Genetics of MASLD: a diabetes perspective

Area of Science:

• Genetics and Metabolic Diseases
• Hepatology
• Diabetes Research

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) is common in type 2 diabetes, but its clinical course is unpredictable.
• Conventional risk factors do not fully explain the heterogeneity of MASLD in diabetic patients.
• Human genetic studies reveal distinct biological pathways underlying hepatic steatosis and its complications.

Purpose of the Study:

• To review the genetic architecture of hepatic steatosis and MASLD in the context of type 2 diabetes.
• To explore how genetic variations influence disease mechanisms, clinical outcomes, and treatment responses.
• To discuss the translational implications of MASLD genetics for patient management and therapeutic development.

Main Methods:

• Review of family studies, genome-wide association studies (GWAS), imaging genetics, and Mendelian randomization.
• Analysis of genetic loci affecting liver fat, disease severity, and progression.
• Examination of gene-diabetes and gene-environment interactions.

Main Results:

• Multiple genetic loci influence liver fat accumulation and MASLD progression through diverse mechanisms.
• Genetic variations contribute to heterogeneous clinical presentations and outcomes in diabetic patients with MASLD.
• Similar degrees of liver fat can reflect different underlying biological processes with varying clinical implications.

Conclusions:

• Genetic evidence supports a mechanism-based framework for understanding MASLD heterogeneity in diabetes.
• Genetics offers a foundation for more precise risk stratification and personalized management strategies.
• Future research needs ancestry-diverse studies, improved phenotyping, and integration of genetic data into clinical trials.