P4608 - Effects of Steatotic Liver Disease-Associated Genetic Risk Alleles on Longitudinal Outcomes: A Systematic Review and Meta-Analysis

Matthew Kubina, MD¹, Vitchapong Prasitsumrit, MD², Jarell Tan, ³, Ethan Quek, ⁴, Dhiraj Peddu, MD¹, Ankit Mishra, MD¹, Whitney Townsend, ¹, Eugene Wong, MD⁵, Karn Wijarnpreecha, MD⁶, Vincent Chen, MD^7
1University of Michigan, Ann Arbor, MI; ²Siriraj Hospital, Mahidol University, Bangkok, Samut Sakhon, Thailand; ³Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; ⁴Singapore General Hospital, Singapore, Singapore; ⁵Changi General Hospital, Simei, Singapore; ⁶Banner Health, Phoenix, AZ; ⁷Michigan Medicine, Ann Arbor, MI

Introduction: Genetic variants in genes including PNPLA3, TM6SF2, MBOAT7, HSD17B13, and GCKR have been associated with risk of steatotic liver disease (SLD). While these variants may also influence risk of liver-related complications and mortality, these longitudinal outcomes have been less well-studied. Here, we performed a systematic review and meta-analysis to determine the impact of SLD-associated genetic variants on hepatic and extrahepatic complications, and overall and cause-specific mortality in SLD.





Methods: We searched the PubMed, Embase, and Medline databases from inception through March 18^th, 2024. We included studies on adults with SLD that reported effects of pre-specified genetic predictors on outcomes of incident liver-related outcomes, incident cardiovascular disease, or overall or cause-specific mortality. Predictors were SLD-associated variants in PNPLA3, TM6SF2, HSD17B13, MBOAT7, and GCKR. We pooled hazard ratios (HR) along with 95% confidence intervals (CI) using random effect models for outcomes with sufficient studies and patients necessary for analysis. These were reviewed by two independent reviewers, with conflicts resolved with a third reviewer.





Results: Our search resulted in 6188 initial studies, with 47 studies and a total of 621,356 patients included in the final analysis. Compared to PNPLA3-rs738409-CC genotype, GG genotype was associated with significantly higher cirrhosis incidence (HR 2.27 [95% CI 1.61-3.19]), hepatocellular carcinoma (HCC) incidence (HR 1.84 [95% CI 1.06-3.20]), liver-related events (LRE) (HR 3.27 [95% CI 1.54-6.97]), and liver-related mortality (HR 3.15 [95% confidence interval 2.36-4.20]), but not cardiovascular disease incidence/mortality, or all-cause mortality. TM6SF2-rs58542926-CT or TT genotype was not associated with all-cause mortality. MBOAT7 was significantly associated with higher cirrhosis incidence (HR 1.37 [95% CI 1.12-1.69]), but not all-cause mortality. There were insufficient studies on other outcomes for these variants, or any studies on HSD17B13 or GCKR, to allow for meta-analysis. Nearly all patients included had metabolic dysfunction-associated SLD with a paucity of data available on alcohol-related liver disease.



Discussion: PNPLA3 risk variant is strongly associated with risk of liver-related outcomes and liver-specific mortality, but not all-cause mortality or cardiovascular mortality. Our findings suggest genetic variants such as PNPLA3 should be incorporated in risk-stratification of SLD patients.









Disclosures:


Matthew Kubina, MD¹, Vitchapong Prasitsumrit, MD², Jarell Tan, ³, Ethan Quek, ⁴, Dhiraj Peddu, MD¹, Ankit Mishra, MD¹, Whitney Townsend, ¹, Eugene Wong, MD⁵, Karn Wijarnpreecha, MD⁶, Vincent Chen, MD⁷. P4608 - Effects of Steatotic Liver Disease-Associated Genetic Risk Alleles on Longitudinal Outcomes: A Systematic Review and Meta-Analysis, ACG 2024 Annual Scientific Meeting Abstracts. Philadelphia, PA: American College of Gastroenterology.