title: Clozapine-induced agranulocytosis in schizophrenic Caucasians: confirming clues for associations with human leukocyte class I and II antigens.
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.
authors.affiliation: Department of Psychiatry and Psychotherapy, Charité-University Medicine Berlin, Berlin, Germany. michael.dettling@charite.de
authors.forename: M
authors.initials: M
authors.lastname: Dettling
authors.forename: I
authors.initials: I
authors.lastname: Cascorbi
authors.forename: C
authors.initials: C
authors.lastname: Opgen-Rhein
authors.forename: R
authors.initials: R
authors.lastname: Schaub
mesh_terms: D000328:Adult; D000380:Agranulocytosis / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology; D014150:Antipsychotic Agents / Q000009:adverse effects*; D016022:Case-Control Studies; D003024:Clozapine / Q000009:adverse effects*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D018570:Risk Assessment; D012307:Risk Factors; D012559:Schizophrenia / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D016896:Treatment Outcome; D044465:White People / Q000235:genetics*
chemical_list: D014150:Antipsychotic Agents; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D003024:Clozapine