Transcriptome‐wide association study for persistent hepatitis B virus infection and related hepatocellular carcinoma

Abstract

Background & Aims Previous genome‐wide association studies (GWAS) have identified multiple susceptible variants associated with persistent hepatitis B virus (HBV) infection. However, most of these variants are located in the noncoding regions, which make it difficult to determine the effective genes underlying these associations. We performed a two‐stage study, in the first stage we integrated RNA sequencing data of liver tissues and high‐density genotyping data from the Genotype‐Tissue Expression (GTEx) project with our previous GWAS data to conduct a transcriptome‐wide association study (TWAS) on HBV infection. Firstly, the cis‐heritable genes were screened by a genetic relatedness matrix of genome‐wide complex trait analysis (GCTA) from GTEx data. Then, the genetic expression of 2587 cis‐heritable genes was predicted by restricted maximum likelihood (REML) of genome‐wide efficient mixed‐model association (GEMMA) in our GWAS data with 951 HBV carrier cases and 937 HBV cleared controls. Next, we investigated the associations between predictive expression levels and persistent HBV infection risk. Gene set enrichment analysis (GSEA) was applied to infer the function of the identified genes. To identify the causal single nucleotide polymorphisms (SNPs) of HBV infection risk, we conducted the expression quantitative trait loci (eQTL)‐based stepwise logistic regression analysis in the regions around 1 Mb of these genes and validated the association between 994 health controls and 994 HBV‐persistent infection cases by genotyping experiment. In the second stage, 1538 HBV‐related hepatocellular carcinoma (HCC) cases and 1465 persistent HBV infection controls were collected to determine the effect of these variants on HBV‐related HCC as well, which were examined by the additive model in logistic regression analysis. We identified seven genes associated with HBV infection. In the classic human leukocyte antigen (HLA) region, three novel genes BAK1, HLA‐DOB and C4A (Z range from −3.95 to −3.64, P range from 7.84 × 10−5 to 2.00 × 10−4), as well as two genes (HLA‐DPA1 and HLA‐DPB1) were reported by previous GWAS. In the non‐HLA region, immune related at newly identified loci, PARP9 (Z = 3.69, P = 2.20 × 10−4) at 3q21.1. At 22q11.21, we identified TMEM191A (Z = 3.55, P = 3.80 × 10−4) as a target gene in addition to the reported non‐cis‐heritable gene UBE2L3. After further stepwise logistic regression analysis and validation, we identified eight variants independently associated with persistent HBV infection. Among those variants, the additive model showed that two SNPs associated with HBV‐related HCC risk (rs9272714 and rs9394194, OR range from 1.20 to 1.25, P range from 1.19 × 10−4 to 3.97 × 10−4). By integrating transcriptome data, our study not only identified new susceptibility loci of persistent HBV infection but also determined the potential target genes at reported loci, which provided insight into the genetic aetiology of persistent HBV infection and related HCC.

Identification of Anoikis-Related Subgroups and Prognosis Model in Liver Hepatocellular Carcinoma

“…Interestingly, BAK expression was decreased in colorectal tumors and remained unchanged in most conditions [37], but increased BAK expression was strongly associated with a poor prognosis in patients with non-small cell lung cancer [38], which indicates that the role of BAK is unclear in different types of cancers. Consistent with our results, BAK1 has been identified as a prognostic gene in pyroptosis-related HCC and is associated with persistent hepatitis B virus infectionrelated HCC [39,40]. In this study, we found that the expression of BAK1 was upregulated in the high-risk group compared to the low-risk group.…”

Potential role of SNP rs2071475 in rheumatoid arthritis and inflammatory bowel disease in the East Asian population: a Mendelian randomization study

“…A large-scale meta-analysis has identified that HLA-DOB is significantly upregulated in RA (Afroz et al 2017 ). Previous researches have indicated that human leukocyte antigen HLA-DOB, which can influence several alleles involved in antigen presentation, plays a crucial role in viral infections (Denzin et al 2017 ; Han et al 2020 ). Simultaneously, a study involving transcriptome analysis of the colon found that HLA-DOB was significantly upregulated only in patients with CD, while there was no significant change in patients with UC (Yang et al 2019 ).…”

Inositol 1,4,5‐trisphosphate receptor gene variants are related to the risk of breast cancer in a Chinese population

“…33 HLA-DOB expression has been shown to be of prognostic relevance in the NSCLC, ovarian cancer, and in the context of hepatitis C virus infection and clearance. [34][35][36] UQCC2 is one of three critical components necessary for the assembly of respiratory chain complex III and, through its ability to modulate respiratory chain activity, it can influence insulin secretion, myogenesis, and the mitochondrial production of ATP. 37 As such, these findings suggest that the identified SNP in ITPR3 and associated genes identified in eQTL analyses all have the potential to influence breast cancer development.…”

“…The overexpression of the glutamate metabotropic receptor GRM4 in MDA‐MB‐231 cells has been linked to the inhibition of tumor cell migration, invasion, and proliferation, and the upregulation of this gene has also been linked to a better breast cancer patient prognosis 33 . HLA‐DOB expression has been shown to be of prognostic relevance in the NSCLC, ovarian cancer, and in the context of hepatitis C virus infection and clearance 34–36 . UQCC2 is one of three critical components necessary for the assembly of respiratory chain complex III and, through its ability to modulate respiratory chain activity, it can influence insulin secretion, myogenesis, and the mitochondrial production of ATP 37 .…”