Genotype–phenotype association between HLA and carbamazepine-induced hypersensitivity reactions: Strength and clinical correlations.

Abstract: Background: Increasing studies reported genetic susceptibility to drug hypersensitivity reactions, as exemplified by the HLA-A*31:01 and HLA-B*15:02 association with carbamazepine (CBZ)-induced hypersensitivity reactions, such as maculopapular exanthema (MPE), drug rash with eosinophilia and systemic symptoms (DRESS), and Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Objective: To carry out a comprehensive analysis on the clinical spectrum and HLA genotype–phenotype correlations in CBZ-induced hypersensitivity reactions. Methods: We analyzed the clinical information of 194 patients with CBZ hypersensitivity (51 MPE, 23 DRESS, 112 SJS/TEN, and 8 cases with other phenotypes), and 152 CBZ-tolerant controls. All are Han Chinese. We examined the HLA-A/HLA-B genotypes, gene dosage, and drug dosage effects. Results: CBZ-SJS/TEN showed the strongest association with the HLA-B*15:02 allele (Pc=5.8×10−43; odds ratio (OR) (95% CI)=97.6(42.0–226.8)), in which HLA-B*15:02 was identified in all patients (25/25) with SJS/TEN with >5% body surface area (BSA) skin detachment, but lost its 100% association (85.1%, 74/87) in SJS with <5% BSA detachment. In contrast, HLA-B*40:01 showed negative association with CBZ-induced SJS/TEN ((Pc=8.3×10−5; OR (95% CI)=0.22(0.1–0.4)). By comparison, CBZ-induced MPE/DRESS had no association with HLA-B*15:02, but linked to HLA-A*31:01 (Pc=2.7×10−3; OR (95% CI)=6.86(2.4–19.9), and HLA-B*51:01 (Pc=0.01; OR (95% CI)=4.56(2.0–10.5)). No gene dosage or CBZ dosage effects was observed. Conclusion: This study reported the different strength of HLA association with CBZ hypersensitivity in Han Chinese. With the increasing application of pharmacogenetic markers, the HLA genotype–phenotype correlations and the results of the test need to be carefully interpreted for CBZ-induced hypersensitivity reactions. [Copyright &y& Elsevier]