TBX5 Variants are Associated with Susceptibility to and the Incidence of Liver Cirrhosis and Hepatocellular Carcinoma in the Chinese Population: A Multicenter and Follow-Up Study

JinJian Yao; Xiaochun Mao; Qigang Sun; Biao Wu; Weiling Yu; Yanjing Huang; Shuai Luo; Jia Zeng; Jusheng Lin

doi:10.2147/IDR.S410151

TBX5 Variants are Associated with Susceptibility to and the Incidence of Liver Cirrhosis and Hepatocellular Carcinoma in the Chinese Population: A Multicenter and Follow-Up Study

Infect Drug Resist. 2023 May 2:16:2653-2665. doi: 10.2147/IDR.S410151. eCollection 2023.

Authors

JinJian Yao^#^{1

2}, Xiaochun Mao^#³, Qigang Sun^#⁴, Biao Wu⁵, Weiling Yu⁶, Yanjing Huang⁷, Shuai Luo¹, Jia Zeng¹, Jusheng Lin²

Affiliations

¹ Department of Emergency, Hainan General Hospital, Haikou, Hainan, People's Republic of China.
² Institute of Liver and Gastrointestinal Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
³ Department of Ophthalmology, Xiangyang Central Hospital Affiliated to Hubei University of Arts and Science, Xiangyang, Hubei, People's Republic of China.
⁴ Department of Hepatobiliary and Pancreatic Surgery, Hainan General Hospital, Haikou, Hainan, People's Republic of China.
⁵ Infectious Disease, Hainan General Hospital, Haikou, Hainan, People's Republic of China.
⁶ Oncology Department, Haikou City People's Hospital, Haikou, Hainan, People's Republic of China.
⁷ Oncology Department of Hainan General Hospital, Haikou, Hainan, People's Republic of China.

^# Contributed equally.

Abstract

Purpose: Liver cirrhosis (LC) and hepatocellular carcinoma (HCC) are progressions affected by genetic predispositions, and persistent hepatitis B virus infection also demonstrates genetic susceptibility. All HBV-related outcomes have been compared in parallel to identify risk polymorphism in HBV progression.

Methods: The multiple-stage association study filtered and validated the risk SNPs for HBV progression and explored their association with persistent infection, with a total of 8906 subjects in China from three sites. Cox proportional hazards models and Kaplan-Meier Log rank tests were used to determine the time to the progressive event in relation to the risk SNPs.

Results: Rs3825214 in TBX5 replicated a specific association with LC and HCC in 4 progression cohorts and was not related to persistent infection, naivety to HBV infection and natural clearance in 3 persistent cohorts. In combined samples, rs3825214 was associated with an increased risk of LC (P<0.001; OR = 1.98) and HCC (P<0.001; OR = 1.68). The results of bioinformatics analysis indicated that rs3825214 genotypes change RNA structure and intron excision ratio. In the follow-up of 571 hospital-based persistent HBV infection patients, ninety-three (16.29%) developed LC, and seventy-four (12.96%) progressed to HCC at a median follow-up of 5.1 years. Rs3825214 was associated with HCC and LC events in Cox proportional hazards models (P<0.001).

Conclusion: We identified and confirmed that genetic variants in TBX5 are significantly associated with susceptibility to and the incidence of LC and HCC.

Keywords: TBX5; follow-up; hepatitis B virus; hepatocellular carcinoma; liver cirrhosis; polymorphism.

Grants and funding

This research was funded by the Province Natural Science Foundation of Hainan, grant number: 818MS131 and National Basic Research Program of China (973 Program, No. 2007CB512903).