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Multicenter Study
. 2024 Oct;18(5):1434-1447.
doi: 10.1007/s12072-024-10709-y. Epub 2024 Jul 17.

Dose-response relationship between serum N-glycan markers and liver fibrosis in chronic hepatitis B

Collaborators, Affiliations
Multicenter Study

Dose-response relationship between serum N-glycan markers and liver fibrosis in chronic hepatitis B

Chi Zhang et al. Hepatol Int. 2024 Oct.

Abstract

Background: Evaluation of liver fibrosis played a monumental role in the diagnosis and monitoring of chronic hepatitis B (CHB). We aimed to explore the value of serum N-glycan markers in liver fibrosis.

Methods: This multi-center (33 hospitals) study recruited 760 treatment-naïve CHB patients who underwent liver biopsy. Serum N-glycan markers were analyzed by DNA sequencer-assisted fluorophore-assisted with capillary electrophoresis (DSA-FACE) technology. First, we explore the relationship between 12 serum N-glycan markers and the fibrosis stage. Then, we developed a Px score for diagnosing significant fibrosis using the LASSO regression. Next, we compared the diagnostic performances between Px, LSM, APRI, and FIB-4. Finally, we explored the relationships between glycosyltransferase gene and liver fibrosis with RNA-transcriptome sequencing.

Results: We included 622 CHB participants: male-dominated (69.6%); median age 42.0 (IQR 34.0-50.0); 287 with normal ALT; 73.0% with significant fibrosis. P5(NA2), P8(NA3), and P10(NA4) were opposite to the degree of fibrosis, while other profiles (except for P0[NGA2]) increased with the degree of fibrosis. Seven profiles (P1[NGA2F], P2[NGA2FB], P3[NG1A2F], P4[NG1A2F], P7[NA2FB], P8[NA3], and P9[NA3Fb]) were selected into Px score. Px score was associated with an increased risk of significant fibrosis (for per Px score increase, the risk of significant fibrosis was increased by 3.54 times (OR = 4.54 [2.63-7.82]) in the fully-adjusted generalized linear model. p for trend was <0.001. The diagnostic performance of the Px score was superior to others. Glycosyltransferase genes were overexpressed in liver fibrosis, and glycosylation and glycosyltransferase-related pathways were significantly enriched.

Conclusions: Serum N-glycan markers were positively correlated with liver fibrosis. Px score had good performance in distinguishing significant fibrosis.

Keywords: Chronic hepatitis B; Diagnostic performance; Liver fibrosis; RNA-transcriptome sequencing; Serum N-glycan markers.

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Conflict of interest statement

Cuiying Chen, Junli Zhang, and Chao Zhang are from Sysdiagno (Nanjing) Biotechnology Company Limited. Chi Zhang, Yiqi Liu, Lin Wang, Xueen Liu, Guiqiang Wang, Hui Zhuang, and Hong Zhao declare that they have no conflicts of interest or financial conflicts to disclose.

Figures

Fig. 1
Fig. 1
The value of 12 N-glycan peaks in different liver fibrosis stage. a Representative N-glycan peaks of different liver fibrosis stages; b structure of 12 N-glycan peaks; c N-glycan profiles abundances between different liver fibrosis stages. Fibrosis stages were evaluated by Ishak scoring system, and significant fibrosis was defined as F ≥ 3. The data in figure C was represented as the median (interquartile range), and student t-test (Gaussian distribution) or Kruskal–Wallis H-test (skewed distribution) were used to detect the differences among fibrosis stage
Fig. 2
Fig. 2
Correlation between 12 N-glycan peaks abundances and risk of significant fibrosis by restricted cubic spline
Fig. 3
Fig. 3
Developing a significant fibrosis prediction model Px score using least absolute shrinkage and selection operator (LASSO) regression. a LASSO coefficient path; b LASSO regularization path; c coefficients of each N-glycan peak; d correlation between predicted value and observed value
Fig. 4
Fig. 4
The diagnostic value of Px for significant liver fibrosis. a Distribution of Px among different fibrosis stage b restricted cubic spline of Px for diagnosis of significant fibrosis
Fig. 5
Fig. 5
Relationship between glycosyltransferases and liver fibrosis. a Volcano plot of genes differentially expressed between significant fibrosis and mild fibrosis in the GSE84044 dataset. Blue nodes represent down-regulation in significant fibrosis; red nodes represent up-regulation; and gray nodes represent no significant difference between them. b Intersection of differentially expressed genes (DEGs) in the GSE84044 and glycosyltransferases-related genes. c Expression of 3 representative glycosyltransferase genes (CHST4, SLC51B, and TUSC3) in different fibrosis stage; d GO enrichment analysis of glycosyltransferases-related DEGs; e KEGG enrichment analysis of glycosyltransferases-related DEGs

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