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. 2020 Dec 1;13(1):180.
doi: 10.1186/s12920-020-00835-5.

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

Fengming Sun  1   2 , Wenting Tan  1   2 , Yunjie Dan  1   2 , Xiuhua Wang  1   2 , Yanzhi Guo  1   2 , Guohong Deng  3   4
Affiliations

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

Fengming Sun et al. BMC Med Genomics. .

Abstract

Background: 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.

Methods: 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).

Results: 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.

Conclusions: 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.

Keywords: Acute-on-chronic liver failure; Copy number variations; GWAS; HBV-ACLF; HBV-related ACLF.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Overall analysis methods and genotyping results. a Overall flow chart of genotyping and analysis. Some intermediate results and final results were marked in the figure. The normal distribution test was applied to verify the randomness of the results (b), and the distribution of the CNV number of each individual was very close to normal (P = 2.2 × 10–16). However, the distribution showed significant difference between HBV-related ACLF cases and AsC controls (c), indicating the potential host CNVs difference of the HBV-related ACLF
Fig. 2
Fig. 2
Expression patterns of the potential disease-related genes. Data collection and Expressional calculation was illustrated in the methods part. Low copy number of cell adhesion molecules (CAMs) genes may decrease its expressional level (a). More copies of MST1L in HBV-related ACLF likely increase the expressional level (b). The mean expression level of HLA-A was both relatively higher in HBV-related ACLF (c) and HBV-related ALF (d) patients than that of controls
Fig. 3
Fig. 3
GWAS results of common CNVs for HBV-ACLF. Fisher's exact test was applied to detect all candidate associations for both gained and lost genotypes. The top two highest signals were marked with text description, and the locations were extracted based on the human genome assembly version of NCBI36/hg18
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