Abstract
Clozapine-induced agranulocytosis (CA) is still among the least understood adverse drug reactions in psychopharmacology. In particular, its genetic background is far from being clarified. Within the framework of a case–control study, we performed human leukocyte antigen (HLA) genotyping and haplotype analyses in 42 non-Jewish Caucasian schizophrenic patients (N=42) suffering from CA and 75 non-Jewish Caucasian schizophrenic patients treated with clozapine without developing CA. While controlling for age (P<0.0001) and sex (P=0.835), testing of the alleles from both HLA-loci resulted in borderline results for Cw2 (P=0.085, odds ratio (OR)=0.36, 95% confidence interval (CI): 0.08–1.23), Cw7 (P=0.058, OR=2.0, 95% CI: 0.87–4.63) and DRB5*0201 (P=0.005, adjusted OR=22.15). For haplotype analysis, we obtained significant association results with CA for the two-locus haplotypes HLA-Cw-B (P=0.022) and HLA-DRB5-DRB4 (P=0.050), and for the three-locus haplotype HLA-Cw-B-DRB5 (P=0.030). The complex nature of CA implies that many genes might play a role, but currently, only HLA associations with CA are identified as clinically relevant.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 6 print issues and online access
$259.00 per year
only $43.17 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Bénichou C, Solal-Celigny P . Standardization of definitions and criteria for causality assessment of adverse drug reactions. Drug-induced blood cytopenias: report of an international consensus meeting. Nouv Rev Fr Hematol 1993; 33: 257–262.
Vincent PC . Drug-induced aplastic anaemia and agranulocytosis. Drugs 1986; 31: 52–63.
Liu ZC, Uetrecht JP . Metabolism of ticlopidine by activated neutrophils: implications for ticlopidine-induced agranulocytosis. Drug Metab Dispos 2000; 8: 726–730.
Gardner I, Popovic M, Zahid N, Uetrecht JP . A comparison of the covalent binding of clozapine, procainamide, and vesnarinone to human neutrophils in vitro and rat tissues in vitro and in vivo. Chem Res Toxicol 2005; 18: 1384–1394.
Hennen J, Baldessarini RJ . Suicidal risk during treatment with clozapine: a meta-analysis. Schizophr Res 2005; 73: 139–145.
Alvir JM, Lieberman JA, Safferman AZ, Schwimmer JL, Schaaf JA . Clozapine-induced agranulocytosis. Incidence and risk factors in the United States. N Engl J Med 1993; 329: 162–167.
Ibanez L, Vidal X, Ballarin E, Laporte JR . Population-based drug-induced agranulocytosis. Arch Intern Med 2005; 25: 869–874.
Oyesanmi O, Kunkel EJS, Monti D, Field HL . Hematologic side effects of psychotropics. Psychosomatics 1999; 40: 414–421.
Palmblad J, Papadaki HA, Eliopoulos D . Acute and chronic neutropenias. What is new? J Intern Med 2001; 250: 476–491.
Guest I, Uetrecht J . Drugs that induce neutropenia/agranulocytosis may target specific components of the stromal cell extracellular matrix. Med Hypotheses 1999; 2: 145–151.
Marchesi C, Paini M, Tamborini S, Ampollini P, Maggini C . Recurrence of clozapine-induced agranulocytosis. J Clin Psychopharmacol 2005; 25: 276–277.
Dettling M, Sachse C, Muller-Oerlinghausen B, Roots I, Brockmoller J, Rolfs A et al. Clozapine-induced agranulocytosis and hereditary polymorphisms of clozapine metabolizing enzymes: no association with myeloperoxidase and cytochrome P4502D6. Pharmacopsychiatry 2000; 33: 218–220.
Price KO . Ethnicity and clozapine-induced agranulocytosis. Clin Pharmacy 1991; 10: 743–744.
Horáèek J, Libiger J, Höschl C, Borzova K, Hendrychová I . Clozapine-induced concordant agranulocytosis in monozygotic twins. Int J Psychiatry Clin Pract 2001; 5: 71–73.
Pirmohamed M, Park BK . Genetic susceptibility to adverse drug reactions. Trends Pharmacol Sci 2001; 22: 298–305.
Lieberman JA, Yunis J, Egea E, Canoso RT, Kane JM, Yunis EJ . HLA-B38, DR4, DQw3 and clozapine-induced agranulocytosis in Jewish patients with schizophrenia. Arch Gen Psychiatry 1990; 47: 945–948.
Yunis JJ, Corzo D, Salazar M, Lieberman JA, Howard A, Yunis EJ . HLA associations in clozapine-induced agranulocytosis. Blood 1995; 86: 1177–1183.
Claas FHJ, Abott PA, Witvliet MD, Amaro JD, Barnes PM, Krupp P . No direct clinical relevance of the human leukocyte antigen (HLA−) system in clozapine-induced agranulocytosis. Drug Safety 1992; 7 (Suppl 1): 3–6.
