| Title: | Proteomic signature of metabolic dysfunction-associated steatotic liver disease and risk of atherosclerotic cardiovascular disease |
| Journal: | Cardiovascular Diabetology |
| Published: | 14 Dec 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41392280/ |
| DOI: | https://doi.org/10.1186/s12933-025-03034-7 |
Publication 17174
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Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with increased atherosclerotic cardiovascular disease (ASCVD) risk. However, evidence on proteomic mechanisms linking MASLD to ASCVD is limited. This study aims to identify proteomic signatures of MASLD and ASCVD subtypes (ischemic heart disease [IHD], peripheral artery disease [PAD], and stroke), evaluate mediating effects of proteins, and develop a proteomic-based ASCVD risk prediction model in MASLD patients. Among 40,913 UK Biobank participants (median follow-up 13.42 years [interquartile range, 12.52-14.22]), 14,425 (35.26%) had MASLD at baseline, and 6,014 (14.70%) developed ASCVD during follow-up (4,420 IHD, 866 PAD, and 1,767 stroke events; subtypes not mutually exclusive). We constructed a binary variable representing proteomics-inferred MASLD (cProMASLD) from MASLD-associated proteins. Two-step Mendelian randomization was applied to assess the mediating effects of proteins associated with MASLD and ASCVD subtypes. Furthermore, we integrated the all shared proteins associated with both MASLD and ASCVD subtypes into the conventional SCORE2 model to develop a prediction model specifically for ASCVD subtypes in the MASLD population, named Pro-SCORE2. Both MASLD and cProMASLD were significantly associated with an increased risk of ASCVD subtypes, with stronger associations observed for cProMASLD (IHD: HR 1.50 [95% CI 1.41-1.60] vs. 1.58 [1.48-1.68]; PAD: 1.25 [1.09-1.44] vs. 1.43 [1.24-1.64]; stroke: 1.19 [1.08-1.31] vs. 1.21[1.10-1.34]). After adjusting for MASLD, cProMASLD remained positively associated with ASCVD risk. This suggests that cProMASLD may capture MASLD-related physiological heterogeneity beyond clinical MASLD classification. We found 15, 3, and 3 proteins mediating the associations of MASLD with IHD, PAD, and stroke, respectively, including FABP4 (MASLD-IHD, mediation proportion: 15.12%), IL7R (MASLD-PAD, 7.45%), and EDA2R (MASLD-stroke, 9.24%). The Pro-SCORE2 significantly improved ASCVD risk prediction in the MASLD population, with a c-index increase of 7.5-9.6% and a 10-year AUC increase of 5.8-9.2% compared to SCORE2. These findings may offer new insights for risk stratification and potential therapeutic targets for ASCVD in MASLD patients.</p>
19 Keywords
- Adult
- Aged
- Atherosclerosis
- Biomarkers
- Fatty Liver
- Female
- Humans
- Male
- Mendelian Randomization Analysis
- Middle Aged
- Peripheral Arterial Disease
- Predictive Value of Tests
- Prognosis
- Proteomics
- Risk Assessment
- Risk Factors
- Stroke
- Time Factors
- United Kingdom
7 Authors
- Lulu Pan
- Mujie Shen
- Yahang Liu
- Chen Huang
- Ruilang Lin
- Guoyou Qin
- Yongfu Yu
1 Application
| Application ID | Title |
|---|---|
| 98410 | The integration of epidemiological and genomic data to examine the relationship between early life exposure and aging-associated health outcomes later in life |
Enabling scientific discoveries that improve human health