Meta-Analysis: Effects of Steatotic Liver Disease-Associated Genetic Risk Alleles on Longitudinal Outcomes

Matthew Kubina; Vitchapong Prasitsumrit; Jarell Tan; Joo Wei Ethan Quek; Dhiraj Peddu; Ankit Mishra; Pojsakorn Danpanichkul; Jake P Mann; Eric Trépo; Stephan Buch; Daniel Q Huang; Cheng Han Ng; Mark D Muthiah; Yu Jun Wong; Karn Wijarnpreecha; Vincent L Chen

doi:10.1111/apt.70256

Meta-Analysis: Effects of Steatotic Liver Disease-Associated Genetic Risk Alleles on Longitudinal Outcomes

Aliment Pharmacol Ther. 2025 Jun 28. doi: 10.1111/apt.70256. Online ahead of print.

Authors

Matthew Kubina¹, Vitchapong Prasitsumrit², Jarell Tan³, Joo Wei Ethan Quek⁴, Dhiraj Peddu¹, Ankit Mishra¹, Pojsakorn Danpanichkul², Jake P Mann^{5

6}, Eric Trépo^{7

8}, Stephan Buch^{9

10}, Daniel Q Huang¹¹, Cheng Han Ng^{11

12

13}, Mark D Muthiah^{3

11}, Yu Jun Wong^{14

15}, Karn Wijarnpreecha^{16

17

18}, Vincent L Chen¹⁹

Affiliations

¹ Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
² Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, USA.
³ Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
⁴ Singapore General Hospital, Singapore, Singapore.
⁵ Department of Immunology and Immunotherapy, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham, UK.
⁶ Liver Unit, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.
⁷ Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium.
⁸ Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium.
⁹ Department of Medicine I, Dresden University Hospital, Dresden, Germany.
¹⁰ Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden (TU Dresden), Dresden, Germany.
¹¹ Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore.
¹² Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
¹³ Division of Gastroenterology, Department of Medicine, School of Medicine, Kurume University, Kurume, Japan.
¹⁴ Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore, Singapore.
¹⁵ Duke-NUS Medical School, Singapore, Singapore.
¹⁶ Department of Medicine, Division of Gastroenterology and Hepatology, University of Arizona College of Medicine, Phoenix, Arizona, USA.
¹⁷ Department of Internal Medicine, Division of Gastroenterology and Hepatology, Banner University Medical Center, Phoenix, Arizona, USA.
¹⁸ BIO5 Institute, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona, USA.
¹⁹ Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.

PMID: 40580198
DOI: 10.1111/apt.70256

Abstract

Background: Genetic variants associated with risk of steatotic liver disease (SLD) may also influence clinical events.

Aims: To perform a systematic review and meta-analysis to determine the impact of SLD-associated genetic variants on hepatic and extrahepatic complications in SLD.

Methods: We searched PubMed, Embase and Medline databases from inception through July 4th, 2024 for studies on adults with SLD that reported effects of PNPLA3, TM6SF2, MBOAT7, HSD17B13 and GCKR variants on the incidence of cirrhosis, major adverse liver outcomes (MALO), cardiovascular disease, extrahepatic malignancy and overall or cause-specific mortality. We pooled hazard ratios and 95% confidence intervals from these outcomes to allow for comparison.

Results: We screened 6475 studies and included 40 in the final analysis. PNPLA3-rs738409-GG genotype (vs. CC genotype) was associated with significantly higher incidence of MALO (sHR 2.30 [95% CI 1.66-3.18]), liver-related mortality (sHR 2.83 [95% CI 1.58-5.06]) and all-cause mortality (HR 1.24 [95% CI 1.04-1.47]). TM6SF2-rs58542926-CT or TT (vs. CC) genotype was associated with a higher incidence of hepatocellular carcinoma (sHR 2.12 [95% CI 1.66-2.70]). MALO was significantly associated with MBOAT7 -rs641738-TT (vs. CC) genotype (sHR 1.21 [95% CI 1.1-1.33]). Limitations in the literature include inconsistent outcome reporting and distribution of fibrosis stage, and a relative paucity of studies on both alcohol-associated liver disease and non-PNPLA3 genetic variants.

Conclusions: Variants in PNPLA3, TM6SF2 and MBOAT7 are significantly associated with hepatic outcomes, especially with advanced baseline liver disease, with modest effects on extrahepatic outcomes. Routine genotyping may improve risk stratification in SLD patients with advanced liver disease.

Keywords: ALD; MASLD; cardiovascular diseases; fatty liver; genotype; hepatocellular carcinoma; liver cirrhosis; risk assessment.

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Abstract

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