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 suscep tibility to clozapine-induced agranulocytosis (CA) we performed HLA-genotyp ing in a sample of German schizophrenic patients, who suffered from this ha ematotoxic 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 majo r 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 gen etic background. All other antigens revealed no association to this haemato toxic reaction. In addition, we did not find gender-related effects, wherea s age seemed to be a further major risk factor of CA (P < 0.0003). Thus, HL A loci may serve as genetic marker to identify subjects of different ethnic subgroups prone to this severe idiosyncratic drug reaction of clozapine, F urther 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.