Study improves our understanding of steatotic liver disease in an understudied population
PHOENIX, Ariz. (May 15, 2025) — Researchers at the Translational Genomics Research Institute (TGen), part of City of Hope, have identified several genetic variants related to the accumulation of liver fat in normal-weight individuals, a population often overlooked in studies of metabolic liver disease.
Their findings, published today in JHEP Reports, provide a glimpse into possible genetic determinants of metabolic dysfunction-associated steatotic liver disease or MASLD.
MASLD and its severe progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are typically associated with obesity, but the new study emphasizes that the underlying biology of the disease is much more complex than its relationship with body mass index (BMI).
“Our findings reveal genetic factors for MASLD that exist regardless of weight,” said Johanna K. DiStefano, Ph.D., a professor in TGen’s Early Detection and Prevention Division, head of its Metabolic Disease Research Unit, and senior author of the paper. “This challenges the common belief that thin individuals are inherently healthier.”
“By understanding these factors, we might better predict the trajectory of the disease in each individual, regardless of BMI. This is especially important for people with a normal weight, as they might not be identified as being at risk otherwise,” she added
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Formerly known as non-alcoholic fatty liver disease, MASLD affects about 30% of the global population, a number that is expected to nearly double by 2040. People with MASH have a greater risk of deadly and disabling conditions such as fibrosis, cirrhosis, and hepatocellular carcinoma.
The researchers analyzed data from 10,918 normal weight people (with a BMI less than 25) in the UK Biobank in a genome-wide association study, looking for variants related to excess fat in liver cells. DiStefano and her colleagues performed further fine genome mapping and gene expression studies to help them focus on the specific variants that could potentially cause liver fat accumulation.
According to DiStefano, the next step will be to characterize the function of these genes, learning more about how they might affect metabolic stress or fatty acid breakdown to lead to liver fat accumulation.
The causal variants uncovered in the study were predominantly in genes on chromosomes 19 and 22, the researchers found. Some of the variants have been identified previously in genetic studies of MASLD in people with obesity.
“This means that genetic risk occurs independently of weight, which is an interesting discovery,” said Ignazio Piras, Ph.D., a research associate professor in TGen’s Early Detection and Prevention Division and the paper’s first author. “But we also identified new genes or new variants that could point to genetic risk factors that are specific for individuals without obesity-related factors involved.”
Future studies should look for these variants and others in a more diverse population, he noted, since the UK Biobank participants are predominantly of European ancestry. But there are few existing databanks that include both detailed genetic data and liver fat measurements for a large number of non-European individuals with a normal BMI.
It’s important to learn more about how steatotic liver disease occurs in normal weight people, DiStefano said, because recent studies increasingly show connections between liver disease and the risks of developing other metabolic diseases such as type 2 diabetes, and vice-versa.
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The National Institute of Diabetes and Digestive and Kidney Diseases funded this research
About TGen, part of City of Hope
Translational Genomics Research Institute (TGen) is a Phoenix, Arizona-based nonprofit organization dedicated to conducting groundbreaking research with life-changing results. TGen is part of City of Hope, a world-renowned independent research and treatment center for cancer, diabetes and other life-threatening diseases. This precision medicine affiliation enables both institutes to complement each other in research and patient care, with City of Hope providing a significant clinical setting to advance scientific discoveries made by TGen. TGen is focused on helping patients with neurological disorders, cancer, diabetes and infectious diseases through cutting-edge translational research (the process of rapidly moving research toward patient benefit). TGen physicians and scientists work to unravel the genetic components of both common and complex rare diseases in adults and children. Working with collaborators in the scientific and medical communities worldwide, TGen makes a substantial contribution to help patients through efficiency and effectiveness of the translational process.
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