Novel susceptibility loci for hepatocellular carcinoma in chronic HBV carriers.
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ABSTRACT:
SUBMITTER: Matsuda K
PROVIDER: S-EPMC3924631 | biostudies-literature | 2012 Dec
REPOSITORIES: biostudies-literature
Publications
Novel susceptibility loci for hepatocellular carcinoma in chronic HBV carriers.
Hepatobiliary surgery and nutrition 20121201 1
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Project description:Genome-wide association studies (GWAS) have recently identified KIF1B as susceptibility locus for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). To further identify novel susceptibility loci associated with HBV-related HCC and replicate the previously reported association, we performed a large three-stage GWAS in the Han Chinese population. 523,663 autosomal SNPs in 1,538 HBV-positive HCC patients and 1,465 chronic HBV carriers were genotyped for the discovery stage. Top candidate SNPs were genotyped in the initial validation samples of 2,112 HBV-positive HCC cases and 2,208 HBV carriers and then in the second validation samples of 1,021 cases and 1,491 HBV carriers. We discovered two novel associations at rs9272105 (HLA-DQA1/DRB1) on 6p21.32 (OR?=?1.30, P?=?1.13×10?¹?) and rs455804 (GRIK1) on 21q21.3 (OR?=?0.84, P?=?1.86×10??), which were further replicated in the fourth independent sample of 1,298 cases and 1,026 controls (rs9272105: OR?=?1.25, P?=?1.71×10??; rs455804: OR?=?0.84, P?=?6.92×10?³). We also revealed the associations of HLA-DRB1*0405 and 0901*0602, which could partially account for the association at rs9272105. The association at rs455804 implicates GRIK1 as a novel susceptibility gene for HBV-related HCC, suggesting the involvement of glutamate signaling in the development of HBV-related HCC.
| S-EPMC3395595 | biostudies-literature
Project description:Recent genome-wide association studies (GWAS) have identified several common susceptibility loci associated with the risk of hepatocellular carcinoma (HCC) or chronic hepatitis B infection (CHB). However, the relationship between these genetic variants and survival of patients with hepatitis B virus (HBV)-related HCC is still unknown. In this study, 22 single nucleotide polymorphisms (SNPs) were genotyped among 330 HBV-related HCC patients using the MassARRAY system from Sequenom. Cox proportional hazards regression was used to examine the effects of genotype on survival time under an additive model with age, sex, smoking status and clinical stage as covariates. We identified four SNPs on 6p21 (rs1419881 T>C, rs7453920 G>A,rs3997872 G>A and rs7768538 T>C), and two SNPs on 8p12 (rs2275959 C>T and rs7821974 C>T) significantly associated with survival time of HBV-related HCC patients. Our results suggest that HCC or CHB susceptibility loci might also affect the prognosis of patients with HBV-related HCC.
| S-EPMC4079718 | biostudies-literature
Project description:BackgroundA recent genome-wide association study has identified a new susceptibility locus, kinesin family member 1B gene (KIF1B), strongly associated with progression from chronic hepatitis B (CHB) to hepatitis B virus-related hepatocellular carcinoma (HCC) in Chinese population, this study was carried out to explore the role of the genetic variants in KIF1B in the development of chronic hepatitis B.Methodology/principal findingsThree KIF1B polymorphisms (rs8019, rs17401924, and rs17401966) were selected and genotyped in 473 CHB patients and 580 controls with no history of CHB. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression model. None of these three SNPs showed association with CHBs after adjusting for age and gender. Equivalence-based method analysis confirmed the absence of association. In the further haplotype analysis, three common haplotypes were observed in this study population, but no significant effect was also found for haplotypes in the progression to CHB.Conclusions/significanceThis study showed the new locus identified for HCC, KIF1B, was not associated with progression to CHB, implying distinct genetic susceptibility factor contributes to the progression from hepatitis B virus infection to HCC. Nevertheless, further comprehensive analyses are warranted to dissect the mechanism.