Dettling M, Cascorbi I, Roots I, Muller-Oerlinghausen B . Genetic determinants of clozapine-induced agranulocytosis: recent results of HLA− subtyping in a non-Jewish Caucasian sample. Arch Gen Psychiatry 2001; 58: 93–94.
Dettling M, Schaub RT, Mueller-Oerlinghausen B, Roots I, Cascorbi I . Further evidence of human leukocyte antigen-encoded susceptibility to clozapine-induced agranulocytosis independent of ancestry. Pharmacogenetics 2001; 11: 135–141.
Chen J, Peters U, Foster C, Chatterjee N . A haplotype-based test of association using data from cohort and nested case–control epidemiologic studies. Hum Hered 2004; 58: 18–29.
Mosyagin I, Cascorbi I, Schaub R, Krueger T, Dettling M . Drug-induced agranulocytosis: impact of different Fcγ receptor polymorphisms? J Clin Psychopharmacol 2005; 25: 435–439.
Husain Z, Levitan E, Larsen CE, Mirza NM, Younes S, Yunis EJ et al. HLA-Cw7 zygosity affects the size of a subset of CD158b+ natural killer cells. J Clin Immunol 2002; 22: 28–36.
Marin L, Torio A, Muro M, Fernandez-Parra R, Minguela A, Bosch V et al. Alloimmune neonatal neutropenia and thrombocytopenia associated with maternal anti HNA-1a, HPA-3b, and HLA antibodies. Pediatr Allergy Immunol 2005; 16: 279–282.
Prat E, Tomaru U, Sabater L, Park DM, Granger R, Kruse N et al. HLA-DRB5*0101 and -DRB1*1501 expression in the multiple sclerosis-associated HLA-DR15 haplotype. J Neuroimmunol 2005; 167: 108–119.
Miretti MM, Walsh EC, Ke X, Delgado M, Griffiths M, Hunt S et al. A high-resolution linkage-disequilibrium map of the human major histocompatibility complex and first generation of taq single-nucleotide polymorphisms. Am J Hum Genet 2005; 76: 634–646.
Piertney SB, Oliver MK . The evolutionary ecology of the major histocompatibility complex. Heredity 2006; 96: 7–21.
Ostrousky O, Meged S, Loewenthal R, Valevski A, Weizman A, Carp H et al. NQO2 gene is associated with clozapine-induced agranulocytosis. Tissue Antigens 2003; 62: 483–491.
Mosyagin I, Dettling M, Roots I, Mueller-Oerlinghausen B, Cascorbi I . Impact of myeloperoxidase and NADPH-oxidase polymorphisms in drug-induced agranulocytosis. J Clin Psychopharmacol 2004; 24: 613–617.
Fehsel K, Loeffler S, Krieger K, Henning U, Agelink M, Kolb-Bachofen V et al. Clozapine induces oxidative stress and proapoptotic gene expression in neutrophils of schizophrenic patients. J Clin Psychopharmacol 2005; 25: 419–426.
R Development Core Team. R Foundation for Statistical Computing, Version 2.1.1 (2005-06-20), ISBN 3-900051-07-0. 2005.
Sham PC, Curtis D . Monte Carlo tests for associations between disease alleles at highly polymorphic loci. Ann Hum Genet 1997; 59: 97–105.
Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA . Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet 2002; 70: 425–434.
Sinnwell JP, Schaid DJ . Statistical Analysis of Haplotypes with Traits and Covariates when Linkage Phase is Ambiguous, The Haplo.stats Package URL:http://mayoresearch.mayo.edu/mayo/research/biostat/schaid.cfm. 2003.
McCullagh P, Nelder JA . Generalized Linear Models. Chapman and Hall: London, 1983.
Lake S, Lyon H, Silverman E, Weiss S, Laird N, Schaid D . Estimation and tests of haplotype–environment interaction when linkage phase is ambiguous. Hum Hered 2003; 55: 56–65.
Acknowledgements
This study was supported by Grant 01 EC 9406 from the German Federal Ministry of Education and Research. We thank all participating patients and supporting doctors.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Dettling, M., Cascorbi, I., Opgen-Rhein, C. et al. Clozapine-induced agranulocytosis in schizophrenic Caucasians: confirming clues for associations with human leukocyte class I and II antigens. Pharmacogenomics J 7, 325–332 (2007). https://doi.org/10.1038/sj.tpj.6500423
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.tpj.6500423
Keywords
This article is cited by
-
Pharmacogenomics: current status and future perspectives
Nature Reviews Genetics (2023)
-
HLA-DQB1 6672G>C (rs113332494) is associated with clozapine-induced neutropenia and agranulocytosis in individuals of European ancestry
Translational Psychiatry (2021)
-
Adverse drug reactions triggered by the common HLA-B*57:01 variant: a molecular docking study
Journal of Cheminformatics (2017)
-
More than 25 years of genetic studies of clozapine-induced agranulocytosis
The Pharmacogenomics Journal (2017)
-
Correlation Between Serum Concentrations of N-Desmethylclozapine and Granulocyte Levels in Patients with Schizophrenia: A Retrospective Observational Study
CNS Drugs (2017)