Genome-Wide Association Study to Identify Genetic Factors Linked to HBV Reactivation Following Liver Transplantation in HBV-Infected Patients

Abstract

This study utilized a genome-wide association study (GWAS) to investigate the genetic variations linked to the risk of hepatitis B virus (HBV) reactivation in patients who have undergone liver transplantation (LT), aiming to enhance understanding and improve clinical outcomes. Genotyping performed on a selected patients from the Korean Organ Transplantation Registry (KOTRY) data using high-throughput platforms with the Axiom Korea Biobank array 1.1. The discovery cohort included 21 patients who experienced HBV reactivation (cases) and 888 patients without HBV reactivation (controls) following LT. The replication cohort consisted of 5 patients with HBV reactivation (cases) and 312 patients without HBV reactivation (controls) after LT. Additive logistic regression analysis was conducted using PLINK software ver 1.9, with adjustments for age and gender. The GWAS findings from the discovery cohort were validated using the replication cohort. The GWAS identified several single-nucleotide polymorphisms (SNPs) in the RGL1, CDCA7L, and AQP9 genes that were significantly linked to HBV reactivation after LT, with genome-wide significance thresholds set at p < 10^-7. Down-regulation of RGL1 cDNAs was observed in primary duck hepatocytes infected with duck HBV. Overexpression of CDCA7L was found to promote hepatocellular carcinoma cell proliferation and colony formation, whereas knocking down CDCA7L inhibited these processes. Additionally, the absence of AQP9 triggered immune and inflammatory responses, leading to mild and scattered liver cell pyroptosis, accompanied by compensatory liver cell proliferation. This study provides critical insights into the genetic factors influencing HBV reactivation after LT, identifying significant associations with SNPs in RGL1, CDCA7L, and AQP9. These findings hold promise for developing predictive biomarkers and personalized management strategies to improve outcomes for HBV-infected LT recipients.

Keywords: AQP9; CDCA7L; HBV reactivation; RGL1; genome-wide association study; hepatitis B; hepatocellular carcinoma; liver transplantation.

Figure 1

Genome-wide association study (GWAS) revealed that RGL1 is associated with HBV reactivation after LT. (a) Manhattan plot of GWAS of HBV reactivation in Korean liver transplantation recipient. Variants are plotted on the x-axis of the Manhattan plot according to their chromosomal position, and their –log10 (p-value) is shown on the y-axis. The red line shows the genome-wide significance threshold (p < 5 × 10⁻⁸). (b) QQ-plot of p-values from a GWAS comparing patients with HBV reactivation after LT to those in a control group in the entire cohort. The red line indicates the expected distribution under the null hypothesis in the Q-Q plot.