{
  "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.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 33,
  "authors": [
    {
      "name": "N. Verweij"
    },
    {
      "name": "G. Hindy"
    },
    {
      "name": "Q. Nguyen"
    },
    {
      "name": "O. Sosina"
    },
    {
      "name": "K. A. Mohammadi"
    },
    {
      "name": "T. Bedi"
    },
    {
      "name": "J. Herman"
    },
    {
      "name": "K. Landheer"
    },
    {
      "name": "B. Geraghty"
    },
    {
      "name": "S. Somersan-Karakaya"
    },
    {
      "name": "A. Locke"
    },
    {
      "name": "L. Ganel"
    },
    {
      "name": "A. Gilly"
    },
    {
      "name": "R. Lanche"
    },
    {
      "name": "S. Hectors"
    },
    {
      "name": "M. Germino"
    },
    {
      "name": "G. H. Imperato"
    },
    {
      "name": "I. Anidi"
    },
    {
      "name": "L. Choleva"
    },
    {
      "name": "E. Labriola-Tompkins"
    },
    {
      "name": "M. Effendi"
    },
    {
      "name": "K. Tuckwell"
    },
    {
      "name": "S. Aziz-Zaman"
    },
    {
      "name": "J. Witkin"
    },
    {
      "name": "J. L. Miller"
    },
    {
      "name": "T.-H. Schwantes-An"
    },
    {
      "name": "Regeneron Genetics Center"
    },
    {
      "name": "GHS-RGC DiscovEHR Collaboration"
    },
    {
      "name": "Penn Medicine Biobank"
    },
    {
      "name": "Colorado Center for Personalized Medicine"
    },
    {
      "name": "Mayo Clinic-RGC Project Generation"
    },
    {
      "name": "Malmo Diet and Cancer Study"
    },
    {
      "name": "Indiana University School"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/c45cwvb0kyhvy.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.27.26364101",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.09.27.26364101v1.full",
  "id": "c45cwvb0kyhvy",
  "issns": [],
  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.09.27.26364101v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "medrxiv",
      "gastroenterology"
    ],
    [
      "openalex",
      "2713|Liver Disease Diagnosis and Treatment"
    ]
  ],
  "openalex": "W7214672044",
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.09.27.26364101v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-27",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/c45cwvb0kyhvy.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:35Z",
      "native_id": "10.64898/2026.09.27.26364101",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.09.27.26364101v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2713|Liver Disease Diagnosis and Treatment",
      "subfield": "epidemiology-public-health"
    }
  ],
  "title": "Causal relationship between liver fat reduction and clinical outcomes in human genetic studies and randomized clinical trials of metabolic-dysfunction associated steatohepatitis",
  "title_text": "Causal relationship between liver fat reduction and clinical outcomes in human genetic studies and randomized clinical trials of metabolic-dysfunction associated steatohepatitis",
  "type": "preprint",
  "updated_at": "2026-10-30T12:19:35Z",
  "url": "https://research.draconitic.com/paper/c45cwvb0kyhvy",
  "venue": "medRxiv",
  "versions": []
}