Copy number gain of pro-inflammatory genes in patients with HBV-related acute-on-chronic liver failure

Host genetic factors such as single nucleotide variations may play a crucial role in the onset and progression of HBV-related acute-on-chronic liver failure (ACLF). However, the underlying genomic copy number variations (CNVs) involved in the pathology are currently unclear.

We genotyped two cohorts with 389 HBV-related ACLF patients and 391 asymptomatic HBV carriers (AsCs), and then carried out CNV-based global burden analysis and a genome-wide association study (GWAS).

For 1874 rare CNVs, HBV-related ACLF patients exhibited a high burden of deletion segments with a size of 100-200 kb (P value = 0.04), and the related genes were significantly enriched in leukocyte transendothelial migration pathway (P value = 4.68 × 10^-3). For 352 common CNVs, GWAS predicted 17 significant association signals, and the peak one was a duplication segment located on 1p36.13 (~ 38 Kb, P value = 1.99 × 10^-4, OR = 2.66). The associated CNVs resulted in more copy number of pro-inflammatory genes (MST1L, DEFB, and HCG4B) in HBV-related ACLF patients than in AsC controls.

Our results suggested that the impact of host CNV on HBV-related ACLF may be through decreasing natural immunity and enhancing host inflammatory response during HBV infection. The findings highlighted the potential importance of gene dosage on excessive hepatic inflammation of this disease.