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The major histocompatibility complex region marked by HSP70-1 and HSP70- 2
variants is associated with clozapine-induced agranulocytosis in two
different ethnic groups
D Corzo, JJ Yunis, M Salazar, JA Lieberman, A Howard, Z Awdeh, CA Alper and EJ Yunis
Division of Immunogenetics, Dana-Farber Cancer Institute, Boston, MA 02115,
USA.
Genes of the major histocompatibility complex (MHC) have been associated
with susceptibility to drug-induced adverse reactions. We previously found
that clozapine-induced agranulocytosis (CA) is associated with the
HLA-DRB1*0402, DRB4*0101, DQB1*0302, DQA1*0301 haplotype in Ashkenazi
Jewish patients and with the HLA-DRB1*1601, DRB5*02, DQB1*0502, DQA1*0102
haplotype in non-Jewish patients. In the present study, we tested the
hypothesis that the variants of the heat- shock protein 70 (HSP-70) encoded
by the HSP-70 loci located within the MHC region and known to be involved
in apoptosis and regulation of cell proliferation could play an important
role in molecular mechanisms of CA. First, we analyzed HSP70-2 polymorphism
in risk-associated haplotypes from HLA homozygous cells and normal
individuals and confirmed that the HSP70-2 9-kb variant was associated
invariably with DR4 (HLA-DRB1*0402, DQB1*0302) and DR2 (HLA-DRB1*01601,
DQB1*0502, DQA1*0102 and HLA-DRB1*1501, DQB1*0602) haplotypes, which were
the haplotypes found increased in Jewish and non-Jewish patients with CA,
respectively. The 9.0-kb variant was also found to be associated with
HLA-B44, DRB1*0401 and HLA-B44, DRB1*07 haplotypes. Second, in patients
with CA (12 Ashkenazi Jewish and 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 susceptibility to CA. The clozapine-treated control group
had an excess number of HSP70-1 C and HSP70-2 8.5-kb variants, consistent
with genetic resistance to CA associated with those variants. This finding
supports our hypothesis that a dominant gene within the MHC region (marked
by HSP70-1 and HSP70-2), but not necessarily HLA, is associated with CA in
two different ethnic groups.
Volume 86,
Issue 10,
pp. 3835-3840,
11/15/1995
Copyright © 1995 by The American Society of Hematology
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