| Title: | Genome-wide interaction study with BMI identifies CYP7A1 and GIPR as genetic modulators of MASLD |
| Journal: | Clinical and Molecular Hepatology |
| Published: | 2 Jun 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40452229/ |
| DOI: | https://doi.org/10.3350/cmh.2025.0159 |
| URL: | https://www.e-cmh.org/upload/pdf/cmh-2025-0159.pdf |
Publication 15103
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Abstract
BACKGROUND/AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) may progress to liver inflammation, fibrosis, cirrhosis and hepatocellular carcinoma. So far, genome-wide association studies explain a small fraction of MASLD heritability.</p>
METHODS: We sought to identify novel genetic determinants of MASLD by exploring interactions between genetic variants and body mass index (BMI). First, we examined genome-wide interactions with BMI for circulating alanine aminotransferase (ALT) levels using UK Biobank data. For identified loci, we next examined associations with hepatic proton density fat fraction (PDFF) in 35,146 independent UK Biobank participants. Associations with PDFF were replicated in four independent European cohorts, followed by a phenome-wide association study. Finally, we used human liver epigenomic maps and CRISPR/Cas9 experiments in vitro and in vivo to functionally characterize the CYP7A1 locus.</p>
RESULTS: Thirteen loci interact with BMI for ALT (P<5E-8), including eight well-known genetic modulators of MASLD. Two loci-UBXN2B/CYP7A1 and GIPR-are additionally associated with PDFF. For the intronic rs34783010 in GIPR, the minor T allele is associated with lower BMI and higher HbA1c and liver triglyceride content in humans. The UBXN2B/CYP7A1 locus is associated with PDFF in four additional European cohorts. Epigenomic data and in vitro experiments in human liver cells prioritise rs10504255 and CYP7A1 as the functional effectors in this locus. Perturbation of CYP7A1 orthologues using CRISPR/Cas9 results in less liver fat in 10-day-old, metabolically challenged zebrafish larvae.</p>
CONCLUSION: A genome-wide single nucleotide polymorphism×BMI design fuelled identification of two MASLD genes: CYP7A1 and GIPR.</p>
15 Keywords
- Adaptor Proteins, Signal Transducing
- Aged
- Alanine Transaminase
- Animals
- Body Mass Index
- Cholesterol 7-alpha-Hydroxylase
- Fatty Liver
- Female
- Genome-Wide Association Study
- Humans
- Liver
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
- Zebrafish
21 Authors
- Oveis Jamialahmadi
- Endrina Mujica
- Lowri Morris
- Rosellina Margherita Mancina
- Ester Ciociola
- Sami F. Qadri
- Samantha Maurotti
- Francesco Malvestiti
- Ruifang Li-Gao
- Luisa Ronzoni
- Federica Tavaglione
- Hannah Maude
- Amin Allalou
- Anastasia Emmanouilidou
- Umberto Vespasiani-Gentilucci
- Frits Richard Rosendaal
- Hannele Yki-Järvinen
- Inês Cebola
- Luca Valenti
- Marcel den Hoed
- Stefano Romeo
1 Application
| Application ID | Title |
|---|---|
| 37142 | UNDERSTANDING THE GENETIC ARCHITECTURE OF CHRONIC LIVER DISEASE |
Enabling scientific discoveries that improve human health