Genome-wide association study identified new susceptible genetic variants in HLA class I region for hepatitis B virus-related hepatocellular carcinoma

Abstract

We have performed a genome-wide association study (GWAS) including 473 Japanese HBV (hepatitis B virus)-positive HCC (hepatocellular carcinoma) patients and 516 HBV carriers including chronic hepatitis and asymptomatic carrier individuals to identify new host genetic factors associated with HBV-derived HCC in Japanese and other East Asian populations. We identified 65 SNPs with P values < 10−4 located within the HLA class I region and three SNPs were genotyped in three independent population-based replication sets. Meta-analysis confirmed the association of the three SNPs (rs2523961: OR = 1.73, P = 7.50 × 10−12; rs1110446: OR = 1.79, P = 1.66 × 10−13; and rs3094137: OR = 1.73, P = 7.09 × 10−9). We then performed two-field HLA genotype imputation for six HLA loci using genotyping data to investigate the association between HLA alleles and HCC. HLA allele association testing revealed that HLA-A*33:03 (OR = 1.97, P = 4.58 × 10−4) was significantly associated with disease progression to HCC. Conditioning analysis of each of the three SNPs on the HLA class I region abolished the association of HLA-A*33:03 with disease progression to HCC. However, conditioning the HLA allele could not eliminate the association of the three SNPs, suggesting that additional genetic factors may exist in the HLA class I region.

High-throughput identification of human SNPs affecting regulatory element activity

“…Finally, we overlaid the HepG2 SuRE data with a recent GWAS that linked SNPs to the risk of hepatitis B virus (HBV) related hepatocellular carcinoma (HCC), a type of cancer prevalent in Asia42. This study identified 61 candidate SNPs in a ~200 kb region that includes the HLA class 1 locus.…”

Advanced Therapeutics, Vaccinations, and Precision Medicine in the Treatment and Management of Chronic Hepatitis B Viral Infections; Where Are We and Where Are We Going?

“…So too, the presence of SNP loci (rs9277535) at HLA-DPB1 might also be a valuable predictive factor for CHB in HBeAg-negative patients, however further verifications of this conclusion are recommended due to study limitations [110]. Another GWAS based study involving Japanese CHB patients, with and without HCC, has led to the identification of SNP loci in the HLA class I region (in HLA-DR, -DQ, and -DP genes) associated with HBV-related HCC disease progression [114].…”

Comparison of hepatitis B virus genotypes B and C among chronically hepatitis B virus‐infected patients who received nucleos(t)ide analogs: A multicenter retrospective study

“…15 Additionally, some single-nucleotide polymorphisms in several genes including HLA class I and II have been shown to be associated with HBV-related HCC. [16][17][18] It has been reported that NAs reduced HCC risk, but the effect is not adequate, especially in patients with advanced liver fibrosis. 6,[19][20][21] The HBV genomic sequences are heterogeneous, and based on differences of >8%, 22 10 genotypes (A to J) have been reported so far.…”

“…Recently, the hepatitis B X protein genotype was reported to be associated with HCC development and HCC proliferation in vitro and in vivo . Additionally, some single‐nucleotide polymorphisms in several genes including HLA class I and II have been shown to be associated with HBV‐related HCC . It has been reported that NAs reduced HCC risk, but the effect is not adequate, especially in patients with advanced liver fibrosis …”