There are different HLA associations in patients with clozapine-induced agranulocytosis (CA): in Jewish patients, HLA-B38, DR4 (DRB1*0402, DQB1*0302, DQA1*0301, DPB1*0401), HSP70 9.0-A, and in non-Jewish patients, HLA-DR2 (DRB1*1602, DQB1*0502, DQA1*0102), HSP70 9.0-A, HLA-B44, DR7 (DRB1*0701, DQB1*0202, DQB1*0201), HSP70 9.0-A. The haplotypes HLA-B8, DR3 (DRB1*0301, DQB1*0201, DQA1*0501, DPB1*0401), HSP70 8.5-C and HLA-B44, DR4 (DRB1*0401, DQB1*0301, DQA1*0301), HSP70 9.0-A are associated with protection. Preliminary studies suggest that common variants of non-HLA genes (TNF DNA constellations; a,b,c,d,e microsatellites, n intron of TNFB and -308 of promoter region of TNFa) (given in the gene order b,a,n,c, -308, e,d) within the major histocompatibility complex (MHC) are associated with the HLA CA markers. Also, clozapine and its metabolites can produce an increase of cytotoxicity or apoptosis of neutrophils. The induction of cell death of neutrophils by clozapine and its metabolites was significantly less in a homozygous HLA-B8, DR3, TNF-3, 2, 1, 1, 2, 3, 1 (associated with resistance to CA) than in HLA-B7, DR2, TNF-4 11, 2, 1, 1, 3, 3, 1 or in homozygous HLA-B38, DR4, TNF 4, 10, 2, 1, 1, 3, 3, individuals (associated with susceptibility to CA). Therefore, non-HLA MHC markers may underlie the hematologic complications of CA in patients with schizophrenia. This project has the following specific aims: 1) typing non-schizophrenic individuals who are a) homozygous or heterozygous for carrying different extended HLA haplotypes and b) homozygous or heterozygous for TNF constellations that may or may not be part of HLA extended haplotypes; 2) typing of CA patients of Jewish and non-Jewish ancestry to characterize TNF DNA constellation polymorphisms in order to identify common markers of CA in different ethnic groups; 3) the induction of cell death of neutrophils in the presence or absence of clozapine and its metabolites in selected homozygous and heterozygous individuals of different MHC haplotypes. The study of TNF polymorphism in relation to the physiology of cells in the presence of drugs could lead to the development of strategies for the general understanding of drug adverse reactions.
