Genome-wide Association Study Identifies New Loci Associated With Risk Of HBV Infection And Disease Progression

Zheng Zeng; Liu Hankui; Xu Huifang; Lu Haiying; Yu Yanyan; Xu Xiaoyuan; Yu Min; Zhang Tao; Tian Xiulan; Xi Hongli; Guan Liping; Zhang Jianguo; Stephen James O'Brien

doi:10.1186/s12920-021-00907-0

Genome-wide Association Study Identifies New Loci Associated With Risk Of HBV Infection And Disease Progression

Zheng Zeng
, Liu Hankui
, Xu Huifang
, Lu Haiying
, Yu Yanyan
, Xu Xiaoyuan
, Yu Min
, Zhang Tao
, Tian Xiulan
, Xi Hongli
, Guan Liping
, Zhang Jianguo
, Stephen James O'Brien

Department of Biological Sciences

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

Abstract

Background : Recent studies have identified susceptibility genes of HBV clearance, chronic hepatitis B, liver cirrhosis, hepatocellular carcinoma, and showed the host genetic factors play an important role in these HBV-related outcomes.

Results : In order to discover new susceptibility genes for HBV-related outcomes, we conducted a genome-wide association study in 1031 Chinese participants, including 275 HBV clearance subjects, 92 asymptomatic persistence infection carriers (ASPI), 93 chronic hepatitis B patients (CHB), 188 HBV-related decompensated cirrhosis patients (DC), 214 HBV-related hepatocellular carcinoma patients (HCC) and 169 healthy controls (HC). In the case-control study, we observed novel locus significantly associated with CHB (SNP: rs1264473, Gene: GRHL2 , P = 1.57×10 ^-6 ) and HCC (SNP: rs2833856, Gene: EVA1C , P = 1.62×10 ^-6 ; SNP: rs4661093, Gene: ETV3 , P = 2.26×10 ^-6 ). In the trend study across progressive stages post HBV infection, one novel locus (SNP: rs1537862, Gene: LACE1 , P = 1.85×10 ^-6 ), and three MHC loci ( HLA-DRB1, HLA-DPB1, HLA-DPA2 ) showed significant increased progressive risk from ASPI to CHB. Interestingly, underlying the evolutionary study of HBV-related genes in public database, we found that the derived allele of two HBV clearance related locus, rs3077 and rs9277542, are under strong selection in European population.

Conclusions : In this study, we identified several novel candidate genes associated with individual HBV infectious outcomes, progressive stages, and liver enzymes. Moreover, we identified two SNPs that show selective significance ( HLA-DPA1 , HLA-DPB1 ) in non-East Asian (European, American, South Asian) versus East Asian, indicating that host genetic factors contribute to the ethnic disparities of susceptibility of HBV infection. Taken together, these findings provided a new insight into the role of host genetic factors in HBV related outcomes and progression.

Original language	American English
Article number	84
Journal	BMC Medical Genomics
Volume	14
DOIs	https://doi.org/10.1186/s12920-021-00907-0
State	Published - Jan 13 2021

Bibliographical note

Publisher Copyright:
© 2021, The Author(s).

Funding

This study was supported by the National Natural Science Foundation of China (No. 61972007, No. 30671855), the International Science & Technology Cooperation Program of China (No. 2014DFR31200), Federal funds from the National Cancer Institute, National Institutes of Health, USA (No. N01-CO-12400), Shenzhen Municipal of Government of China (JCYJ20170412153248372, JCYJ20180507183615145). These funding have no conflict of interest. The content of this publication does not necessarily reflect the view of policies of the Department of Health and Human Service, nor does mention of trade name, commercial products or organizations imply endorsement by the U.S. Government. We thank the participants for their involvement in this study. HBV study consortium: Department of Infectious Diseases, Peking University First Hospital, Beijing, China (Zheng Zeng, Yanyan Yu, Xiaoyuan Xu, Haiying Lu); Institute of Liver Diseases Research, Beijing Military General Hospital, Beijing, China (Darong Hu); Beijing Ditan Hospital (Rongbing Wang, Yifan Chen); Department of Surgery, Beijing Institute of Tumor Prevention and Therapy, Beijing, China (Cunyi Hao); Department of Infectious Diseases, Shanxi Medical University, Taiyuan, China (Heping Zhou); Department of Infectious Diseases, Qinhuangdao No. 3 Hospital, Qinhuangdao, China (Zhonghou Han); Department of Surgery, Inner Mongolia Medical College, Hohhot, China (Lidao Bao, Xiping Zhang); Department of Infectious Diseases, Xuzhou No. 3 Hospital, Xuzhou, China (Dasi Guo); Department of Infectious Diseases, Xinjian Medical University, Urumoqi, China (Yaoxin Zhang); Department of Infectious Diseases, the Second Affiliate Hospital of China Medical University, Shenyang, China (Xiaoguang Dou); Institute of Liver Diseases Research, Peking University People’s Hospital, Beijing, China (Lai Wei); Department of Surgery, Peking Union Medical College, Beijing, China (Qiang Qu).

