A Genetic Variant of PPP1CB Influences Risk of Hepatitis B Virus-Related Hepatocellular Carcinoma in Han Chinese: A Pathway Based Analysis

Haoming Mai; Haisheng Xie; Jia Hou; Haitao Chen; Bin Zhou; Jinlin Hou; Deke Jiang

doi:10.2147/JHC.S321939

A Genetic Variant of PPP1CB Influences Risk of Hepatitis B Virus-Related Hepatocellular Carcinoma in Han Chinese: A Pathway Based Analysis

J Hepatocell Carcinoma. 2021 Sep 2:8:1055-1064. doi: 10.2147/JHC.S321939. eCollection 2021.

Authors

Haoming Mai^#¹, Haisheng Xie^#¹, Jia Hou^#¹, Haitao Chen¹, Bin Zhou¹, Jinlin Hou¹, Deke Jiang¹

Affiliation

¹ State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, People's Republic of China.

^# Contributed equally.

Abstract

Purpose: Activation of actin cytoskeleton remodeling is an important stage preceding cancer cell metastasis. Previous genome-wide association studies (GWAS) have identified multiple hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC)-associated risk loci. However, limited sample size or strict significance threshold of GWAS may cause HBV-related HCC risk-associated genetic loci to be undetected. We aimed to investigate the performance of the SNP rs13025377 in PPP1CB in HCC.

Patients and methods: We performed a case-control study including 1161 cases and 1353 controls to evaluate associations between single nucleotide polymorphisms (SNPs) from 98 actin-cytoskeleton regulatory genes and risk of HBV-related HCC. The effects of SNPs on HBV-related HCC risk were assessed under logistic regression model and corrected by false discovery rate (FDR).

Results: We found that rs13025377 in PPP1CB was significantly associated with HBV-related HCC risk [odds ratio (OR) = 0.81, 95% confidence interval (CI) = 0.72~0.91, P = 4.88×10^-4]. The risk allele A of rs13025377 increased PPP1CB expression levels in normal liver tissue. SNP rs4665434 was tagged by rs13025377 (r² = 0.9) and its protective allele disrupted CTCF and Cohesin motifs. According to public datasets, PPP1CB, CTCF and Cohesin expression levels are increased in tumor tissues. Kaplan-Meier plots demonstrated that higher PPP1CB expression was significantly associated with shorter overall survival (OS). Moreover, we observed strong correlation between CTCF, Cohesin, and PPP1CB in various liver tissues. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis confirmed that PPP1CB plays a role in HCC through actin-cytoskeleton regulation.

Conclusion: Thus, these findings indicated that PPP1CB may be a key gene in actin-cytoskeleton regulation and rs13025377 contributes to the risk of HBV-related HCC by regulating PPP1CB expression.

Keywords: CTCF; HBV-related hepatocellular carcinoma; PPP1CB; SNP; cohesin; genome-wide association studies.

Grants and funding

This study was supported by the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (No. 2017BT01S131), the General Program from the Natural Science Foundation of Guangdong Province (No. 2019A1515011423), the General Programs from the National Natural Science Foundation of China (No. 81472618 and 81670535), the National Science and Technology Major Project (No. 2017ZX10202202 and 2018ZX10301202), the Key-Area Research and Development Program of Guangdong Province (No. 2019B020227004), the Innovative Research Team Project of Guangxi Province (No. 2017GXNSFGA198002), the Dean Fund of Nanfang Hospital, Southern Medical University (No. 2018Z005), the Grant for Recruited Talents to Start Scientific Research from Nanfang Hospital, and the Outstanding Youth Development Scheme of Nanfang Hospital, Southern Medical University (No. 2017J001).