| S-EPMC3283615 | biostudies-literature
Project description:Hepatitis B Virus (HBV) DNA integrations into the human genome are considered major causative factors to HBV-associated hepatocellular carcinoma development. In the present study, we investigated whether HBV preferentially integrates parts of its genome in specific genes and evaluated the contribution of the integrations in HCC development per gene. We applied dedicated in-house developed pipelines on all of the available HBV DNA integration data and performed a statistical analysis to identify genes that could be characterized as hotspots of integrations, along with the evaluation of their association with HBV-HCC. Our results suggest that 15 genes are recurrently affected by HBV integrations and they are significantly associated with HBV-HCC. Further studies that focus on HBV integrations disrupting these genes are mandatory in order to understand the role of HBV integrations in clonal advantage gain and oncogenesis promotion, as well as to determine whether inhibition of the HBV-disrupted genes can provide a therapy strategy for HBV-HCC.
| S-EPMC8879149 | biostudies-literature
Project description:BackgroundChronic hepatitis B virus (CHB) infection is a major health problem and leading cause of hepatocellular carcinoma (HCC) worldwide. Several point and deletion mutations on the PreS/S gene have been intensively considered associated with HCC. This study aimed to describe the characteristics of HBV PreS/S mutations in Vietnamese CHB-infected patients and their association with HCC.MethodsThis cross-sectional study was conducted from 02/2020 to 03/2021, recruited Vietnamese CHB-infected patients with HBV-DNA >3 log10-copies/mL and successful PreS/S gene sequencing. Mutations were detected by direct Sanger sequencing.Results247 CHB-infected patients were recruited, characterized by 68.8% males, 54.7% HBV genotype B, 57.5% HBeAg positive, 23.1% fibrosis score ≥F3 and 19.8% HCC. 61.8% amino acid replacements were detected throughout the PreS1/PreS2/S genes. The most common point-mutations included N/H51Y/T/S/Q/P (30.4%), V68T/S/I (44.9%), T/N87S/T/P (46.2%) on PreS1 gene; T125S/N/P (30.8%), I150T (42.5%) on PreS2 gene; S53L (37.7%), A184V/G (39.3%), S210K/N/R/S (39.3%) on S gene. The rates of case(s) with any point-mutation on the Major Hydrophylic Region (MHR) and the "a" determinant region were 63.6% and 39.7%, respectively. Most of S point-mutations were presented with low rates such as T47A/E/V/K (9.3%), P120S/T (8.5%), G145R (2%). On multivariable analysis, males (OR = 4.51, 95%CI 1.78-11.4, p = 0.001), age≥40 (OR = 5.5, 95%CI 2.06-14.68, p = 0.001), W4P/R/Y on PreS1 (OR = 11.56, 95%CI 1.99-67.05, p = 0.006) and 4 S point-mutations as: T47A/E/V/K (OR = 3.67, 95%CI 1.19-11.29, p = 0.023), P120S/T (OR = 3.38, 95%CI 1.09-10.49, p = 0.035), S174N (OR = 29.73, 95%CI 2.12-417.07, p = 0.012), P203R (OR = 8.45, 95%CI 1.43-50.06, p = 0.019) were associated with HCC.ConclusionsWe detected 61% amino acid changes on PreS/S regions in Vietnamese CHB patients. One point-mutation at amino acid 4 on PreS1 gene and 4 point-mutations at amino acids 47, 120, 174, and 203 on S gene were associated with HCC. Further investigations are recommended to further clarify the relationship and interaction between mutations in HBV genome and HCC progression.