Funders	Funder number
Beijing Ditan Hospital
Beijing Institute of Tumor Prevention and Therapy
Beijing Military General Hospital
Department of Infectious Diseases
Inner Mongolia Medical College
Institute of Liver Diseases Research
Second Affiliate Hospital of China Medical University, Shenyang, China
Shanxi Medical University, Taiyuan, China
Shenzhen Municipal of Government of China	JCYJ20180507183615145, JCYJ20170412153248372
National Institutes of Health	N01-CO-12400
National Institutes of Health
National Cancer Institute
Department of Surgery
Peking University First Hospital
National Natural Science Foundation of China	61972007, 30671855
National Natural Science Foundation of China
Xinjiang Medical University
Peking University
International Science and Technology Cooperation Programme	2014DFR31200
International Science and Technology Cooperation Programme

ASJC Scopus Subject Areas

Genetics(clinical)
Genetics

Keywords

GWAS
HBV infection
Host genetic factors
SNPs
disease progression
Disease progression

Disciplines

Biology
Genetics and Genomics
Life Sciences

Access to Document

10.1186/s12920-021-00907-0

Genome-wide Association Study Identifies New Loci Associated WithFinal published version, 560 KBLicense: Unspecified

Cite this

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title = "Genome-wide Association Study Identifies New Loci Associated With Risk Of HBV Infection And Disease Progression",

abstract = " Background : Recent studies have identified susceptibility genes of HBV clearance, chronic hepatitis B, liver cirrhosis, hepatocellular carcinoma, and showed the host genetic factors play an important role in these HBV-related outcomes. Results : In order to discover new susceptibility genes for HBV-related outcomes, we conducted a genome-wide association study in 1031 Chinese participants, including 275 HBV clearance subjects, 92 asymptomatic persistence infection carriers (ASPI), 93 chronic hepatitis B patients (CHB), 188 HBV-related decompensated cirrhosis patients (DC), 214 HBV-related hepatocellular carcinoma patients (HCC) and 169 healthy controls (HC). In the case-control study, we observed novel locus significantly associated with CHB (SNP: rs1264473, Gene: GRHL2 , P = 1.57×10 -6 ) and HCC (SNP: rs2833856, Gene: EVA1C , P = 1.62×10 -6 ; SNP: rs4661093, Gene: ETV3 , P = 2.26×10 -6 ). In the trend study across progressive stages post HBV infection, one novel locus (SNP: rs1537862, Gene: LACE1 , P = 1.85×10 -6 ), and three MHC loci ( HLA-DRB1, HLA-DPB1, HLA-DPA2 ) showed significant increased progressive risk from ASPI to CHB. Interestingly, underlying the evolutionary study of HBV-related genes in public database, we found that the derived allele of two HBV clearance related locus, rs3077 and rs9277542, are under strong selection in European population. Conclusions : In this study, we identified several novel candidate genes associated with individual HBV infectious outcomes, progressive stages, and liver enzymes. Moreover, we identified two SNPs that show selective significance ( HLA-DPA1 , HLA-DPB1 ) in non-East Asian (European, American, South Asian) versus East Asian, indicating that host genetic factors contribute to the ethnic disparities of susceptibility of HBV infection. Taken together, these findings provided a new insight into the role of host genetic factors in HBV related outcomes and progression.",

keywords = "GWAS, HBV infection, Host genetic factors, SNPs, disease progression, Disease progression",

author = "Zheng Zeng and Liu Hankui and Xu Huifang and Lu Haiying and Yu Yanyan and Xu Xiaoyuan and Yu Min and Zhang Tao and Tian Xiulan and Xi Hongli and Guan Liping and Zhang Jianguo and O'Brien, \{Stephen James\}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = jan,

day = "13",

doi = "10.1186/s12920-021-00907-0",

language = "American English",

volume = "14",

journal = "BMC Medical Genomics",

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TY - JOUR

T1 - Genome-wide Association Study Identifies New Loci Associated With Risk Of HBV Infection And Disease Progression

