N. Verweij, G. Hindy, Q. Nguyen, O. Sosina, K. A. Mohammadi, T. Bedi, J. Herman, K. Landheer, B. Geraghty, S. Somersan-Karakaya, A. Locke, L. Ganel, A. Gilly, R. Lanche, S. Hectors, M. Germino, G. H. Imperato, I. Anidi, L. Choleva, E. Labriola-Tompkins, M. Effendi, K. Tuckwell, S. Aziz-Zaman, J. Witkin, J. L. Miller, T.-H. Schwantes-An, Regeneron Genetics Center, GHS-RGC DiscovEHR Collaboration, Penn Medicine Biobank, Colorado Center for Personalized Medicine, Mayo Clinic-RGC Project Generation, Malmo Diet and Cancer Study, Indiana University School
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.