TNF alpha promoter region gene polymorphisms in carbamazepine-hypersensitive patients

Objective: To evaluate whether the major histocompatibility complex contain s susceptibility genes for carbamazepine hypersensitivity. Carbamazepine hy persensitivity is immune-mediated, although factors determining its occurre nce and severity are unknown. Methods: Using PCR in 60 carbamazepine-hypers ensitive patients, 37 with nonserious (Group I) and 23 with serious (Group II) reactions, and 313 control subjects (63 patients on carbamazepine witho ut adverse effects and 250 healthy volunteers), the association with polymo rphisms in the promoter region of the tumor necrosis factor alpha (TNF alph a) gene (positions -308 and -238), and with HLA-DR3 and -DQ2 was determined . Results: The frequency of the variant allele (TNF2) at the -308 position was increased in Group II but not Group I carbamazepine-hypersensitive pati ents compared with all control subjects (p = 0.01; OR = 2.4), as was the fr equency of HLB-DR3 (p = 0.01; OR = 3.3), HLA-DQB (p = 0.04; OR = 2.7), and the TNF2-DR3-DQ2 haplotypes (p = 0.02; OR = 3.2). None of the alleles were independently associated with serious carbamazepine hypersensitivity. For t he -238 polymorphism, there was a difference in the genotype, but not in th e allelic, frequencies between Group II hypersensitive patients and all con trol subjects. Conclusions: The TNF2 allele was associated with severe, but not nonserious, carbamazepine hypersensitivity reactions, suggesting that hypersecretion of tumor necrosis factor a may be a determinant of the sever ity of tissue damage. However, the association of the TNF2 allele with carb amazepine hypersensitivity was not independent of HLA-DR3 and -DQ2, and the refore the possibility that it constitutes a passive component of the TNF2- DR3-DQ2 haplotype cannot be excluded.