ABSTRACT Background and Aims Fluoroquinolone exposure can give rise to drug‐induced liver injury. Genetic risk factors for this form of liver injury are poorly understood but some evidence suggests that HLA genes contribute. This study aimed to characterise HLA risk factors for fluoroquinolone‐induced liver injury in a European population. Methods From the previously described iDILIC cohort, 22 cases of fluoroquinolone‐induced liver injury were identified, with most cases ( n = 13) related to ciprofloxacin. Liver injury cases due to other drugs ( n = 458), also from iDILIC, served as controls. HLA genotypes were imputed from genome‐wide association analysis data using SNPtoHLA. Frequency differences between cases and controls for HLA alleles, HLA amino acids and HLA families were assessed by applying a logistic regression model. Results HLA‐significant associations were detected for HLA class I and II alleles with individual allelic associations detected for HLA‐B*44:03 , HLA‐A*29:02 , HLA‐C*16:01, HLA‐DQA1*03:01 and several HLA‐DRB1 alleles. Combined HLA‐B*44 alleles were associated with DILI with an odds ratio of 5.33 95% confidence interval 2.45–11.61; p = 2.5 × 10 −5 . Serine at position‐167 in HLA‐B, specific to B*44:02, B*44:03 and B*45:01 , was associated with a significantly increased risk of liver injury ( p = 4.7 × 10 −6 ), but no other HLA‐B amino acids were significant. The B*44 association was also significant among ciprofloxacin cases only. Conclusions A novel HLA‐B*44 association with fluoroquinolone‐induced liver injury has been identified and a previously reported but weaker association with HLA‐DQA1*03:01 confirmed. The B*44 findings suggest a mechanism involving inappropriate recognition of drug‐modified self peptides by serine‐167 in pocket A of the HLA‐B protein.
Nicoletti et al. (Fri,) studied this question.