Tumor necrosis factor constellation polymorphism and clozapine-induced
agranulocytosis in two different ethnic groups
D Turbay, J Lieberman, CA Alper, JC Delgado, D Corzo, JJ Yunis and EJ Yunis
Department of Pathology, Harvard Medical School, Dana-Farber Cancer
Institute, Boston, MA 02115, USA.
Genes of the major histocompatibility complex (MHC) are associated with
susceptibility to different immune and nonimmune mediated diseases. We had
reported that the drug adverse reaction, clozapine-induced agranulocytosis
(CA), is associated with different HLA types and HSP70 variants in
Ashkenazi Jewish and non-Jewish patients, suggesting that a gene within the
MHC region is associated with CA. This study was designed to find common
genetic markers for this disorder in both ethnic groups. The tumor necrosis
factor (TNF) microsatellites d3 and b4 were found in higher frequencies in
both Jewish and non-Jewish patients: 51 of 66 (77%) and 48 of 66 (57%),
respectively. Comparisons of these frequencies with those of controls, 28
of 66 (42%) and 18 of 66 (27%), were statistically significant (corrected P
value = .001 for the d3 allele and .0005 for the b4 allele). On the other
hand, the TNF microsatellite b5 was underrepresented in the group of
patients, 9 of 66 (14%), when compared with the control subjects, 43 of 66
(65%) (corrected P value = .0005), probably related to protection from CA.
Our results show a strong association of some genetic variants of the TNF
loci with susceptibility to CA in two different ethnic groups suggesting
involvement of TNF and/or associated gene(s) products in the pathogenesis
of this hematologic-drug adverse reaction.
Volume 89,
Issue 11,
pp. 4167-4174,
06/01/1997
Copyright © 1997 by The American Society of Hematology
