title: Genetic risk factors for clozapine-induced neutropenia and agranulocytosis in a Dutch psychiatric population.
abstract: Prescription of clozapine is complicated by the occurrence of clozapine-induced reduction of neutrophils. The aim of this study was to identify genetic risk factors in a population of 310 Dutch patients treated with clozapine, including 38 patients developing neutropenia and 31 patients developing agranulocytosis. NQO2 1541AA (NRH quinone oxidoreductase 2; protects cells against oxidative metabolites) was present at a higher frequency in agranulocytosis patients compared with control (23% versus 7%, P=0.03), as was ABCB1 (ABC-transporter-B1; drug efflux transporter) 3435TT (32% versus 20%, P=0.05). In patients developing neutropenia, ABCB1 3435TT and homozygosity for GSTT1null(glutathione-S-transferase; conjugates reactive clozapine metabolites into glutathione) were more frequent compared with control (34% versus 20%, P=0.05 and 31% versus 14%, P=0.03), whereas GSTM1nullwas less frequent in these patients (31% versus 52%, P=0.03). To investigate whether combinations of the identified genetic risk factors have a higher predictive value, should be confirmed in a larger case-control study.
authors.affiliation: Department of Clinical Chemistry, St Jansdal Hospital, Harderwijk, The Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: van der Weide
authors.affiliation: Department of Clinical Chemistry, St Jansdal Hospital, Harderwijk, The Netherlands.|Psychiatric Hospital GGz Centraal, Dependance Meerkanten, Ermelo, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Loovers
authors.affiliation: Department of Clinical Chemistry, St Jansdal Hospital, Harderwijk, The Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: Pondman
authors.affiliation: Mental Health Services Rivierduinen, Oegstgeest, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Bogers
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: van der Straaten
authors.affiliation: Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Langemeijer
authors.affiliation: Mental Health Services North-Holland North, Heerhugowaard, The Netherlands.
authors.forename: D
authors.initials: D
authors.lastname: Cohen
authors.affiliation: AIMMS-Division of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, VU Amsterdam, Amsterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Commandeur
authors.affiliation: Department of Clinical Chemistry, St Jansdal Hospital, Harderwijk, The Netherlands.|Psychiatric Hospital GGz Centraal, Dependance Meerkanten, Ermelo, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: van der Weide
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000328:Adult; D000380:Agranulocytosis / Q000139:chemically induced / Q000235:genetics*; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use; D016022:Case-Control Studies; D003024:Clozapine / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D001523:Mental Disorders / Q000188:drug therapy / Q000235:genetics; D008875:Middle Aged; D009426:Netherlands; D009503:Neutropenia / Q000139:chemically induced / Q000235:genetics*; D000071184:Pharmacogenomic Variants; D011808:Quinone Reductases / Q000235:genetics; D012189:Retrospective Studies; D012307:Risk Factors
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D014150:Antipsychotic Agents; C419642:NRH - quinone oxidoreductase2; D011808:Quinone Reductases; D003024:Clozapine