Causal relationship between liver fat reduction and clinical outcomes in human genetic studies and randomized clinical trials of metabolic-dysfunction associated steatohepatitis
Year: 2026
Type: preprint
Abstract: Reliance on invasive liver biopsy endpoints is a major limiting factor in new therapeutic development for metabolic dysfunction-associated steatohepatitis (MASH). While liver fat accumulation is considered a driver of early disease, liver fat reduction is not recognized as a surrogate endpoint by health authorities. Here, we conducted the largest-to-date genome-wide association study (GWAS) of liver fat in 79,642 people with magnetic resonance imaging and developed a polygenic score with liver fat-lowering alleles across 55 genomic loci. In a separate set of 714,886 individuals, a 30% relative liver fat reduction due to the polygenic score was associated with 39% lower odds of liver cirrhosis and 41% lower odds of hepatocellular carcinoma, consistent with a strong causal relationship between lifelong liver fat differences and advanced liver clinical outcomes. A systematic review and meta-analysis of 20 randomized controlled trials including a total of 3,502 MASH patients showed that treatment-induced liver fat reductions were associated with MASH resolution (meta-regression slope in % units of the outcome for each 1% relative reduction in liver fat from baseline, β = -0.70%, p<0.001) and fibrosis improvement (β = -0.24%, p<0.001). These findings demonstrate the profound etiologic impact of liver fat in MASH and provide compelling evidence for liver fat reductions as a reasonably likely surrogate endpoint for future clinical development.
Source: medRxiv
Authors: Niek Verweij, George Hindy, Quang Nguyen, Olukayode Sosina, Kusha A Mohammadi, Tejasv Bedi, Joseph Herman, Karl Landheer, Benjamin Geraghty, Selin Somersan-Karakaya, Adam Locke, Liron Ganel, Arthur Gilly, Rouel Lanche, Stefanie Hectors, Mary Germino, Gavin H. Imperato, Ifeanyi Anidi, Lauryn Choleva, Emily Labriola-Tompkins, Muhammad Effendi, Katie Tuckwell, Sonya Aziz-Zaman, Jane Witkin, Jutta L Miller, Tae-Hwi Schwantes-An, Penn Medicine Biobank, Malmö Diet and Cancer Study, Mount Sinai Million Health Discoveries Program, Rohit Loomba, Naga P. Chalasani, Rong Liu, Mark Sleeman, Viktoria Gusarova, Gary A Herman, Jonathan Marchini, Aris Baras, Thomas D Norton, Luca A. Lotta, David J Lederer
Language: English
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7214672044