Genetic Drivers of Steatosis and Cardiovascular Health, With Andrea Branch, PhD

The relationship between metabolic-associated steatotic liver disease (MASLD) and cardiovascular disease has long been observed, but the mechanisms driving this connection have proven difficult to untangle.

In a session at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025, Andrea Branch, PhD, a professor of medicine in the division of liver diseases and an associate professor of surgery at Icahn School of Medicine at Mount Sinai, broke down recent advancements in the field’s understanding of different genetic variants driving steatosis and their impact on cardiovascular risk or protection.

“The bottom line from my talk, which was largely the work of other people… [was] the variants, the increased steatosis, and the fact that they segregate into these 2 clusters: one increases liver fat and increases triglycerides, concordant a second set of genetic variants that increase liver fat, decrease serum triglycerides, and decrease cardiovascular disease,” Branch explained to HCPLive. “It's possible to tell where an individual patient is on the spectrum of genomic risk for one set or the other by doing genomic analysis.”

By calculating a polygenic risk score from a patient’s genomic profile, Branch says clinicians may be able to assess whether an individual’s liver fat pattern skews toward the concordant or discordant category. The emergence of Mendelian randomization research has enabled this progress, allowing researchers to separate the inherent genetic risk for liver fat accumulation from lifestyle or environmental influences such as excess adiposity by using genetic variation as a natural randomization tool.

“I think it's likely that a person's genomic makeup will be part of deciding on interventions,” Branch said, referencing a University of Michigan study showing that individuals with a certain variant in the PNPLA3 gene had a greater reduction in markers of liver injury when treated with GLP-1 receptor agonists, indicating that genomic background may influence treatment efficacy.

The discussion is also broadening beyond germline genetics, with Branch emphasizing that mitochondrial mutations and somatic mutations appear to be early markers of cellular injury. She points to recent data showing that somatic mutations appear early in MASLD, before advanced fibrosis is detectable, highlighting the need for earlier intervention.

As the field moves toward more personalized approaches, genomic insights may soon help guide both risk assessment and therapeutic strategy, allowing earlier and more targeted management of MASLD.

Editors’ note: Branch reports no relevant disclosures.

References

1. Zheng M, Allington G, Vilarinho S. Genomic medicine for liver disease. Hepatology. 2022;76(3):860-868. doi:10.1002/hep.32364

2. Urias E, Tedesco NR, Oliveri A, et al. PNPLA3 Risk Allele Association With ALT Response to Semaglutide Treatment. Gastroenterology. 2024;166(3):515-517.e2. doi:10.1053/j.gastro.2023.11.018