Human Leukocyte Antigen Genotypes Affect Hepatitis B Virus Mutations Associated With Hepatocellular Carcinoma

Various viral mutations have been reported to influence disease pathogenesis in infectious diseases. However, these mutations may remain undetected due to patient population changes. Although many causes have been proposed, the exact reasons remain unclear. This study analyzed viral mutations linked to hepatocellular carcinoma (HCC) in patients with hepatitis B by comparing factors between condition-matched patient groups of different human leukocyte antigen (HLA) genotypes.

HLA genotypes of 2281 healthy individuals, 370 patients with hepatitis B virus (HBV)-derived HCC, and 408 patients with chronic hepatitis B were analyzed to identify HLA genotypes associated with HCC development. Patients with HCC were grouped by HLA-DPB1 genotype to identify HBV genomic variants linked to HCC.

The HLA-DPB1*02:01, 04:01, and 04:02 alleles suppressed chronic hepatitis B (CHB) and HCC development (P = 4.53 × 10^-9, 3.20 × 10^-3, and 3.03 × 10^-4, respectively). Conversely, HLA-DPB1*05:01 and 09:01 alleles were significantly associated with CHB and HCC development (P = 1.01 × 10^-7, 6.51 × 10^-8, respectively). Among HLA-DPB1*02:01 patients, the S166L amino acid (AA) mutation in the PreS/S region of the HBV genome was significantly identified. HLA-DPB1*05:01 homozygous patients significantly had K130M/V131I AA mutations in the X region of the HBV genome, whereas HLA-DPB1*05:01-09:01 heterozygous patients significantly had the H94Y AA mutation in the X region. Stratification by HLA genotype changed the mutation position and strengthened the odds ratios for developing HCC due to viral mutations.

Our analysis revealed that viral mutations associated with HCC vary by HLA genotype. These findings suggest a host-pathogen genetic interaction. HLA genotype stratification may aid in advancing personalized genomic medicine, which has been challenging to apply to chronic diseases.