title: Pharmacogenomic Study of Clozapine-Induced Agranulocytosis/Granulocytopenia in a Japanese Population.
abstract: Clozapine-induced agranulocytosis (CIA)/clozapine-induced granulocytopenia (CIG) (CIAG) is a life-threatening event for schizophrenic subjects treated with clozapine.
  
  
  
  To examine the genetic factor for CIAG, a genome-wide pharmacogenomic analysis was conducted using 50 subjects with CIAG and 2905 control subjects.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi.
authors.forename: Takeo
authors.initials: T
authors.lastname: Saito
authors.affiliation: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi.
authors.forename: Masashi
authors.initials: M
authors.lastname: Ikeda
authors.affiliation: Research Group for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama.
authors.forename: Taisei
authors.initials: T
authors.lastname: Mushiroda
authors.affiliation: Research Group for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ozeki
authors.affiliation: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kondo
authors.affiliation: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi.
authors.forename: Ayu
authors.initials: A
authors.lastname: Shimasaki
authors.affiliation: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi.
authors.forename: Kohei
authors.initials: K
authors.lastname: Kawase
authors.affiliation: Department of Hygiene, Fujita Health University School of Medicine, Toyoake, Aichi.
authors.forename: Shuji
authors.initials: S
authors.lastname: Hashimoto
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka.
authors.forename: Hidenaga
authors.initials: H
authors.lastname: Yamamori
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Yasuda
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka.
authors.forename: Michiko
authors.initials: M
authors.lastname: Fujimoto
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ohi
authors.affiliation: 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.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Takeda
authors.affiliation: Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Kamatani
authors.affiliation: Department of Psychiatry, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima.
authors.forename: Shusuke
authors.initials: S
authors.lastname: Numata
authors.affiliation: Department of Psychiatry, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Ohmori
authors.affiliation: Department of Neuropsychiatry, Ehime University Graduate School of Medicine, Shitsukawa.
authors.forename: Shu-Ichi
authors.initials: S
authors.lastname: Ueno
authors.affiliation: Department of Psychiatry, Faculty of Medicine, Nara Medical University, Kashihara, Nara.
authors.forename: Manabu
authors.initials: M
authors.lastname: Makinodan
authors.affiliation: Department of Psychiatry, Faculty of Medicine, Nara Medical University, Kashihara, Nara.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Nishihata
authors.affiliation: Kusakabe Memorial Hospital, Yamanasi, Yamanasi; RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Kubota
authors.affiliation: Division of Clinical Research, National Hospital Organization Kikuchi Hospital, Koshi, Kumamoto.
authors.forename: Takemi
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Chiba University Center for Forensic Mental Health, Chiba, Chiba.
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Kanahara
authors.affiliation: Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido.
authors.forename: Naoki
authors.initials: N
authors.lastname: Hashimoto
authors.affiliation: Department of Psychiatry, Okehazama Hospital, Toyoake, Aichi.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Fujita
authors.affiliation: Department of Psychiatry, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki.
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Nemoto
authors.affiliation: Department of Psychiatry, Gifu University Graduate School of Medicine, Gifu.
authors.forename: Taku
authors.initials: T
authors.lastname: Fukao
authors.affiliation: Department of Psychiatry, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto.
authors.forename: Taro
authors.initials: T
authors.lastname: Suwa
authors.affiliation: Osaka Psychiatric Medical Center, Hirakata, Osaka.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Noda
authors.affiliation: Okayama Psychiatric Medical Center, Kita-ku, Okayama.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yada
authors.affiliation: Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama City, Okayama.
authors.forename: Manabu
authors.initials: M
authors.lastname: Takaki
authors.affiliation: National Hospital Organization Ryukyu Hospital, Kunigami-gun, Okinawa.
authors.forename: Naoya
authors.initials: N
authors.lastname: Kida
authors.affiliation: National Hospital Organization Ryukyu Hospital, Kunigami-gun, Okinawa.
authors.forename: Taku
authors.initials: T
authors.lastname: Otsuru
authors.affiliation: National Hospital Organization Ryukyu Hospital, Kunigami-gun, Okinawa.
authors.forename: Masaru
authors.initials: M
authors.lastname: Murakami
authors.affiliation: Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama; Laboratory for Omics Informatics, Omics Research Center, National Cerebral and Cardiovascular Center, Osaka.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.affiliation: RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.affiliation: 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.
authors.forename: Ryota
authors.initials: R
authors.lastname: Hashimoto
authors.affiliation: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi.
authors.forename: Nakao
authors.initials: N
authors.lastname: Iwata
mesh_terms: D000328:Adult; D000380:Agranulocytosis / Q000139:chemically induced* / Q000235:genetics*; D000483:Alleles; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D003024:Clozapine / Q000009:adverse effects*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D015235:HLA-B Antigens / Q000235:genetics*; D006650:Histocompatibility Testing; D006801:Humans; D008297:Male; D000071185:Pharmacogenomic Testing; D012307:Risk Factors; D012680:Sensitivity and Specificity; D055815:Young Adult
chemical_list: D015235:HLA-B Antigens; C082943:HLA-B59 antigen; D003024:Clozapine
keywords: Genome-wide association study; Human leukocyte antigen; Pharmacogenomics; Schizophrenia; Side effect; Single nucleotide polymorphism