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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.·2023·Nature Medicine
DOI 10.1038/s41591-023-02602-2PMC PMC10667096

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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.

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Metadata

Authors
Kendall, T. J., Jimenez-Ramos, M., Turner, F., Ramachandran, P., Minnier, J., McColgan, M. D., Alam, M., Ellis, H., Dunbar, D. R., Kohnen, G., Konanahalli, P., Oien, K. A., Bandiera, L., Menolascina, F., Juncker-Jensen, A., Alexander, D., Mayor, C., Guha, I. N., & Fallowfield, J. A.
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2023-10-30
Volume
29
Issue
11
Pages
2939-2953
ISSN
  • 1078-8956
  • 1546-170X
DOI
10.1038/s41591-023-02602-2
PMC
PMC10667096
Cited by
92
References
17
Language
en
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