Further evidence of human leukocyte antigen-encoded susceptibility to clozapine-induced agranulocytosis independent of ancestry

To further examine the human leukocyte antigen (HLA)-encoded genetic susceptibility to clozapine-induced agranulocytosis (CA) we performed HLA-genotyping in a sample of German schizophrenic patients, who suffered from this haematotoxic side-effect, Thirty-one schizophrenic patients with CA (17 women and 14 men) and 77 schizophrenic comparison subjects (40 women and 37 men) were included in the study. HLA-genotyping included identification of major histocompatibility complex (MHC) class I (HLA-A, B, Cw) and class II (HLA-DR, DQ) antigens, CA was significantly associated with HLA-Cw*7 (P < 0.02), DQB*0502 (P < 0.04), DRB1*0101 (P < 0.03) and DRB3*0202 (P < 0.02). These HLA-haplotypes are also partly linlred to other diseases with a strong genetic background. All other antigens revealed no association to this haematotoxic reaction. In addition, we did not find gender-related effects, whereas age seemed to be a further major risk factor of CA (P < 0.0003). Thus, HLA loci may serve as genetic marker to identify subjects of different ethnic subgroups prone to this severe idiosyncratic drug reaction of clozapine, Further studies are needed to investigate whether these associations with CA are due to causal involvement or linkage disequilibrium. Pharmacogenetics 11:135-141 (C) 2001 Lippincott Williams & Wilkins.