| S-EPMC8989215 | biostudies-literature
Project description:The hepatitis B virus (HBV) PreS mutations C1653T, T1753V, and A1762T/G1764A were reported as a strong risk factor of hepatocellular carcinoma (HCC) in a meta-analysis. HBV core promoter overlaps partially with HBx coding sequence, so the nucleotide 1762 and 1764 mutations induce HBV X protein (HBx) 130 and 131 substitutions. We sought to elucidate the impact of HBx mutations on HCC development. Chronically HBV-infected patients were enrolled in this study: 42 chronic hepatitis B (CHB) patients, 23 liver cirrhosis (LC) patients, and 31 HCC patients. Direct sequencing showed HBx131, HBx130, HBx5, HBx94, and HBx38 amino acid mutations were common in HCC patients. Of various mutations, HBx130+HBx131 (double) mutations and HBx5+HBx130+HBx131 (triple) mutations were significantly high in HCC patients. Double and triple mutations increased the risk for HCC by 3.75-fold (95% confidence interval [CI] = 1.101 to 12.768, P = 0.033) and 5.34-fold (95% CI = 1.65 to 17.309, P = 0.005), respectively, when HCC patients were compared to CHB patients. Functionally, there were significantly higher levels of NF-κB activity in cells with the HBx5 mutant and with the double mutants than that of wild-type cells and the triple-mutant cells. The triple mutation did not increase NF-κB activity. Other regulatory pathways seem to exist for NF-κB activation. In conclusion, a specific HBx mutation may contribute to HCC development by activating NF-κB activity. The HBx5 mutation in genotype C2 HBV appears to be a risk factor for the development of HCC and may be used to predict the clinical outcomes of patients with chronic HBV infection.
| S-EPMC3122615 | biostudies-literature
Project description:PurposeThis study was conducted to investigate the differentially expressed profiles of long non-coding RNAs (lncRNAs) in HBV-associated HCC (HBV-HCC), which may serve as potential diagnostic biomarkers and therapeutic targets.MethodsTo examine the differentially expressed profiles of lncRNAs and mRNAs using microarray analysis, we collected 15 specimens: five HBV-associated HCC tissues, five paired adjacent peritumoral liver tissues (APLT), and five distant peritumoral liver tissues (DPLT). Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to predict the biological roles and potential signaling pathways of these dysregulated mRNAs. In addition, lncRNA-mRNA co-expression network and signal transduction pathway network (Signal-net) were employed to further explore the potential target genes and roles of dysregulated lncRNAs in HBV-HCC pathogenesis. Finally, quantitative real-time PCR (qRT-PCR) was used to confirm the expression of six selected dysregulated lncRNAs.ResultsA total number of 719 lncRNAs and 3438 mRNAs were significantly more dysregulated in HBV-HCC tissues than in APLT and DPLT (fold change > 2, P < 0.05, FDR < 0.05). Additionally, 337 GO terms and 53 KEGG pathways were established to be significantly enriched. These dysregulated mRNAs were mainly enriched in metabolism-related biological processes. Additionally, lncRNA-mRNA coexpression network analysis showed that NONHSAT053785 is at the core of the network. Furthermore, the Signal-net analysis showed that CYP3A4 was gene with the highest degree. Finally, the data of five of the six selected differentially expressed lncRNAs were in agreement with the microarray data obtained by qRT-PCR verification.ConclusionOur study revealed the differentially expressed profiles of lncRNAs and mRNAs for HBV-HCC, and five novel dysregulated lncRNAs were identified in HBV-HCC tissues. The aforementioned dysregulated lncRNAs may represent potential diagnostic biomarkers and therapeutic targets of HBV-HCC, which needs to be validated in future studies.
| S-EPMC6885655 | biostudies-literature
Project description:BACKGROUND: A recent genome-wide association study (GWAS) using chronic HBV (hepatitis B virus) carriers with and without hepatocellular carcinoma (HCC) in five independent Chinese populations found that one SNP (rs17401966) in KIF1B was associated with susceptibility to HCC. In the present study, a total of 580 HBV-derived HCC cases and 1351 individuals with chronic hepatitis B (CHB) or asymptomatic carrier (ASC) were used for replication studies in order to evaluate the reported association with HBV-derived HCC in other East Asian populations. RESULTS: We did not detect any associations between rs17401966 and HCC in the Japanese cohorts (replication 1: OR?=?1.09, 95?% CI?=?0.82-1.43; replication 2: OR?=?0.79, 95?% CI?=?0.54-1.15), in the Korean cohort (replication 3: OR?=?0.95, 95?% CI?=?0.66-1.36), or in the Hong Kong Chinese cohort (replication 4: OR?=?1.17, 95?% CI?=?0.79-1.75). Meta-analysis using these cohorts also did not show any associations with P?=?0.97. CONCLUSIONS: None of the replication cohorts showed associations between rs17401966 and HBV-derived HCC. This may be due to differences in the genetic diversity among the Japanese, Korean and Chinese populations. Other reasons could be the high complexity of multivariate interactions between the genomic information and the phenotype that is manifesting. A much wider range of investigations is needed in order to elucidate the differences in HCC susceptibility among these Asian populations.
