Genetic variants associated with severe cutaneous adverse reactions induced by carbamazepine.

Abstract

AIM\nCarbamazepine (CBZ) is one of the most common causative drugs of severe cutaneous adverse drug reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reactions with eosinophilia and systemic symptoms (DRESS). Although genetic polymorphisms of the human leukocyte antigens (HLA) are well recognized key elements for the susceptibility to CBZ-induced SCARs, some evidence suggest that polymorphisms of microsomal epoxide hydrolase 1 (EPHX1) may also contribute to the risk of these SCARs. This study investigated the association between the HLA and EPHX1 polymorphisms on CBZ-induced SCARs in large sample sizes and well-defined SCARs patients.\n\n\nMETHODS\nNinety-one CBZ-induced SCARs Thai patients and 144 CBZ-tolerant patients were enrolled in the study. The genotypes of HLA-A, HLA-B and EPHX1 were determined.\n\n\nRESULTS\nOnly two HLA alleles including HLA-B*15:02 and HLA-A*24:07 were statistically significant association with CBZ-induced SJS/TEN. The highest risk was observed in patients with HLA-B*15:02 allele (OR = 44.33, 95% CI = 20.24-97.09, Pc = 6.80 x 10-29 ). Moreover, HLA-B75 serotypes were significantly associated with CBZ-induced SJS/TEN groups with an OR of 81.00 (95% CI =32.39-202.56, Pc = 3.84 x 10-34 ). There is no association between EPHX1 c.337T>C polymorphism and all phenotypes of CBZ-induced SCARs.\n\n\nCONCLUSION\nThe HLA-B*15:02 allele is the strongest genetic marker for the prediction of SJS/TEN induced by CBZ in Thai population. Screening for other alleles in the HLA-B75 serotype increases sensitivity for prediction of a life-threatening SCARs caused by CBZ.