Multi-clustering Study on the Association Between Human Leukocyte Antigen and Hepatitis B Virus-related Hepatocellular Carcinoma and Cirrhosis in Viet Nam

Background: Human leukocyte antigen (HLA) class II molecules are cell surface receptor proteins found on antigen-presenting cells. Polymorphisms and mutations in the gene can affect the immune system and the progression of hepatitis B.

Aim: To study the relation between rs2856718 of , rs3077, and rs9277535 of , hepatitis B virus (HBV)-related cirrhosis, and hepatocellular carcinoma (HCC).

Methods: In this case-control study, the genotypes of these single nucleotide polymorphisms (SNPs) were screened in 315 healthy controls, 471 chronic hepatitis B patients, 250 patients with HBV-related liver cirrhosis, and 251 patients with HCC using TaqMan real-time PCR. We conducted Hardy-Weinberg equilibrium and linkage disequilibrium tests on the genotype distributions of rs2856718, rs3077, and rs9277535 before hierarchical clustering analysis to build the complex interaction between the markers in each patient group.

Results: The physical distance separating these SNPs was 29816 kB with the disequilibrium (D') values ranging from 0.07 to 0.34. The close linkage between rs3077 and rs9277535 was attributed to a distance of 21 kB. The D' value decreased from moderate in the healthy control group (D' = 0.50, < 0.05) to weak in the hepatic disease group (D' < 0.3, < 0.05). In a combination of the three variants rs2856718, rs3077, and rs9277535, the A allele decreased hepatic disease risk [A-A-A haplotype, risk ratio (RR) = 0.44 (0.14; 1.37), < 0.05]. The G allele had the opposite effect [G-A/G-G haplotype, RR = 1.12 (1.02; 1.23), < 0.05]. In liver cancer cases, the A-A-A/G haplotype increased the risk of HCC by 1.58 ( < 0.05).

Conclusion: Rs9277535 affects liver fibrosis progression due to HBV infection, while rs3077 is associated with a risk of HBV-related HCC. The link between rs2856718, rs3077, and rs9277535 and disease risk was determined using a multi-clustering analysis.