AU - Zeng, Zheng

AU - Hankui, Liu

AU - Huifang, Xu

AU - Haiying, Lu

AU - Yanyan, Yu

AU - Xiaoyuan, Xu

AU - Min, Yu

AU - Tao, Zhang

AU - Xiulan, Tian

AU - Hongli, Xi

AU - Liping, Guan

AU - Jianguo, Zhang

AU - O'Brien, Stephen James

PY - 2021/1/13

Y1 - 2021/1/13

N2 - Background : Recent studies have identified susceptibility genes of HBV clearance, chronic hepatitis B, liver cirrhosis, hepatocellular carcinoma, and showed the host genetic factors play an important role in these HBV-related outcomes. Results : In order to discover new susceptibility genes for HBV-related outcomes, we conducted a genome-wide association study in 1031 Chinese participants, including 275 HBV clearance subjects, 92 asymptomatic persistence infection carriers (ASPI), 93 chronic hepatitis B patients (CHB), 188 HBV-related decompensated cirrhosis patients (DC), 214 HBV-related hepatocellular carcinoma patients (HCC) and 169 healthy controls (HC). In the case-control study, we observed novel locus significantly associated with CHB (SNP: rs1264473, Gene: GRHL2 , P = 1.57×10 -6 ) and HCC (SNP: rs2833856, Gene: EVA1C , P = 1.62×10 -6 ; SNP: rs4661093, Gene: ETV3 , P = 2.26×10 -6 ). In the trend study across progressive stages post HBV infection, one novel locus (SNP: rs1537862, Gene: LACE1 , P = 1.85×10 -6 ), and three MHC loci ( HLA-DRB1, HLA-DPB1, HLA-DPA2 ) showed significant increased progressive risk from ASPI to CHB. Interestingly, underlying the evolutionary study of HBV-related genes in public database, we found that the derived allele of two HBV clearance related locus, rs3077 and rs9277542, are under strong selection in European population. Conclusions : In this study, we identified several novel candidate genes associated with individual HBV infectious outcomes, progressive stages, and liver enzymes. Moreover, we identified two SNPs that show selective significance ( HLA-DPA1 , HLA-DPB1 ) in non-East Asian (European, American, South Asian) versus East Asian, indicating that host genetic factors contribute to the ethnic disparities of susceptibility of HBV infection. Taken together, these findings provided a new insight into the role of host genetic factors in HBV related outcomes and progression.

AB - Background : Recent studies have identified susceptibility genes of HBV clearance, chronic hepatitis B, liver cirrhosis, hepatocellular carcinoma, and showed the host genetic factors play an important role in these HBV-related outcomes. Results : In order to discover new susceptibility genes for HBV-related outcomes, we conducted a genome-wide association study in 1031 Chinese participants, including 275 HBV clearance subjects, 92 asymptomatic persistence infection carriers (ASPI), 93 chronic hepatitis B patients (CHB), 188 HBV-related decompensated cirrhosis patients (DC), 214 HBV-related hepatocellular carcinoma patients (HCC) and 169 healthy controls (HC). In the case-control study, we observed novel locus significantly associated with CHB (SNP: rs1264473, Gene: GRHL2 , P = 1.57×10 -6 ) and HCC (SNP: rs2833856, Gene: EVA1C , P = 1.62×10 -6 ; SNP: rs4661093, Gene: ETV3 , P = 2.26×10 -6 ). In the trend study across progressive stages post HBV infection, one novel locus (SNP: rs1537862, Gene: LACE1 , P = 1.85×10 -6 ), and three MHC loci ( HLA-DRB1, HLA-DPB1, HLA-DPA2 ) showed significant increased progressive risk from ASPI to CHB. Interestingly, underlying the evolutionary study of HBV-related genes in public database, we found that the derived allele of two HBV clearance related locus, rs3077 and rs9277542, are under strong selection in European population. Conclusions : In this study, we identified several novel candidate genes associated with individual HBV infectious outcomes, progressive stages, and liver enzymes. Moreover, we identified two SNPs that show selective significance ( HLA-DPA1 , HLA-DPB1 ) in non-East Asian (European, American, South Asian) versus East Asian, indicating that host genetic factors contribute to the ethnic disparities of susceptibility of HBV infection. Taken together, these findings provided a new insight into the role of host genetic factors in HBV related outcomes and progression.

KW - GWAS

KW - HBV infection

KW - Host genetic factors

KW - SNPs

KW - disease progression

KW - Disease progression

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UR - https://www.scopus.com/pages/publications/85103230153#tab=citedBy

U2 - 10.1186/s12920-021-00907-0

DO - 10.1186/s12920-021-00907-0

M3 - Article

SN - 1755-8794

VL - 14

JO - BMC Medical Genomics

JF - BMC Medical Genomics

M1 - 84

ER -

Genome-wide Association Study Identifies New Loci Associated With Risk Of HBV Infection And Disease Progression

Abstract

Bibliographical note

Funding

ASJC Scopus Subject Areas

Keywords

Disciplines

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