Deep metabolic phenotyping of humans with protein-altering variants in TM6SF2 using a genome-first approach

The genome-first approach expands insights into genetic risk factors for steatotic liver disease with <i>TM6SF2</i> being a focal point due to its known association with plasma lipid traits. Our findings validated the association of two missense variants (E167K and L156P) with increased risk of hepatic steatosis on CT and MRI scans, as well as the risk of clinically diagnosed hepatocellular carcinoma independent of the common <i>PNPLA3</i> I48M risk variant. Notably, we also identified a predicted deleterious missense variant (P216L) linked to steatotic risk and demonstrated that an aggregated gene burden of rare putative loss-of-function variants was associated with the risk of hepatic steatosis. Combined, this study sets the stage for future mechanistic investigations into the functional consequences of <i>TM6SF2</i> variants in metabolic dysfunction-associated steatotic liver disease.

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Publication Details

Journal
JHEP Reports
Published
2024-10-11
DOI
https://doi.org/10.1016/j.jhepr.2024.101243
Citations
7
Primary Topic
Liver Disease Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
2.71

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article

Deep metabolic phenotyping of humans with protein-altering variants in TM6SF2 using a genome-first approach

Nicholas J. Hand, Kate Townsend Creasy, Eleonora Scorletti, Kai Markus Schneider et al.
7 citations
JHEP Reports
Liver Disease Diagnosis and Treatment
2.71
article

Deep metabolic phenotyping of humans with protein-altering variants in TM6SF2 using a genome-first approach

Nicholas J. Hand, Kate Townsend Creasy, Eleonora Scorletti, Kai Markus Schneider, Carolin Victoria Schneider, Helen Huang, Michael C. Phillips, Daniel James Rader, Cecilia Vitali, David Zhang, Joseph Park
article en
7 citations

Abstract

The genome-first approach expands insights into genetic risk factors for steatotic liver disease with <i>TM6SF2</i> being a focal point due to its known association with plasma lipid traits. Our findings validated the association of two missense variants (E167K and L156P) with increased risk of hepatic steatosis on CT and MRI scans, as well as the risk of clinically diagnosed hepatocellular carcinoma independent of the common <i>PNPLA3</i> I48M risk variant. Notably, we also identified a predicted deleterious missense variant (P216L) linked to steatotic risk and demonstrated that an aggregated gene burden of rare putative loss-of-function variants was associated with the risk of hepatic steatosis. Combined, this study sets the stage for future mechanistic investigations into the functional consequences of <i>TM6SF2</i> variants in metabolic dysfunction-associated steatotic liver disease.

JHEP ReportsVol. 7(1)
Regeneron (United States) (US), Cornell University (US), Presbyterian Hospital (US), Translational Therapeutics (United States) (US), Technische Universität Dresden (DE), University of Pennsylvania (US), RWTH Aachen University (DE)
Deutsche Forschungsgemeinschaft, Ministerium für Innovation, Wissenschaft und Forschung des Landes Nordrhein-Westfalen, Center for Information Technology
Zero hunger
Openalex Percentile: Top 9%
Liver Disease Diagnosis and Treatment
2.71
DOIOpen Access PDFOpenAlex
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