Integrated Transcriptomic and Proteomic Analysis Identifies Plasma Biomarkers of Hepatocellular Failure in Alcohol-Associated Hepatitis

Argemí, Josepmaria; Kedia, Komal; Gritsenko, Marina; Clemente‐Sánchez, Ana; Asghar, Aliya; Herranz, José M.; Liu, Zhang–Xu; Atkinson, Stephen R.; Smith, Richard D.; Norden-Krichmar, Trina M.; Day, Le; Stolz, Andrew; Tayek, John A.; Bataller, Ramón; Morgan, Timothy R.; Jacobs, Jon

doi:10.1016/j.ajpath.2022.08.009

Cited by 5 publications

(4 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The final models showed that the 3-peptide model was equally accurate in predicting 90-day mortality as the composite one (MELD+3-peptides; Figure 6A). One peptide (APOC1) has been shown to be a marker of AH severity in a recent plasma proteomic study 39 . The other 2 peptides (CALD1 and BIN2) are both cytoskeletal proteins that have not been previously associated with AH and warrant further investigation.…”

Section: Discussionmentioning

confidence: 92%

See 1 more Smart Citation

A plasma peptidomic signature reveals extracellular matrix remodeling and predicts prognosis in alcohol-associated hepatitis

Sayed,

Dolin,

Wilkey

et al. 2024

Hepatology Communications

Self Cite

View full text Add to dashboard Cite

Background: Alcohol-associated hepatitis (AH) is plagued with high mortality and difficulty in identifying at-risk patients. The extracellular matrix undergoes significant remodeling during inflammatory liver injury and could potentially be used for mortality prediction. Methods: EDTA plasma samples were collected from patients with AH (n = 62); Model for End-Stage Liver Disease score defined AH severity as moderate (12–20; n = 28) and severe (>20; n = 34). The peptidome data were collected by high resolution, high mass accuracy UPLC-MS. Univariate and multivariate analyses identified differentially abundant peptides, which were used for Gene Ontology, parent protein matrisomal composition, and protease involvement. Machine-learning methods were used to develop mortality predictors. Results: Analysis of plasma peptides from patients with AH and healthy controls identified over 1600 significant peptide features corresponding to 130 proteins. These were enriched for extracellular matrix fragments in AH samples, likely related to the turnover of hepatic-derived proteins. Analysis of moderate versus severe AH peptidomes was dominated by changes in peptides from collagen 1A1 and fibrinogen A proteins. The dominant proteases for the AH peptidome spectrum appear to be CAPN1 and MMP12. Causal graphical modeling identified 3 peptides directly linked to 90-day mortality in >90% of the learned graphs. These peptides improved the accuracy of mortality prediction over the Model for End-Stage Liver Disease score and were used to create a clinically applicable mortality prediction assay. Conclusions: A signature based on plasma peptidome is a novel, noninvasive method for prognosis stratification in patients with AH. Our results could also lead to new mechanistic and/or surrogate biomarkers to identify new AH mechanisms.

show abstract

Section: Discussionmentioning

confidence: 92%

“…One peptide (APOC1) has been shown to be a marker of AH severity in a recent plasma proteomic study. [39] The other 2 peptides (CALD1 and BIN2) are both cytoskeletal proteins that have not been previously associated with AH and warrant further investigation.…”

Section: Discussionmentioning

confidence: 94%

A plasma peptidomic signature reveals extracellular matrix remodeling and predicts prognosis in alcohol-associated hepatitis

Sayed,

Dolin,

Wilkey

et al. 2024

Hepatology Communications

Self Cite

View full text Add to dashboard Cite

show abstract

“…The final models showed that the 3-peptide model was equally accurate in predicting 90-day mortality as the composite one (MELD+3-peptides; Figure 3C ). One peptide (APOC1) has been shown to be a marker of AH severity in a recent plasma proteomic study [29]. The other two peptides (CALD1 and BIN2) are both cytoskeletal proteins that have not been previously associated with AH and warrant further investigation.…”

Section: Discussionmentioning

confidence: 99%

A plasma peptidomic signature reveals extracellular matrix remodeling and predicts prognosis in alcohol-related hepatitis

Sayed,

Dolin,

Wilkey

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Alcohol-related hepatitis (AH) is plagued with high mortality and difficulty in identifying at-risk patients. The extracellular matrix undergoes significant remodeling during inflammatory liver injury that can be detected in biological fluids and potentially used for mortality prediction. EDTA plasma samples were collected from AH patients (n= 62); Model for End-Stage Liver Disease (MELD) score defined AH severity as moderate (12-20; n=28) and severe (>20; n=34). The peptidome data was collected by high resolution, high mass accuracy UPLC-MS. Univariate and multivariate analyses identified differentially abundant peptides, which were used for Gene Ontology, parent protein matrisomal composition and protease involvement. Machine learning methods were used on patient-specific peptidome and clinical data to develop mortality predictors. Analysis of plasma peptides from AH patients and healthy controls identified over 1,600 significant peptide features corresponding to 130 proteins. These were enriched for ECM fragments in AH samples, likely related to turnover of hepatic-derived proteins. Analysis of moderate versus severe AH peptidomes showed a shift in abundance of peptides from collagen 1A1 and fibrinogen A proteins. The dominant proteases for the AH peptidome spectrum appear to be CAPN1 and MMP12. Increase in hepatic expression of these proteases was orthogonally-validated in RNA-seq data of livers from AH patients. Causal graphical modeling identified four peptides directly linked to 90-day mortality in >90% of the learned graphs. These peptides improved the accuracy of mortality prediction over MELD score and were used to create a clinically applicable mortality prediction assay. A signature based on plasma peptidome is a novel, non-invasive method for prognosis stratification in AH patients. Our results could also lead to new mechanistic and/or surrogate biomarkers to identify new AH mechanisms.Lay summaryWe used degraded proteins found the blood of alcohol-related hepatitis patients to identify new potential mechanisms of injury and to predict 90 day mortality.

show abstract

“…By applying proteome microarrays, one recent study found that livers from patients with sAH contain a large number of autoantibodies that are not present in circulation, and deposition of these antibodies likely participates in sAH inflammation (31). Studies combining transcriptomics with proteomics have identified and validated potential plasma biomarkers of ALD (109,110). Several other studies investigating circulating biomarkers for ALD have identified lncRNAs, small RNAs, metabolites, proteins, and the circulating transcriptome as potential identifiers of ALD (111)(112)(113)(114)(115)(116)(117)(118).…”

Section: Application Of Cutting-edge Technologies In Aldmentioning

confidence: 99%

Alcohol-associated liver disease

Mackowiak,

Fu,

Maccioni

et al. 2024

Journal of Clinical Investigation

View full text Add to dashboard Cite

show abstract

Integrated Transcriptomic and Proteomic Analysis Identifies Plasma Biomarkers of Hepatocellular Failure in Alcohol-Associated Hepatitis

Cited by 5 publications

References 36 publications

A plasma peptidomic signature reveals extracellular matrix remodeling and predicts prognosis in alcohol-associated hepatitis

A plasma peptidomic signature reveals extracellular matrix remodeling and predicts prognosis in alcohol-associated hepatitis

A plasma peptidomic signature reveals extracellular matrix remodeling and predicts prognosis in alcohol-related hepatitis

Alcohol-associated liver disease

Contact Info

Product

Resources

About