| Title: | UK Biobank-Based Genetic and Proteomic Network Insights into Metabolic Dysfunction-Associated Steatotic Liver Disease Pathogenesis |
| Journal: | International Journal of Molecular Sciences |
| Published: | 28 Apr 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42123504/ |
| DOI: | https://doi.org/10.3390/ijms27093920 |
| URL: | https://www.mdpi.com/1422-0067/27/9/3920/pdf?version=1777373520 |
Publication 20209
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized as a systemic disorder shaped by genetic variants and network-level interactions beyond obesity and insulin resistance. This study aimed to define the genetic and proteomic architecture of MASLD by integrating GWAS and plasma proteomic profiling from the UK Biobank. Genome-wide association analyses were conducted under additive and dominant models, with functional annotations performed using SIFT, PolyPhen-2, PROVEAN, REVEL, CADD, MutationTaster, and conservation metrics (GERP++, phyloP, phastCons, and B-statistic). Differential protein expression was assessed using the Olink® platform, and STRING was applied for protein-protein interaction analysis. MASLD patients showed male predominance and significant differences in hepatic (AST, ALT, GGT, PDFF), metabolic (glucose, triglycerides, TyG index), and inflammatory markers (CRP, neutrophils, NLR, CAR). GWAS confirmed PNPLA3 (rs738409, I148M) and TM6SF2 (rs58542926, E167K) as major risk variants, while SAMM50 and NCAN showed weaker but conserved associations. Proteomics revealed downregulation of IGFBP2, IGFBP1, PON3, CKB, and APOF and upregulation of CPM, IGSF9, GUSB, ACY1, AFM, LEP, and GSTA1/3. PPI analysis identified ADIPOQ, LEP, FGF21, and ADH1B as central hubs in metabolic and inflammatory regulation. MASLD should be regarded as a network disease involving lipid metabolism, insulin/IGF signaling, mitochondrial function, and ECM-inflammatory pathways. These findings highlight PNPLA3 and TM6SF2 as major genetic drivers, while SAMM50, NCAN, and peripheral proteins contribute regulatory roles, suggesting novel biomarkers and therapeutic targets.</p>
20 Keywords
- Acyltransferases
- Aged
- Biological Specimen Banks
- Biomarkers
- Fatty Liver
- Female
- Gene Regulatory Networks
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Humans
- Lipase
- Male
- Membrane Proteins
- Middle Aged
- Phospholipases A2, Calcium-Independent
- Polymorphism, Single Nucleotide
- Protein Interaction Maps
- Proteomics
- UK Biobank
- United Kingdom
4 Authors
- Sang Wook Kang
- Su Kang Kim
- Ju Yeon Ban
- Min Su Park
Enabling scientific discoveries that improve human health