Rochester, MN – A newly discovered rare genetic variant is directly linked to metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), according to research from Mayo Clinic’s Center for Individualized Medicine. The finding challenges previous understandings of the disease, which largely attributed its development to a combination of genetic predisposition and lifestyle factors. This research suggests that, in some cases, a single inherited mutation can be a primary driver of the condition.
MASLD affects roughly one-third of adults worldwide and is poised to become the leading cause of cirrhosis and liver transplants, highlighting the urgency of understanding its underlying causes. The study, published in the journal Hepatology, offers a new lens through which to view this increasingly prevalent health concern and potentially identify new therapeutic targets. Understanding the genetic roots of fatty liver disease is a critical step toward more effective prevention and treatment strategies.
Genetic Variant Disrupts Liver Function
Researchers pinpointed the genetic variant to the MET gene, which plays a crucial role in liver repair and fat metabolism. When the MET gene doesn’t function correctly, fat accumulates within liver cells, leading to inflammation. Over time, this inflammation can progress to fibrosis, scarring, cirrhosis, and even liver cancer. The discovery stemmed from genomic analysis of a woman and her father, both diagnosed with MASLD, who surprisingly lacked common risk factors like diabetes or high cholesterol.
“This discovery opens a window into how rare inherited genetic variants can drive common diseases,” says Filippo Pinto e Vairo, M.D., Ph.D., medical director of the Program for Rare and Undiagnosed Diseases at Mayo Clinic’s Center for Individualized Medicine. “It provides new insights into this disease pathogenesis and potential therapeutic targets for future research.”
Collaboration Confirms Genetic Link
Extensive genetic analysis, examining over 20,000 genes, revealed a subtle alteration in the MET gene. Collaboration with scientists from the Medical College of Wisconsin’s John &. Linda Mellowes Center for Genomic Sciences and Precision Medicine, led by Raul Urrutia, M.D., confirmed that this mutation interfered with a critical biological process. Specifically, a single “swapped letter” within the DNA sequence disrupted the gene’s message, hindering the liver’s ability to process fat effectively. This specific variant had not been previously documented in scientific literature or public genetic databases.
“This study demonstrates that rare diseases are not rare but often hidden in the large pool of complex disorders, underscoring the immense power of individualized medicine in identifying them, and enabling the design of advanced diagnostics and targeted therapies,” Dr. Urrutia stated.
Tapestry Study Reveals Wider Impact
To determine if the mutation was isolated to the family, researchers analyzed data from Mayo Clinic’s Tapestry study, a large exome sequencing initiative examining genetic factors influencing disease. The Tapestry project has analyzed germline DNA from more than 100,000 participants across the United States, creating a vast genomic database.
Among nearly 4,000 adults in the Tapestry study with MASLD, approximately 1% carried rare variants in the MET gene potentially contributing to the condition. Notably, nearly 18% of these variants occurred in the same key region identified in the original family, strengthening the evidence of the gene’s role in liver disease. “This finding could potentially affect hundreds of thousands, if not millions, of people worldwide with or at risk for metabolic dysfunction-associated steatotic liver disease,” says Konstantinos Lazaridis, M.D., lead author and the Carlson and Nelson Endowed Executive Director for the Center for Individualized Medicine.
Dr. Lazaridis emphasized the value of the Tapestry study in uncovering hidden genetic factors. “Once a pathogenic variant is discovered, interrogating our Tapestry data repository is giving us a clearer lens into the hidden layers of disease, and this discovery is one of the first to demonstrate its scientific significance,” he explained. “This finding highlights the profound value of studying familial diseases and the merit of large-scale genomic datasets, which can reveal rare genetic variations with broader implications for population health.”
The Future of Genomic Medicine in Liver Disease
This research underscores the growing importance of genomic medicine in clinical care. Since its launch in 2019, the Program for Rare and Undiagnosed Diseases at Mayo Clinic has provided comprehensive genomic testing to over 3,200 patients, working with nearly 300 clinicians across 14 divisions to deliver precision diagnostics for challenging cases, including rare liver diseases.
Future studies will focus on how this discovery can inform the development of targeted treatments and improve the diagnosis and management of MASLD. The identification of this genetic link represents a significant step forward in understanding and addressing this complex and increasingly common liver condition.
Disclaimer: This article is for informational purposes only and should not be considered medical advice. Please consult with a qualified healthcare professional for any health concerns or before making any decisions related to your health or treatment.
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