Genetic risk accentuates dietary effects on hepatic steatosis, inflammation and fibrosis in a population-based cohort

Vincent L Chen; Xiaomeng Du; Antonino Oliveri; Yanhua Chen; Annapurna Kuppa; Brian D Halligan; Michael A Province; Elizabeth K Speliotes

doi:10.1016/j.jhep.2024.03.045

Genetic risk accentuates dietary effects on hepatic steatosis, inflammation and fibrosis in a population-based cohort

J Hepatol. 2024 Apr 4:S0168-8278(24)00230-7. doi: 10.1016/j.jhep.2024.03.045. Online ahead of print.

Authors

Vincent L Chen¹, Xiaomeng Du¹, Antonino Oliveri¹, Yanhua Chen¹, Annapurna Kuppa¹, Brian D Halligan¹, Michael A Province², Elizabeth K Speliotes³

Affiliations

¹ Division of Gastroenterology and Hepatology, University of Michigan Health System, Ann Arbor, MI, USA.
² Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA.
³ Division of Gastroenterology and Hepatology, University of Michigan Health System, Ann Arbor, MI, USA; Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: espeliot@med.umich.edu.

PMID: 38582304
DOI: 10.1016/j.jhep.2024.03.045

Abstract

Background & aims: Steatotic liver disease (SLD), characterized by elevated liver fat content (LFC), is influenced by genetics and diet. However, whether diet has differential effect based on genetic risk is not well-characterized. We aimed to determine how genetic factors interact with diet to affect SLD in a large national biobank.

Methods: We included UK Biobank participants with dietary intake measured by 24-hour recall and genotyping. The primary predictors were dietary pattern, PNPLA3-rs738409-G, TM6SF2-rs58542926-T, a 16-variant hepatic steatosis polygenic risk score (PRS), and gene-environment interactions. The primary outcome was LFC, and secondary outcomes were iron-controlled T1 time (cT1, a measure of liver inflammation and fibrosis) and liver-related events/mortality.

Results: 21,619 participants met inclusion criteria. In non-interaction models, Mediterranean diet and intake of fruit/vegetables/legumes and fish associated with lower LFC, while higher red/processed meat intake and all genetic predictors associated with higher LFC. In interaction models, all genetic predictors interacted with Mediterranean diet and fruit/vegetable/legume intake; the steatosis PRS interacted with fish intake; and TM6SF2 genotype interacted with red/processed meat intake, to affect LFC. Dietary effects on LFC were up to 3.8 times as high in PNPLA3-rs738409-GG vs. -CC individuals, and 1.4-3.0 times as high in the top vs. bottom quartile of the steatosis PRS. Gene-diet interactions were stronger in participants with vs. without overweight. The steatosis PRS interacted with Mediterranean diet and fruit/vegetable/legume intake to affect cT1 and most dietary and genetic predictors associated with risk of liver-related events or mortality by age 70.

Conclusions: Effects of diet on LFC and cT1 were markedly accentuated in patients at increased genetic risk for SLD, implying dietary interventions may be more impactful in these populations.

Keywords: 24 hour recall; Mediterranean diet; PNPLA3; SLD; TM6SF2; gene-environment interaction; polygenic risk score.