Abstract
Aim: Genetic polymorphisms of human leukocyte antigen (HLA) class II molecules are associated with chronic hepatitis B virus (HBV) infection. We aimed to investigate the impacts of HLA-II haplotypes on viral evolution and the risks of HBV-caused liver diseases. Methods: HLA-DR-DQ-DP haplotypes were estimated in 1210 healthy controls, 296 HBV clearance subjects, 301 asymptomatic hepatitis B surface antigen carriers, 770 chronic hepatitis B patients, 443 HBV-related liver cirrhosis (LC) patients, and 1037 HBV-related hepatocellular carcinoma (HCC) patients. HBV mutations were determined by sequencing. The associations of HLA-DR-DQ-DP haplotypes with viral mutations and the risks of liver diseases were assessed by multivariate logistic regression. Results: Compared to HBV-free subjects, the haplotypes CCAACG, CCGACG, TCAATA, and TCGATA were associated with decreased HCC risk, with an odds ratio (OR) [95% confidence interval (CI)] of 0.62 (0.40-0.95), 0.60 (0.39-0.92), 0.73 (0.54-0.98), and 0.58 (0.42-0.78), respectively. CCAACG, CCGACG, and TCAATA were significantly associated with decreased frequencies of the HCC-risk HBV mutations: preS1 deletion, APOBEC-signature HBV mutations in the core promoter and preS regions, A51C/T, G104C/T, and G146C/T. TCGATA and TTAACG were associated with increased LC risk, with an OR (95%CI) of 1.54 (1.03-2.30) and 2.23 (1.50-3.33), respectively. However, TCGATA and TTAACG were not consistently associated with the cirrhosis-risk HBV mutations. Conclusion: CCAACG, CCGACG, and TCAATA are inversely associated with HCC risk, possibly because they are involved in creating an immune microenvironment attenuating the generation of HCC-risk HBV mutations. TCGATA and TTAACG might predispose the polarity of immunity towards Th17 isotype related to LC.
Highlights
Primary liver cancer (PLC) is the sixth most common cancer and the third leading cause of cancer-related deaths, with an incidence-to-mortality ratio of nearly 1:1 (905,677 vs. 830,180 in 2020)[1]
Compared to hepatitis B virus (HBV)-free subjects, the haplotypes CCAACG, CCGACG, TCAATA, and TCGATA were associated with decreased Hepatocellular carcinoma (HCC) risk, with an odds ratio (OR) [95% confidence interval (CI)] of 0.62 (0.40-0.95), 0.60 (0.39-0.92), 0.73 (0.54-0.98), and 0.58 (0.42-0.78), respectively
CCAACG, CCGACG, and TCAATA were significantly associated with decreased frequencies of the HCC-risk HBV mutations: preS1 deletion, APOBECsignature HBV mutations in the core promoter and preS regions, A51C/T, G104C/T, and G146C/T
Summary
Primary liver cancer (PLC) is the sixth most common cancer and the third leading cause of cancer-related deaths, with an incidence-to-mortality ratio of nearly 1:1 (905,677 vs. 830,180 in 2020)[1]. Hepatocellular carcinoma (HCC) accounts for 94.6% of PLC in eastern China. Immunization of infants against hepatitis B virus (HBV) has reduced their risk of developing HCC, 87.5% of HCC is attributed to chronic HBV infection in eastern China[3,4]. There are approximately 94 million subjects chronically infected with HBV in mainland China[5]. We speculated that 32% male and 9% female subjects with chronic HBV infection might die of HCC before the average life (75 years old) in mainland China, based on the epidemiological data in Taiwan[6]. The key issue to decrease HCC-caused premature death is to identify the HBV-infected subjects who are more likely to develop HCC or postoperative relapse, which is essential for specific prophylaxis of this deadly malignancy
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