TUMOR-NECROSIS-FACTOR CONSTELLATION POLYMORPHISM AND CLOZAPINE-INDUCED AGRANULOCYTOSIS IN 2 DIFFERENT ETHNIC-GROUPS

Genes of the major histocompatibility complex (MHC) are associated wit h susceptibility to different immune and nonimmune mediated diseases. We had reported that the drug adverse reaction, clozapine-induced agra nulocytosis (CA), is associated with different HLA types and HSP70 var iants in Ashkenazi Jewish and non-Jewish patients, suggesting that a g ene within the MHC region is associated with CA, This study was design ed to find common genetic markers for this disorder in both ethnic gro ups, The tumor necrosis factor (TNF) microsatellites d3 and b4 were fo und in higher frequencies in both Jewish and nonJewish patients: 51 of 66 (77%) and 48 of 66 (57%), respectively, Comparisons of these frequ encies 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 microsatelli te b5 was underrepresented in the group of patients, 9 of 66 (14%), wh en compared with the control subjects, 43 of 66 (65%) (corrected P val ue = .0005), probably related to protection from CA, Our results show a strong association of some genetic variants of the TNF loci with sus ceptibility to CA in two different ethnic groups suggesting involvemen t of TNF and/or associated gene(s) products in the pathogenesis of thi s hematologic-drug adverse reaction. (C) 1997 by The American Society of Hematology.