Abstract
BackgroundHost 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.MethodsWe 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).ResultsFor 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.ConclusionsOur 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.
Highlights
Host genetic factors such as single nucleotide variations may play a crucial role in the onset and progression of Hepatitis B Virus (HBV)-related acute-on-chronic liver failure (ACLF)
The mean values of CNV number per individual (CNPI) were statistically different between the HBV-related ACLF and the Asymptomatic HBV carrier (AsC) group (P value = 0.02, Fig. 1c), which were 117 ± 83 and 106 ± 26 respectively
Global burden analysis of rare Copy number variation (CNV) Overall, HBV-related ACLF patients exhibited a significantly higher number of rare CNVs per person than the AsC controls (P value = 0.03; Ratio of RATE: 2.78/0.66), but the proportion of samples containing rare CNVs showed no difference between the two groups (P value = 0.42; ratio of PROP: 0.29/0.28) (Table 1)
Summary
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). The underlying genomic copy number variations (CNVs) involved in the pathology are currently unclear. Caused by severe acute exacerbation of chronic hepatitis B (CHB), HBV-related acute-onchronic liver failure (ACLF) is a severe life-threatening. Host genetic factors likely play a crucial role in the pathogenesis of HBV-related ACLF. Previous results deepen our understanding of HBVrelated ACLF and confirm the importance of host genetic factors in the pathogenesis of the disease. In addition to SNPs, copy number variations (CNVs) as another main type of genetic variations exhibit a high diversity in human population and are associated with many human diseases [7]. Direct evidences of association between host CNVs and HBVrelated ACLF remains unknown
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