Clozapine-induced agranulocytosis in schizophrenic Caucasians: confirming clues for associations with human leukocyte class I and II antigens

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 (Cl): 0.08-1.23), Cw7 (P = 0.058, OR = 2.0, 95% Cl: 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.