The protective association of HLA‐C*12:02 and HLA‐DQB1*06:01 with severe acute hepatitis of unknown origin in the Japanese population

Abstract

Global surveillance has been conducted to elucidate the pathogenesis of acute hepatitis of unknown origin (AHUO), However, the factors associated with the aggravation of this serious disease are unclear. Therefore, we conducted a HLA association study to identify HLA alleles or haplotypes predisposing or protective against Japanese AHUO. The HLA 5 locus (HLA‐A, HLA‐B, C, DRB1, and DQB1) 4‐digit genotyping results of 72 AHUO patients who underwent liver transplantation at our institution between 2000 and 2021 were compared to those of 873 healthy Japanese controls. Protective associations of HLA‐B*52:01 (p‐corrected (pc) = 3.15 × 10−3), HLA‐C*12:02 (pc = 1.66 ×10−3), HLA‐DQB1*06:01 (pc = 1.42 × 10−2), and HLA‐DRB1*15:02 (pc = 1.36 × 10−2) with severe AHUO in Japanese patients were observed. The amino acid residues of tryptophan at position 156, which are located in the antigen‐binding grooves of the HLA‐C protein, showed a protective association with AHUO, showing a significant difference from other amino acid variations (pc = 9.0 × 10−4). Furthermore, 5 amino acid residues of the HLA‐DQB1 protein were also protectively associated with AHUO with a significant difference from other amino acid variations (pc = 1.42 × 10−2 to 2.89 × 10−2). These alleles have a protective association with the aggravation of AHUO in the Japanese population.