An integrated gene-to-outcome multimodal database for metabolic dysfunction-associated steatotic liver disease

Kendall, Timothy J.; Jimenez-Ramos, Maria; Turner, Frances; Ramachandran, Prakash; Minnier, Jessica; McColgan, Michael D.; Alam, Masood; Ellis, Harriet; Dunbar, Donald R.; Kohnen, Gabriele; Konanahalli, Prakash; Oien, Karin A.; Bandiera, Lucia; Menolascina, Filippo; Juncker-Jensen, Anna; Alexander, Douglas; Mayor, Charlie; Guha, Indra Neil; Fallowfield, Jonathan A.

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the commonest cause of chronic liver disease worldwide and represents an unmet precision medicine challenge. We established a retrospective national cohort of 940 histologically defined patients (55.4% men, 44.6% women; median body mass index 31.3; 32% with type 2 diabetes) covering the complete MASLD severity spectrum, and created a secure, searchable, open resource (SteatoSITE). In 668 cases and 39 controls, we generated hepatic bulk RNA sequencing data and performed differential gene expression and pathway analysis, including exploration of gender-specific differences. A web-based gene browser was also developed. We integrated histopathological assessments, transcriptomic data and 5.67 million days of time-stamped longitudinal electronic health record data to define disease-stage-specific gene expression signatures, pathogenic hepatic cell subpopulations and master regulator networks associated with adverse outcomes in MASLD. We constructed a 15-gene transcriptional risk score to predict future hepatic decompensation events (area under the receiver operating characteristic curve 0.86, 0.81 and 0.83 for 1-, 3- and 5-year risk, respectively). Additionally, thyroid hormone receptor beta regulon activity was identified as a critical suppressor of disease progression. SteatoSITE supports rational biomarker and drug development and facilitates precision medicine approaches for patients with MASLD.

Citation

Kendall, T. J., Jimenez-Ramos, M., Turner, F., Ramachandran, P., Minnier, J., McColgan, M. D., …Fallowfield, J. A. (2023). An integrated gene-to-outcome multimodal database for metabolic dysfunction-associated steatotic liver disease. Nature Medicine, 29, 2939–2953. https://doi.org/10.1038/s41591-023-02602-2

• Journal Article Type: Article
• Acceptance Date: Sep 20, 2023
• Online Publication Date: Oct 30, 2023
• Publication Date: Oct 30, 2023
• Deposit Date: Oct 31, 2023
• Publicly Available Date: Oct 31, 2023
• Journal: Nature Medicine
• Print ISSN: 1078-8956
• Electronic ISSN: 1546-170X
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 29
• Pages: 2939–2953
• DOI: https://doi.org/10.1038/s41591-023-02602-2
• Keywords: General Biochemistry, Genetics and Molecular Biology, General Medicine
• Public URL: https://nottingham-repository.worktribe.com/output/26799939
• Publisher URL: https://www.nature.com/articles/s41591-023-02602-2