PMID- 32574393
OWN - NLM
STAT- MEDLINE
DCOM- 20210621
LR  - 20210621
IS  - 1478-3231 (Electronic)
IS  - 1478-3223 (Linking)
VI  - 40
IP  - 9
DP  - 2020 Sep
TI  - Transcriptome-wide association study for persistent hepatitis B virus infection 
      and related hepatocellular carcinoma.
PG  - 2117-2127
LID - 10.1111/liv.14577 [doi]
AB  - 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 x 10(-5) to 2.00 x 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 x 10(-4) ) at 3q21.1. At 22q11.21, we identified TMEM191A (Z = 3.55, P = 
      3.80 x 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 x 10(-4) to 3.97 x 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.
CI  - (c) 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
FAU - Han, Jing
AU  - Han J
AUID- ORCID: 0000-0002-6082-4226
AD  - Department of Epidemiology, School of Public Health, Nanjing Medical University, 
      Nanjing, China.
AD  - Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative 
      Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, 
      Nanjing, China.
AD  - Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical 
      University Affiliated Cancer Hospital, Nanjing, China.
FAU - Chen, Congcong
AU  - Chen C
AUID- ORCID: 0000-0002-1343-5711
AD  - Department of Epidemiology, School of Public Health, Nanjing Medical University, 
      Nanjing, China.
AD  - Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative 
      Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, 
      Nanjing, China.
FAU - Wang, Cheng
AU  - Wang C
AUID- ORCID: 0000-0001-9156-8862
AD  - Department of Epidemiology, School of Public Health, Nanjing Medical University, 
      Nanjing, China.
AD  - Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative 
      Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, 
      Nanjing, China.
FAU - Qin, Na
AU  - Qin N
AUID- ORCID: 0000-0003-4416-7112
AD  - Department of Epidemiology, School of Public Health, Nanjing Medical University, 
      Nanjing, China.
AD  - Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative 
      Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, 
      Nanjing, China.
FAU - Huang, Mingtao
AU  - Huang M
AD  - Department of Epidemiology, School of Public Health, Nanjing Medical University, 
      Nanjing, China.
AD  - Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative 
      Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, 
      Nanjing, China.
FAU - Ma, Zijian
AU  - Ma Z
AUID- ORCID: 0000-0002-3044-8442
AD  - Department of Epidemiology, School of Public Health, Nanjing Medical University, 
      Nanjing, China.
AD  - Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative 
      Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, 
      Nanjing, China.
FAU - Zhu, Meng
AU  - Zhu M
AUID- ORCID: 0000-0003-4338-2566
AD  - Department of Epidemiology, School of Public Health, Nanjing Medical University, 
      Nanjing, China.
AD  - Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative 
      Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, 
      Nanjing, China.
FAU - Dai, Juncheng
AU  - Dai J
AUID- ORCID: 0000-0002-4813-0168
AD  - Department of Epidemiology, School of Public Health, Nanjing Medical University, 
      Nanjing, China.
AD  - Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative 
      Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, 
      Nanjing, China.
FAU - Jiang, Yue
AU  - Jiang Y
AUID- ORCID: 0000-0002-6165-1777
AD  - Department of Epidemiology, School of Public Health, Nanjing Medical University, 
      Nanjing, China.
AD  - Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative 
      Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, 
      Nanjing, China.
FAU - Ma, Hongxia
AU  - Ma H
AUID- ORCID: 0000-0002-4031-8756
AD  - Department of Epidemiology, School of Public Health, Nanjing Medical University, 
      Nanjing, China.
AD  - Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative 
      Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, 
      Nanjing, China.
FAU - Jin, Guangfu
AU  - Jin G
AUID- ORCID: 0000-0003-0249-5337
AD  - Department of Epidemiology, School of Public Health, Nanjing Medical University, 
      Nanjing, China.
AD  - Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative 
      Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, 
      Nanjing, China.
FAU - Shen, Hongbing
AU  - Shen H
AUID- ORCID: 0000-0002-2581-5906
AD  - Department of Epidemiology, School of Public Health, Nanjing Medical University, 
      Nanjing, China.
AD  - Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative 
      Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, 
      Nanjing, China.
FAU - Hu, Zhibin
AU  - Hu Z
AUID- ORCID: 0000-0002-8277-5234
AD  - Department of Epidemiology, School of Public Health, Nanjing Medical University, 
      Nanjing, China.
AD  - Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative 
      Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, 
      Nanjing, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200713
PL  - United States
TA  - Liver Int
JT  - Liver international : official journal of the International Association for the 
      Study of the Liver
JID - 101160857
SB  - IM
MH  - *Carcinoma, Hepatocellular/genetics
MH  - Case-Control Studies
MH  - Genetic Predisposition to Disease
MH  - Genome-Wide Association Study
MH  - *Hepatitis B/genetics
MH  - Hepatitis B virus/genetics
MH  - *Hepatitis B, Chronic/genetics
MH  - Humans
MH  - *Liver Neoplasms/genetics
MH  - Polymorphism, Single Nucleotide
MH  - Transcriptome
OTO - NOTNLM
OT  - eQTL
OT  - hepatitis B
OT  - hepatitis B virus-related hepatocellular carcinoma
OT  - transcriptome-wide association
EDAT- 2020/06/24 06:00
MHDA- 2021/06/22 06:00
CRDT- 2020/06/24 06:00
PHST- 2019/11/16 00:00 [received]
PHST- 2020/06/01 00:00 [revised]
PHST- 2020/06/16 00:00 [accepted]
PHST- 2020/06/24 06:00 [pubmed]
PHST- 2021/06/22 06:00 [medline]
PHST- 2020/06/24 06:00 [entrez]
AID - 10.1111/liv.14577 [doi]
PST - ppublish
SO  - Liver Int. 2020 Sep;40(9):2117-2127. doi: 10.1111/liv.14577. Epub 2020 Jul 13.