TY - JOUR
T1 - An integrated gene-to-outcome multimodal database for metabolic dysfunction-associated steatotic liver disease
AU - Kendall, Timothy J.
AU - Jimenez-Ramos, Maria
AU - Turner, Frances
AU - Ramachandran, Prakash
AU - Minnier, Jessica
AU - McColgan, Michael D.
AU - Alam, Masood
AU - Ellis, Harriet
AU - Dunbar, Donald R.
AU - Kohnen, Gabriele
AU - Konanahalli, Prakash
AU - Oien, Karin A.
AU - Bandiera, Lucia
AU - Menolascina, Filippo
AU - Juncker-Jensen, Anna
AU - Alexander, Douglas
AU - Mayor, Charlie
AU - Guha, Indra Neil
AU - Fallowfield, Jonathan A.
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/11
Y1 - 2023/11
N2 - 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.
AB - 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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U2 - 10.1038/s41591-023-02602-2
DO - 10.1038/s41591-023-02602-2
M3 - Article
C2 - 37903863
AN - SCOPUS:85175163805
SN - 1078-8956
VL - 29
SP - 2939
EP - 2953
JO - Nature medicine
JF - Nature medicine
IS - 11
ER -