BACKGROUND AND AIM: The genotype-phenotype interaction in drug-induced liver 
injury (DILI) is a subject of growing interest. Previous studies have linked 
amoxicillin-clavulanate (AC) hepatotoxicity susceptibility to specific HLA 
alleles. In this study we aimed to examine potential associations between HLA 
class I and II alleles and AC DILI with regards to phenotypic characteristics, 
severity and time to onset in Spanish AC hepatotoxicity cases.
METHODS: High resolution genotyping of HLA loci A, B, C, DRB1 and DQB1 was 
performed in 75 AC DILI cases and 885 controls.
RESULTS: The distributions of class I alleles A*3002 (P/Pc = 2.6E-6/5E-5, OR 
6.7) and B*1801 (P/Pc = 0.008/0.22, OR 2.9) were more frequently found in 
hepatocellular injury cases compared to controls. In addition, the presence of 
the class II allele combination DRB1*1501-DQB1*0602 (P/Pc = 5.1E-4/0.014, OR 
3.0) was significantly increased in cholestatic/mixed cases. The A*3002 and/or 
B*1801 carriers were found to be younger (54 vs 65 years, P = 0.019) and were 
more frequently hospitalized than the DRB1*1501-DQB1*0602 carriers. No 
additional alleles outside those associated with liver injury patterns were 
found to affect potential severity as measured by Hy's Law criteria. The 
phenotype frequencies of B*1801 (P/Pc = 0.015/0.42, OR 5.2) and 
DRB1*0301-DQB1*0201 (P/Pc = 0.0026/0.07, OR 15) were increased in AC DILI cases 
with delayed onset compared to those corresponding to patients without delayed 
onset, while the opposite applied to DRB1*1302-DQB1*0604 (P/Pc = 0.005/0.13, OR 
0.07).
CONCLUSIONS: HLA class I and II alleles influence the AC DILI signature with 
regards to phenotypic expression, latency presentation and severity in Spanish 
patients.