Association of HLA-C*03:02 with methimazole-induced liver injury in Graves’ disease patients

Methimazole (MMI) has been used for the treatment of Graves’ Disease (GD) for more than half a century. The MMI treatment has been reported to be associated with hepatotoxicity. Previous studies have demonstrated that human leukocyte antigen (HLA) genetic polymorphisms were associated with many drugs-induced liver injuries. To investigate HLA genetic susceptibility to MMI-induced liver injury (MMI-DILI), we characterized both HLA class I and class Ⅱ in a well-characterized phenotypic cohort with 40 MMI-DILI cases and 118 MMI-tolerant controls. Among the 40 MMI-DILI cases, 57.5% were women and 50% were cholestatic liver damage with occurring time from days to months after MMI dosing. The frequency of HLA-C*03:02 was 6.7% (5/75) in the MMI-DILI case patients and 6.4% (4/62) in MMI-induced cholestatic/mixed liver damage, which were significantly different from the percentage of 0.4% (1/231) in the MMI-tolerant patients (odds ratio (OR) = 15.4, 95% confidence interval (CI) = 1.77–133.9, adjusted P = 0.0292; OR=14.9, 95% CI=2.38–182.9, adjusted P = 0.0323; respectively). HLA-A*02:01 was also found to be associated with MMI-induced cholestatic/mixed liver injury (OR = 3.13, 95%CI=1.45–6.91, adjusted P = 0.0464). The present study demonstrated that individuals carrying HLA-C*03:02 allele are at increased risk of developing MMI-induced DILI. These results may assist doctors to prevent the occurrence of hepatotoxicity in GD patients receiving MMI.