Genotype-First Approach Identifies an Association between rs28374544/FOG2S657G and Liver Disease through Alterations in mTORC1 Signaling
Abstract
:1. Introduction
2. Results
2.1. FOG2S657G Is Associated with Liver Injury and Disease in Multiple Biobank Populations
2.2. Genomic Analysis from a Cohort of Induced Pluripotent Stem Cell Lines Differentiated into Hepatocytes Idenfies an Association between FOG2S657G and mTORC1 Pathway
2.3. Functional In Vitro Studies of FOG2S657G Overexpression in Huh7 Cells Confirm Regulation of mTORC1, DNL, and TG Synthesis
2.4. FOG2S657G Cells Have Reduced Oxidative Phosphorylation in iHeps and Huh7 Cells
3. Discussion
4. Methods
4.1. Meta-Analysis of Biobanks
4.2. Plasma Protein Measurements
4.3. Analysis of Published iPSC-Hepatocyte Data
4.4. Huh7 Cell Culture and Transfection
4.5. Gene Expression
Primer | Sequence |
FOG2 F | TGCTGGACTATCACGAGTGC |
FOG2 R | GACATCAGGGCTGTTTCGTT |
FASN F | CTTCCGAGATTCCATCCTACGC |
FASN R | TGGCAGTCAGGCTCACAAACG |
ACACA F | GGAGAGCATGTCCAATGTTCC |
ACACA R | CGTCCTGTTCATTTCGTGCAA |
GPAM F | TCTTTGGGTTTGCGGAATGTT |
GPAM R | ATGCACATCTCGCTCTTGAATAA |
B2M F | GAGGCTATCCAGCGTACTCCA |
B2M R | CGGCAGGCATACTCATCTTTT |
UBC F | GTGGTGCGTCCAGAGAGAC |
UBC R | GGCCTTCGCCATATCCTTTTC |
IPO8 F | TCCGAACTATTATCGACAGGACC |
IPO8 R | GTTCAAAGAGCCGAGCTACAA |
4.6. Western Blot
4.7. TG Mass Assay
4.8. TG Synthesis Assay
4.9. Seahorse Bioanalyzer Assay
4.10. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Source | Measurement | β | p-Value | Case (N) | Total (N) |
---|---|---|---|---|---|
Genebass | Liver Failure/Cirrhosis | +4.288 | 0.0053 | 234 | 367,963 |
Meta-analysis: PennMedicine Biobank, All of Us, Million Veterans Program | Cirrhosis of the liver without mention of alcohol | +0.068 | 0.01239 | 5665 | 171,129 |
PennMedicine Biobank | Plasma alanine transaminase | +0.23 | 0.03 | 102 | 389 |
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Conlon, D.M.; Kanakala, S.; Cherlin, T.; Ko, Y.-A.; Vitali, C.; Gurunathan, S.; Venkatesh, R.; Woerner, J.; Guare, L.A.; Biobank, P.M.; et al. Genotype-First Approach Identifies an Association between rs28374544/FOG2S657G and Liver Disease through Alterations in mTORC1 Signaling. Genes 2024, 15, 1098. https://doi.org/10.3390/genes15081098
Conlon DM, Kanakala S, Cherlin T, Ko Y-A, Vitali C, Gurunathan S, Venkatesh R, Woerner J, Guare LA, Biobank PM, et al. Genotype-First Approach Identifies an Association between rs28374544/FOG2S657G and Liver Disease through Alterations in mTORC1 Signaling. Genes. 2024; 15(8):1098. https://doi.org/10.3390/genes15081098
Chicago/Turabian StyleConlon, Donna M., Siri Kanakala, Tess Cherlin, Yi-An Ko, Cecilia Vitali, Sharavana Gurunathan, Rasika Venkatesh, Jakob Woerner, Lindsay A. Guare, Penn Medicine Biobank, and et al. 2024. "Genotype-First Approach Identifies an Association between rs28374544/FOG2S657G and Liver Disease through Alterations in mTORC1 Signaling" Genes 15, no. 8: 1098. https://doi.org/10.3390/genes15081098