GENETIC-FACTORS AND RISK OF AGRANULOCYTOSIS FROM METAMIZOL

The role of genetic factors in the pathogenesis of agranulocytosis was investigated in agranulocytosis patients by phenotyping for N-acetylt ransferase and glucose-6-phosphate polymorphism; by typing for gene pr oducts of the major histocompatability complex, ABO-and RH-blood group s, and haemoglobins; and by performing cytogenetic analysis of chromos ome aberrations. Nine persons were identified as agranulocytosis cases in the period from 1982 to 1987 among the population of Sofia. They w ere contacted again 10 years after recovery from the disease. Five of them were associated with metamizol (dipyrone) use. The results obtain ed revealed significant differences between the agranulocytosis patien ts and the healthy population in the human lymphocyte antigen (HLA) al lele frequencies, and in the degree and the frequency of chromosome ab errations. A higher frequency of the HLA24 antigen (relative risk 13.6 0, p = 0.05) and a lower frequency of the DQA10501 allele were eviden t for the ex-agranulocytosis patients as compared to the controls (11% versus 57% respectively, p = 0.05). In the patients exposed to metami zol, an A24-B7 haplotype was found with a frequency higher than that i n the non-exposed patients and the reference group (p<0.05). The HLA-D Qwl antigen and metamizol-related agranulocytosis were evidently assoc iated in all cases (5/5;100%) in contrast to the patients not exposed to metamizol and the controls. The HL-A2 antigen was absent in four of the five metamizol-associated agranulocytosis cases (20%), while in t he control group it was present in 56%. The degree of structural rearr angements (0.62 +/- 0.2%) and the frequency of chromosome breakages (7 .75 +/- 0.68%) in agranulocytosis patients were higher than those in t he healthy population (0.3 +/- 0.12%, p<0.05 and 1.42 +/- 0.27%, p<0.0 1, respectively). The abnormalities affected predominantly chromosomes 1(1p13), 2(2p12) and 5(5p12). No differences were found between the a granulocytosis patients and the healthy population when considering th e haemoglobin subtypes, ABO-and RH-blood groups, glucose-6-phosphate d ehydrogenase activity and the rates of slow and rapid acetylators.