| Title: | Proteomic insights into metabolic dysfunction-associated steatotic disease: Identifying therapeutic targets and assessing on-target side effects |
| Journal: | Life Sciences |
| Published: | 24 Apr 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40287056/ |
| DOI: | https://doi.org/10.1016/j.lfs.2025.123665 |
Publication 15760
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Abstract
AIMS: The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is rising sharply, yet treatment options remain inadequate. To uncover new therapeutic targets for MASLD, we conducted a comprehensive proteome-wide Mendelian randomization (MR) and phenome-wide association study (PheWAS).</p>
MATERIALS AND METHODS: Discovery MR utilized protein quantitative trait loci (pQTL) data on 4907 plasma protein levels from 35,559 individuals, alongside genome-wide association study (GWAS) on MASLD from the Million Veteran Program (68,725 cases / 95,482 controls). Validation comprised five pairwise combinations of these discovery datasets with three additional datasets: pQTL data for 2923 proteins from the UK Biobank, and liver biopsy-confirmed MASLD GWAS (1483 cases/17,781 controls) and MRI-liver fat GWAS (31,377 subjects) (excluding discovery pair). Candidate proteins underwent druggability assessment and on-target side effect evaluation via PheWAS.</p>
KEY FINDINGS: We identified 26 proteins associated with MASLD after Bonferroni correction (P < 1.16 × 10-5), with 19 of them showing no significant reverse association. Interleukin-6 (IL-6), alpha-1-antitrypsin (α1-antitrypsin), 5-hydroxytryptamine receptor 7 (5-HT7R), ephrin-B1 (EFNB1), and protein MENT (CA056) were replicated. Notably, IL-6 (OR = 2.02; 95 % CI 1.54-2.64), 5-HT7R (OR = 2.73; 95 % CI 1.96-3.80), and EFNB1 (OR = 1.82; 95 % CI 1.59-2.08) were positively associated with MASLD risk, whereas α1-antitrypsin (OR = 0.84; 95 % CI 0.78-0.90) and CA056 (OR = 0.90; 95 % CI 0.86-0.94) appeared protective. Among these, IL-6, 5-HT7R, and α1-antitrypsin were druggable. PheWAS identified potential cardiovascular side effects for 5-HT7R and α1-antitrypsin.</p>
SIGNIFICANCE: The integrative study identified several plasma proteins associated with MASLD. IL-6, α1-antitrypsin, 5-HT7R, EFNB1 and CA056 deserve further investigation as potential drug targets for MASLD.</p>
12 Keywords
- Aged
- Fatty Liver
- Female
- Genome-Wide Association Study
- Humans
- Male
- Mendelian Randomization Analysis
- Middle Aged
- Proteome
- Proteomics
- Quantitative Trait Loci
- alpha 1-Antitrypsin
10 Authors
- Luojia Dai
- Zhenqiu Liu
- Chengnan Guo
- Hong Fan
- Chengjun Zhang
- Jiayi Huang
- Xin Zhang
- Shuzhen Zhao
- Haili Wang
- Tiejun Zhang
1 Application
| Application ID | Title |
|---|---|
| 92718 | Deciphering chronic disease - association studies of genome, exposome and phenome |
Enabling scientific discoveries that improve human health