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Genetic risk factors for clozapine-induced neutropenia and agranulocytosis in a Dutch psychiatric population

The Pharmacogenomics Journal volume 17, pages 471–478 (2017)Cite this article

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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 GSTM1null was 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.

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Acknowledgements

We acknowledge and appreciate the support in database mining by D van de Glind, R Herben and B Pijl (GGz Centraal) and B Scholten and M de Lassaquère-van Renselaar (St Jansdal Hospital). We also appreciate the work performed by the DNA technicians.

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Authors and Affiliations

  1. Department of Clinical Chemistry, St Jansdal Hospital, Harderwijk, The Netherlands

    K van der Weide, H Loovers, K Pondman & J van der Weide

  2. Psychiatric Hospital GGz Centraal, Dependance Meerkanten, Ermelo, The Netherlands

    H Loovers & J van der Weide

  3. Mental Health Services Rivierduinen, Oegstgeest, The Netherlands

    J Bogers

  4. Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands

    T van der Straaten

  5. Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands

    E Langemeijer

  6. Mental Health Services North-Holland North, Heerhugowaard, The Netherlands

    D Cohen

  7. AIMMS-Division of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, VU Amsterdam, Amsterdam, The Netherlands

    J Commandeur

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van der Weide, K., Loovers, H., Pondman, K. et al. Genetic risk factors for clozapine-induced neutropenia and agranulocytosis in a Dutch psychiatric population. Pharmacogenomics J 17, 471–478 (2017). https://doi.org/10.1038/tpj.2016.32

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