PUBLICATION
Genome-wide interaction study with BMI identifies CYP7A1 and GIPR as genetic modulators of MASLD
- Authors
- Jamialahmadi, O., Mujica, E., Morris, L., Mancina, R.M., Ciociola, E., Qadri, S.F., Maurotti, S., Malvestiti, F., Li-Gao, R., Ronzoni, L., Tavaglione, F., Maude, H., Allalou, A., Emmanouilidou, A., Vespasiani-Gentilucci, U., Rosendaal, F.R., Yki-Järvinen, H., Cebola, I., Valenti, L., den Hoed, M., Romeo, S.
- ID
- ZDB-PUB-250602-7
- Date
- 2025
- Source
- Clinical and molecular hepatology : (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Adaptor Proteins, Signal Transducing
- Aged
- Alanine Transaminase/blood
- Animals
- Body Mass Index*
- Cholesterol 7-alpha-Hydroxylase*/genetics
- Cholesterol 7-alpha-Hydroxylase*/metabolism
- Fatty Liver*/genetics
- Fatty Liver*/pathology
- Female
- Genome-Wide Association Study*
- Humans
- Liver/metabolism
- Liver/pathology
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
- Zebrafish
- PubMed
- 40452229 Full text @ Clin Mol Hepatol
Citation
Jamialahmadi, O., Mujica, E., Morris, L., Mancina, R.M., Ciociola, E., Qadri, S.F., Maurotti, S., Malvestiti, F., Li-Gao, R., Ronzoni, L., Tavaglione, F., Maude, H., Allalou, A., Emmanouilidou, A., Vespasiani-Gentilucci, U., Rosendaal, F.R., Yki-Järvinen, H., Cebola, I., Valenti, L., den Hoed, M., Romeo, S. (2025) Genome-wide interaction study with BMI identifies CYP7A1 and GIPR as genetic modulators of MASLD. Clinical and molecular hepatology. :.
Abstract
Background 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.
Objective We sought to identify novel genetic determinants of MASLD by exploring interactions between genetic variants and body mass index (BMI).
Design 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.
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.
Conclusion A genome-wide SNPxBMI design fuelled identification of two MASLD genes: CYP7A1 and GIPR.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping