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TNF promoter region gene polymorphisms in carbamazepine-hypersensitive patients

From the Departments of Pharmacology and Therapeutics (Drs. Pirmohamed, Lin, and Park) and Neurological Sciences (Dr. Chadwick), The University of Liverpool, United Kingdom.

Address correspondence and reprint requests to Dr. M. Pirmohamed, Department of Pharmacology and Therapeutics, the University of Liverpool, Ashton Street, Liverpool, L69 3GE, UK; e-mail: munirp{at}liv.ac.uk

OBJECTIVE: To evaluate whether the major histocompatibility complex contains susceptibility genes for carbamazepine hypersensitivity. Carbamazepine hypersensitivity is immune-mediated, although factors determining its occurrence and severity are unknown.

METHODS: Using PCR in 60 carbamazepine-hypersensitive patients, 37 with nonserious (Group I) and 23 with serious (Group II) reactions, and 313 control subjects (63 patients on carbamazepine without adverse effects and 250 healthy volunteers), the association with polymorphisms in the promoter region of the tumor necrosis factor (TNF) 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 patients compared with all control subjects (p = 0.01; OR = 2.4), as was the frequency of HLA-DR3 (p = 0.01; OR = 3.3), HLA-DQ2 (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 the -238 polymorphism, there was a difference in the genotype, but not in the allelic, frequencies between Group II hypersensitive patients and all control subjects.

CONCLUSIONS: The TNF2 allele was associated with severe, but not nonserious, carbamazepine hypersensitivity reactions, suggesting that hypersecretion of tumor necrosis factor may be a determinant of the severity of tissue damage. However, the association of the TNF2 allele with carbamazepine hypersensitivity was not independent of HLA-DR3 and -DQ2, and therefore the possibility that it constitutes a passive component of the TNF2-DR3-DQ2 haplotype cannot be excluded.

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