ERAP-1 and ERAP-2 variants in Liver injury following COVID-19 mRNA Vaccination: A US Multicenter Study

BACKGROUND: The aim of this study is to describe the presenting features, genetic factors, and outcomes of 23 adults who developed liver injury after COVID-19 mRNA vaccination. METHODS: Patients with suspected COVID-19 vaccine hepatitis were enrolled into the Drug-induced Liver Injury Network (DILIN). Causality was assessed using the DILIN expert opinion score. High resolution HLA sequencing was undertaken using Illumina platform. RESULTS: Amongst the 16 high causality cases, median time to onset was 16 days, median age was 63 years, and 75% were female. The injury was hepatocellular in 75% with a median ALT of 497 U/L and 37% had jaundice. An ANA and SMA were detectable in 27% and 36% but only 12% had an elevated IgG level. During follow-up, 37% received a short course of corticosteroids and 88% fully recovered by 6 months with no deaths observed. HLA alleles associated with autoimmune hepatitis were not overrepresented compared to controls but an ERAP-2 variant (rs1263907) and the ERAP-1 Hap6 haplotype were significantly over-represented in the high causality cases versus controls (p=0.026 and 5 x 10- 5 , respectively). Conclusions: Acute liver injury may arise within 8 weeks of COVID-19 mRNA vaccination that is generally mild and self-limited in most patients. The absence of an association with the AIH HLA alleles combined with the significant ERAP-2 and ERAP-1 Hap6 haplotype associations implicate a unique but very rare host immune response to vaccine derived antigens in the pathogenesis of COVID-19 vaccine hepatotoxicity.