To classify patients with metabolic dysfunction-associated steatotic liver disease (MASLD) into subgroups with distinct genetic profiles and disease trajectories.
Approach:
Study Design: Retrospective analysis of electronic health record-linked genomic data from the Mayo Clinic Biobank and Tapestry Study.
Cohorts: Mayo Clinic cohort included 2,042 patients; Tapestry cohort included 2,560 patients after excluding those with incomplete clinical data.
Subgroup Analysis: Latent class analysis of 13 clinical and demographic variables to derive subgroups and evaluate their reproducibility.
Key Findings:
Five subgroups identified: C1 (cardiometabolic MASLD without obesity), C2 (male-predominant cardiorenal MASLD), C3 (female-predominant MASLD with obesity and mood disorders), C4 (polygenic MASLD), C5 (polygenic MASH).
C4 had a mild metabolic profile but substantial liver-specific risk, with a 16% likelihood of liver transplantation over 10 years in the Mayo cohort and 10% in Tapestry.
C5 showed a liver-dominant disease trajectory with elevated risks for MASH, fibrosis, and acute renal failure compared to C1.
Interpretation:
Integrating clinical and genetic information may help distinguish heterogeneous MASLD phenotypes and their differing patterns of progression.
Limitations:
Analysis included only clinical variables significantly associated with MASLD, potentially excluding other informative measures.
Requiring complete clinical data may have limited characterization of disease progression.
Subgroup assignment may have been influenced by probabilities derived from the development cohort.
Conclusion:
Further research is needed to address uncertainty in subgroup assignment and evaluate the framework in additional settings.
In an observational US target trial emulation, glucagon-like peptide-1 receptor agonist initiation was associated with about 3 to 4 more ischemic optic neuropathy cases per 10,000 patients over 18 months than two comparator drug classes.
A living clinical guideline outlines a treatment hierarchy for selected pharmacologic therapies in patients with obesity and selected patients with overweight.