| S-EPMC3407509 | biostudies-literature
Project description:BackgroundThis study aimed to determine whether CD44 polymorphisms were correlated with hepatocellular carcinoma (HCC) and to reveal a new potential target for early prediction, prevention, and diagnosis of HCC.MethodThis study involved 96 cases with chronic hepatitis B (CHB), 96 cases with hepatitis B virus-related liver cirrhosis (LC), 204 cases with HCC related to the hepatitis B virus, and 210 healthy controls. The genotype of rs8193 was determined using the restriction fragment length polymorphism method, while the genotypes of rs10836347 and rs13347 were determined by direct sequencing.ResultsThe results showed that patients with the CD44 rs13347 TT and T allele polymorphisms exhibited higher risks of LC than those carrying the CC genotype and C allele. The CD44 rs13347 CT and TT genotypes and T allele were significantly associated with an increased risk of HCC after adjusting for gender, age, smoking, and alcohol consumption (for CT: odds ratio [OR] = 1.626, 95% confidence interval [CI] = 1.057-2.500, P = .027; for TT: OR = 1.965, 95% CI = 1.043-3.702, P = .037; and for T: OR = 1.461, 95% CI = 1.091-1.956, P = .011). In the rs13347 site of the female population, the CT and TT genotypes were related to the high occurrence of HCC. In the population aged ≥50 years, carriers of the CD44 rs13347 CT and TT alleles were more susceptible to HCC compared with CC carriers. Those who consumed alcohol who carried the rs10836347 CT genotype exhibited a risk factor for HCC.ConclusionFor the CD44 rs13347 site, mutations in the T allele might be a risk factor for HCC.
| S-EPMC6805271 | biostudies-literature
Project description:Sodium taurocholate cotransporting polypeptide (NTCP), encoded by gene SLC10A1, is a receptor for hepatitis B virus (HBV). The aim of the current study was to investigate the role of NTCP polymorphisms in HBV susceptibility, cirrhosis and hepatocarcinogenesis. A total 1221 cases [including 866 chronic hepatitis B (CHB), 238 liver cirrhosis (LC), 117 hepatocellular carcinoma (HCC) patients] and 1232 healthy controls (HCs) were recruited, and 6 single nucleotide polymorphisms (SNPs) were genotyped. Meta-analysis was executed among 14591 CHBs and 12396 HCs to determine the association between NTCP polymorphisms and HBV infection, cirrhosis or hepatocarcinogenesis. The frequency of rs2296651-GA was inversely correlated with CHB, LC or HCC patients [adjusted OR(95%CI)=0.16(0.11-0.23), p<0.001; 0.34(0.21-0.55), p=0.001; or 0.46(0.25-0.83), p=0.008], respectively, compared with HCs. Meta-analysis also showed that NTCP rs2296651-GA was inversely associated with HBV infection [OR(95%CI)=0.532(0.287-0.986), p=0.028, codominant] or HBV-related HCC [OR(95%CI)=0.701(0.564-0.872), p=0.001, recessive]. Furthermore, the frequency of rs943277-GA was positively correlated with HBV infection [adjusted OR(95%CI)=2.42(1.05-5.54), p=0.032, codominant]. Our data suggest that NTCP mutants contribute to the susceptibility of HBV infection or HBV-related HCC.
| S-EPMC5739647 | biostudies-literature