Affinity Proteomics‐Based Non‐Invasive Detection of Clinically Significant Liver Disease

Alimentary Pharmacology & Therapeutics, vol. 64, pp. 74–88

Abstract

BACKGROUND: Non-invasive biomarkers predicting major adverse liver outcomes (MALO) are urgently needed. AIMS: We assessed a novel, proximity extension assay-based high-throughput targeted proteomics. METHODS: Plasma proteomic data (> 2900 proteins) and clinical information were accessed from the population-based UK Biobank cohort, comprising ~52,000 individuals with a median follow-up of > 10 years, including obese (~12,700) and diabetic (~1500) participants. Validation cohorts comprised 287 participants with severe alpha1-antitrypsin deficiency (Pi*ZZ genotype), and 960 people living with HIV, who underwent liver stiffness measurement (LSM) via transient elastography. Selected proteomic parameters were compared to routine measurements. Bayes-moderated linear models (covariates: age and sex) assessed the differential abundance. Logistic regression was used to develop and validate a prognostic score. RESULTS: Routine gamma-glutamyltransferase (GGT) and aspartate aminotransferase (AST) strongly correlated with proteomic measurements (r = 0.92 and r = 0.71, respectively). Similarly, proteomic-based thrombospondin-2 levels correlated with immunoassay-based values (r = 0.85). Twenty proteins were consistently associated with future MALOs/increased liver stiffness in all cohorts. A novel five-component proteomic score derived from the UK Biobank cohort demonstrated superior predictive power for MALOs (AUROC = 0.84) compared to AST-to-platelet-ratio index (AUROC = 0.73) and Fibrosis-4 index (AUROC = 0.72), with stable performance in obese and diabetic subcohorts. In people living with HIV and alpha1-antitrypsin deficiency patients, all five components increased across fibrosis stages and the proteomic score outperformed AST-to-platelet-ratio/Fibrosis-4 index in predicting significant LSM-based liver fibrosis. CONCLUSIONS: We identify a new proteomic score comprising epithelial/hepatic stellate cell markers that yields a robust predictive performance across different liver disease aetiologies. Thereby, we demonstrate the usefulness of emerging proteomic techniques in hepatology. TRIAL REGISTRATION: The registry study is listed at ClinicalTrials.gov (NCT02929940).

Authors 14

1. Sriram Balasubramani Aachen Medical Clinic III

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), University Hospital RWTH Aachen Aachen Germany

2. Katharina Remih Aachen Medical Clinic III

   Universitätsklinikum Aachen · Medizinische Universität Lausitz - Carl Thiem · RWTH Aachen University

   Affiliation as printed

   Department of Gastroenterology and Hepatology Medical University Lausitz‐Carl‐Thiem Cottbus Germany

   Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), University Hospital RWTH Aachen Aachen Germany

3. Anna Sophie Karl Aachen Medical Clinic III

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), University Hospital RWTH Aachen Aachen Germany

4. Julia Borchert Aachen Medical Clinic III

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), University Hospital RWTH Aachen Aachen Germany

5. Christina Schrader Aachen Medical Clinic III

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), University Hospital RWTH Aachen Aachen Germany

6. Malin Fromme Aachen Medical Clinic III

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), University Hospital RWTH Aachen Aachen Germany

7. Can Kayatekin
   Affiliation as printed

   Sanofi Cambridge Massachusetts USA

8. Mikhail N. Levit
   Affiliation as printed

   Sanofi Cambridge Massachusetts USA

9. Pavithra Krishnaswami
   Affiliation as printed

   Sanofi Cambridge Massachusetts USA

10. Louise E. van Eekeren

    Radboud University Nijmegen · Radboud University Medical Center

    Affiliation as printed

    Department of Internal Medicine Radboud University Medical Centre Nijmegen the Netherlands

11. Leo A. B. Joosten

    Radboud University Nijmegen · Iuliu Hațieganu University of Medicine and Pharmacy · Radboud University Medical Center

    Affiliation as printed

    Department of Internal Medicine Radboud University Medical Centre Nijmegen the Netherlands

    Department of Medical Genetics Iuliu Hatieganu University of Medicine and Pharmacy Cluj‐Napoca Romania

12. Twan Otten

    Radboud University Nijmegen · Radboud University Medical Center

    Affiliation as printed

    Department of Internal Medicine Radboud University Medical Centre Nijmegen the Netherlands

13. Petra Tomanová

    Prague University of Economics and Business

    Affiliation as printed

    Prague University of Economics and Business Prague Czech Republic

14. Pavel Strnad corresponding Aachen Medical Clinic III

    Universitätsklinikum Aachen · Medizinische Universität Lausitz - Carl Thiem · RWTH Aachen University

    Affiliation as printed

    Department of Gastroenterology and Hepatology Medical University Lausitz‐Carl‐Thiem Cottbus Germany

    Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), University Hospital RWTH Aachen Aachen Germany