Proteome profiling identifies circulating biomarkers associated with hepatic steatosis in subjects with Prader-Willi syndrome

Front Endocrinol (Lausanne). 2023 Nov 15:14:1254778. doi: 10.3389/fendo.2023.1254778. eCollection 2023.

Abstract

Introduction: Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by loss of expression of paternal chromosome 15q11.2-q13 genes. Individuals with PWS exhibit unique physical, endocrine, and metabolic traits associated with severe obesity. Identifying liver steatosis in PWS is challenging, despite its lower prevalence compared to non-syndromic obesity. Reliable biomarkers are crucial for the early detection and management of this condition associated with the complex metabolic profile and cardiovascular risks in PWS.

Methods: Circulating proteome profiling was conducted in 29 individuals with PWS (15 with steatosis, 14 without) using the Olink Target 96 metabolism and cardiometabolic panels. Correlation analysis was performed to identify the association between protein biomarkes and clinical variables, while the gene enrichment analysis was conducted to identify pathways linked to deregulated proteins. Receiver operating characteristic (ROC) curves assessed the discriminatory power of circulating protein while a logistic regression model evaluated the potential of a combination of protein biomarkers.

Results: CDH2, CTSO, QDPR, CANT1, ALDH1A1, TYMP, ADGRE, KYAT1, MCFD, SEMA3F, THOP1, TXND5, SSC4D, FBP1, and CES1 exhibited a significant differential expression in liver steatosis, with a progressive increase from grade 1 to grade 3. FBP1, CES1, and QDPR showed predominant liver expression. The logistic regression model, -34.19 + 0.85 * QDPR*QDPR + 0.75 * CANT1*TYMP - 0.46 * THOP1*ALDH1A, achieved an AUC of 0.93 (95% CI: 0.63-0.99), with a sensitivity of 93% and specificity of 80% for detecting steatosis in individuals with PWS. These biomarkers showed strong correlations among themselves and were involved in an interconnected network of 62 nodes, related to seven metabolic pathways. They were also significantly associated with cholesterol, LDL, triglycerides, transaminases, HbA1c, FLI, APRI, and HOMA, and showed a negative correlation with HDL levels.

Conclusion: The biomarkers identified in this study offer the potential for improved patient stratification and personalized therapeutic protocols.

Keywords: MAFLD CDH2; PWS; cardiovascular; circulating biomarkers; metabolic; proteome; proteomics; steatosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers
  • Fatty Liver* / diagnosis
  • Humans
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Obesity / complications
  • Prader-Willi Syndrome* / complications
  • Prader-Willi Syndrome* / diagnosis
  • Prader-Willi Syndrome* / genetics
  • Proteome

Substances

  • Proteome
  • Biomarkers
  • SEMA3F protein, human
  • Membrane Proteins
  • Nerve Tissue Proteins

Grants and funding

This work was supported by the Italian Ministry of Health – ricerca corrente. DP was supported from Programma di Cooperazione Interreg V-A Italia-Slovenia 2014-2020 - Bando mirato per progetti standard n. 07/2019 - Progetto “C3B” CUP J95F19000490006, and an intramural grant from the Italian Liver Foundation. PJG was sponsored by a fellowship from Area Science Park concerning the project QuB – Quantum Behavior in Biological Function funded by MUR (CUP J95F21002820001).