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

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

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

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.

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.

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.