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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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, as well as facilitating precision medicine approaches for patients with MASLD.
Original languageEnglish
Pages (from-to)2939–2953
JournalNature Medicine
Issue number11
Publication statusPublished - 30 Oct 2023


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