Causal relationship between liver fat reduction and clinical outcomes in human genetic studies and randomized clinical trials of metabolic-dysfunction associated steatohepatitis
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, {beta} = -0.70%, p<0.001) and fibrosis improvement ({beta} = -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.
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BibTeX
@misc{verweij2026causal,
title = {{Causal relationship between liver fat reduction and clinical outcomes in human genetic studies and randomized clinical trials of metabolic-dysfunction associated steatohepatitis}},
author = {N. Verweij and G. Hindy and Q. Nguyen and O. Sosina and K. A. Mohammadi and T. Bedi and J. Herman and K. Landheer and B. Geraghty and S. Somersan-Karakaya and A. Locke and L. Ganel and A. Gilly and R. Lanche and S. Hectors and M. Germino and G. H. Imperato and I. Anidi and L. Choleva and E. Labriola-Tompkins and M. Effendi and K. Tuckwell and S. Aziz-Zaman and J. Witkin and J. L. Miller and T.-H. Schwantes-An and Regeneron Genetics Center and GHS-RGC DiscovEHR Collaboration and Penn Medicine Biobank and Colorado Center for Personalized Medicine and Mayo Clinic-RGC Project Generation and Malmo Diet and Cancer Study and Indiana University School},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.27.26364101},
url = {https://www.medrxiv.org/content/10.64898/2026.09.27.26364101v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Causal relationship between liver fat reduction and clinical outcomes in human genetic studies and randomized clinical trials of metabolic-dysfunction associated steatohepatitis
AU - N. Verweij
AU - G. Hindy
AU - Q. Nguyen
AU - O. Sosina
AU - K. A. Mohammadi
AU - T. Bedi
AU - J. Herman
AU - K. Landheer
AU - B. Geraghty
AU - S. Somersan-Karakaya
AU - A. Locke
AU - L. Ganel
AU - A. Gilly
AU - R. Lanche
AU - S. Hectors
AU - M. Germino
AU - G. H. Imperato
AU - I. Anidi
AU - L. Choleva
AU - E. Labriola-Tompkins
AU - M. Effendi
AU - K. Tuckwell
AU - S. Aziz-Zaman
AU - J. Witkin
AU - J. L. Miller
AU - T.-H. Schwantes-An
AU - Regeneron Genetics Center
AU - GHS-RGC DiscovEHR Collaboration
AU - Penn Medicine Biobank
AU - Colorado Center for Personalized Medicine
AU - Mayo Clinic-RGC Project Generation
AU - Malmo Diet and Cancer Study
AU - Indiana University School
PY - 2026
DA - 2026/09/27
PB - medRxiv
DO - 10.64898/2026.09.27.26364101
UR - https://www.medrxiv.org/content/10.64898/2026.09.27.26364101v1
AB - 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, {beta} = -0.70%, p<0.001) and fibrosis improvement ({beta} = -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.
ER -