THE MAJOR HISTOCOMPATIBILITY COMPLEX REGION MARKED BY HSP70-1 AND HSP70-2 VARIANTS IS ASSOCIATED WITH CLOZAPINE-INDUCED AGRANULOCYTOSIS IN 2 DIFFERENT ETHNIC-GROUPS

Genes of the major histocompatibility complex (MHC) have been associat ed with susceptibility to drug-induced adverse reactions. We previousl y found that clozapine-induced agranulocytosis (CA) is associated with the HLA-DRB10402, DRB4*0101, DQB1*0302, DQA1*0301 haplotype in Ashke nazi Jewish patients and with the HLA-DRB11601, DRB5*02, DQB1*0502, D QA10102 haplotype in non-Jewish patients. In the present study, we te sted the hypothesis that the variants of the heat-shock protein 70 (HS P-TID) encoded by the HSP-70 loci located within the MHC region and kn own to be involved in apoptosis and regulation of cell proliferation c ould play an important role in molecular mechanisms of CA. First, we a nalyzed HSP70-2 polymorphism in risk-associated haplotypes from HLA ho mozygous cells and normal individuals and confirmed that the HSP70-2 9 -kb variant was associated invariably with DR4 (HLA-DRB10402, DQB1*03 02) and DR2 (HLA-DRB101601, DQB1*0502, DQA1*0102 and HLA-DRB1*1501, D QB10602) haplotypes, which were the haplotypes found increased in Jew ish and non-Jewish patients with CA, respectively. The 9.0-kb variant was also found to be associated with HLA-B44, DRB10401 and HLA-B44, D RB107 haplotypes. Second, in patients with CA (12 Ashkenazi Jewish an d 20 non-Jewish patients), HSP70-1 A and HSP70-2 9.0-kb variants were associated with the MHC haplotypes found by us to be markers of suscep tibility to CA. The clozapine-treated control group had an excess numb er of HSP70-1 C and HSP70-2 8.5-kb variants, consistent with genetic r esistance to CA associated with those variants. This finding supports our hypothesis that a dominant gene within the MHC region (marked by H SP70-1 and HSP70-2), but not necessarily HLA, is associated with CA in two different ethnic groups. (C) 1995 by The American Society of Hema tology.