Unlocking new hope for treating liver disease with genetics

A review has shed light on how genetics can unlock new therapeutic strategies for metabolic dysfunction-associated steatotic liver disease (MASLD), a leading cause of chronic liver disease affecting over one-third of adults worldwide. Researchers led by Dr. Shan Luo from The University of Hong Kong delved into drug-target Mendelian randomization (MR). This innovative method utilizes human genetic data to uncover and validate drug targets. Published in eGastroenterology, this study could pave the way for a new era of precision medicine in hepatology.

MASLD represents a significant public health burden, with its progression linked to metabolic dysfunction. While recent advances in diagnostic criteria and nomenclature have enhanced our understanding of the disease, therapeutic development has lagged. Despite the recent approval of resmetirom, the first treatment for non-cirrhotic MASLD by the U.S. Food and Drug Administration, most investigational drugs fail to reach clinical application. This review highlights the critical need for more efficient and targeted approaches to drug discovery.

Mendelian randomization offers a promising solution. By leveraging naturally occurring genetic variations, this method mimics randomized controlled trials, minimizing confounding factors and enabling researchers to draw causal inferences about the effects of potential drug targets. "Drug targets validated through human genetic evidence are 2.6 times more likely to succeed in clinical trials," said Dr. Luo. The study emphasizes how MR can enhance drug development pipelines by identifying promising targets, evaluating drug repositioning opportunities, and predicting adverse effects.

The review outlines the principles and challenges of designing drug-target MR studies, emphasizing three core assumptions. First, genetic variants must be associated with the target trait—for example, protein expression levels influenced by genetic loci. Second, the association must not be confounded by other factors. Finally, the genetic variant should influence the disease outcome solely through the target trait.

One of the most exciting aspects of drug-target MR is its application to identifying and validating targets for MASLD therapies. The study describes how researchers use genome-wide association studies (GWAS) and proteomic data to pinpoint potential drug targets. Notably, variants influencing the lipoprotein lipase (LPL) pathway were identified as promising candidates for reducing MASLD risk. LPL regulates triglyceride hydrolysis, and its activation could mitigate fat accumulation in the liver, a hallmark of MASLD.

Another area explored is the repositioning of existing drugs for MASLD treatment. For instance, antidiabetic agents such as glucagon-like peptide-1 receptor (GLP-1R) agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors, initially designed for glycemic control, show potential in addressing MASLD due to their broader metabolic effects. Drug-target MR enables researchers to assess the suitability of such therapies for MASLD by analyzing genetic proxies for drug action.

The review also highlights the application of MR in evaluating adjunctive therapies. Given the multifactorial nature of MASLD, combination treatments targeting various disease pathways could be more effective than single-drug interventions. MR studies using factorial designs—akin to clinical trials combining multiple interventions—provide valuable insights into the potential synergies between different therapies.

Dr. Luo’s team emphasizes integrating multi-omics data, including proteomics and transcriptomics, to refine drug-target identification. "The availability of large-scale data from biobanks, such as the UK Biobank, has revolutionized our ability to connect genetic variants with disease traits," said Dr Luo. These advancements could also help address gaps in pediatric MASLD research, where ethical and logistical challenges limit clinical trials.

The implications of this research extend beyond MASLD. Mendelian randomization has proven effective in fields such as cardiology and oncology, where it has guided the development of therapies targeting cholesterol metabolism and cancer pathways. By applying these methods to MASLD, researchers hope to replicate similar successes.

This innovative approach aligns with the global push for precision medicine—tailoring treatments to individual genetic profiles and disease mechanisms. "Our work represents a critical step toward more effective and personalized therapies for MASLD," said Dr. Luo. She emphasized that challenges remain, including the need for better genetic instruments and more comprehensive datasets, but the potential benefits far outweigh the obstacles.

Looking ahead, the study calls for collaboration across disciplines to maximize the potential of MR in drug discovery. Integrating genetic data with clinical and epidemiological research could transform how we approach MASLD and other complex diseases. As the field of gastroenterology evolves, leveraging genetic insights will be key to addressing unmet medical needs and improving patient outcomes worldwide.

See the article: 

Luo S, Zheng M-H, Wong VW-S, et al. Drug-target Mendelian randomisation applied to metabolic dysfunction-associated steatotic liver disease: opportunities and challenges. eGastroenterology 2024;2:e100114. doi:10.1136/egastro-2024-100114

About eGastroenterology

eGastroenterology is a new, open-access, and open peer-reviewed BMJ Journal, which focuses on basic, clinical, translational, and evidence-based medicine research in all areas of gastroenterology (including hepatology, pancreatology, esophagology, and gastrointestinal surgery). eGastroenterology is now indexed by PubMed, Scopus, DOAJ, Dimensions, OpenAlex, ROAD, and COPE, with more to come!

For more information, please visit: egastroenterology.bmj.com and follow us on Twitter (@eGastro_BMJ).