Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, 
      Osaka.
FAU - Takeda, Masatoshi
AU  - Takeda M
AD  - 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.
FAU - Kamatani, Yoichiro
AU  - Kamatani Y
AD  - Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical 
      Sciences, Yokohama.
FAU - Numata, Shusuke
AU  - Numata S
AD  - Department of Psychiatry, Institute of Biomedical Sciences, Tokushima University 
      Graduate School, Tokushima.
FAU - Ohmori, Tetsuro
AU  - Ohmori T
AD  - Department of Psychiatry, Institute of Biomedical Sciences, Tokushima University 
      Graduate School, Tokushima.
FAU - Ueno, Shu-Ichi
AU  - Ueno S
AD  - Department of Neuropsychiatry, Ehime University Graduate School of Medicine, 
      Shitsukawa.
FAU - Makinodan, Manabu
AU  - Makinodan M
AD  - Department of Psychiatry, Faculty of Medicine, Nara Medical University, 
      Kashihara, Nara.
FAU - Nishihata, Yosuke
AU  - Nishihata Y
AD  - Department of Psychiatry, Faculty of Medicine, Nara Medical University, 
      Kashihara, Nara.
FAU - Kubota, Masaharu
AU  - Kubota M
AD  - Kusakabe Memorial Hospital, Yamanasi, Yamanasi; RIKEN Center for Integrative 
      Medical Sciences, Yokohama, Japan.
FAU - Kimura, Takemi
AU  - Kimura T
AD  - Division of Clinical Research, National Hospital Organization Kikuchi Hospital, 
      Koshi, Kumamoto.
FAU - Kanahara, Nobuhisa
AU  - Kanahara N
AD  - Chiba University Center for Forensic Mental Health, Chiba, Chiba.
FAU - Hashimoto, Naoki
AU  - Hashimoto N
AD  - Department of Psychiatry, Hokkaido University Graduate School of Medicine, 
      Sapporo, Hokkaido.
FAU - Fujita, Kiyoshi
AU  - Fujita K
AD  - Department of Psychiatry, Okehazama Hospital, Toyoake, Aichi.
FAU - Nemoto, Kiyotaka
AU  - Nemoto K
AD  - Department of Psychiatry, Division of Clinical Medicine, Faculty of Medicine, 
      University of Tsukuba, Tsukuba, Ibaraki.
FAU - Fukao, Taku
AU  - Fukao T
AD  - Department of Psychiatry, Gifu University Graduate School of Medicine, Gifu.
FAU - Suwa, Taro
AU  - Suwa T
AD  - Department of Psychiatry, Graduate School of Medicine, Kyoto University, 
      Sakyo-ku, Kyoto.
FAU - Noda, Tetsuro
AU  - Noda T
AD  - Osaka Psychiatric Medical Center, Hirakata, Osaka.
FAU - Yada, Yuji
AU  - Yada Y
AD  - Okayama Psychiatric Medical Center, Kita-ku, Okayama.
FAU - Takaki, Manabu
AU  - Takaki M
AD  - Department of Neuropsychiatry, Okayama University Graduate School of Medicine, 
      Dentistry and Pharmaceutical Sciences, Okayama City, Okayama.
FAU - Kida, Naoya
AU  - Kida N
AD  - National Hospital Organization Ryukyu Hospital, Kunigami-gun, Okinawa.
FAU - Otsuru, Taku
AU  - Otsuru T
AD  - National Hospital Organization Ryukyu Hospital, Kunigami-gun, Okinawa.
FAU - Murakami, Masaru
AU  - Murakami M
AD  - National Hospital Organization Ryukyu Hospital, Kunigami-gun, Okinawa.
FAU - Takahashi, Atsushi
AU  - Takahashi A
AD  - Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical 
      Sciences, Yokohama; Laboratory for Omics Informatics, Omics Research Center, 
      National Cerebral and Cardiovascular Center, Osaka.
FAU - Kubo, Michiaki
AU  - Kubo M
AD  - RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
FAU - Hashimoto, Ryota
AU  - Hashimoto R
AD  - 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.
FAU - Iwata, Nakao
AU  - Iwata N
AD  - Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, 
      Aichi.
LA  - eng
PT  - Journal Article
DEP - 20160211
PL  - United States
TA  - Biol Psychiatry
JT  - Biological psychiatry
JID - 0213264
RN  - 0 (HLA-B Antigens)
RN  - 0 (HLA-B59 antigen)
RN  - J60AR2IKIC (Clozapine)
SB  - IM
CIN - Biol Psychiatry. 2016 Oct 15;80(8):e63-5. PMID: 27663067
MH  - Adult
MH  - Agranulocytosis/*chemically induced/*genetics
MH  - Alleles
MH  - Asian People/genetics
MH  - Case-Control Studies
MH  - Clozapine/*adverse effects
MH  - Female
MH  - Genetic Predisposition to Disease/genetics
MH  - Genotype
MH  - HLA-B Antigens/*genetics
MH  - Histocompatibility Testing
MH  - Humans
MH  - Male
MH  - *Pharmacogenomic Testing
MH  - Risk Factors
MH  - Sensitivity and Specificity
MH  - Young Adult
OTO - NOTNLM
OT  - Genome-wide association study
OT  - Human leukocyte antigen
OT  - Pharmacogenomics
OT  - Schizophrenia
OT  - Side effect
OT  - Single nucleotide polymorphism
EDAT- 2016/02/16 06:00
MHDA- 2017/08/08 06:00
CRDT- 2016/02/16 06:00
PHST- 2015/07/22 00:00 [received]
PHST- 2015/10/31 00:00 [revised]
PHST- 2015/12/03 00:00 [accepted]
PHST- 2016/02/16 06:00 [entrez]
PHST- 2016/02/16 06:00 [pubmed]
PHST- 2017/08/08 06:00 [medline]
AID - S0006-3223(15)01041-0 [pii]
AID - 10.1016/j.biopsych.2015.12.006 [doi]
PST - ppublish
SO  - Biol Psychiatry. 2016 Oct 15;80(8):636-42. doi: 10.1016/j.biopsych.2015.12.006. 
      Epub 2016 Feb 11.