Objective:

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.

Sources:

• Nature Communications