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

Area of Science:

• Genetics
• Hepatology
• Internal Medicine

Background:

• Genetic variants influence the risk and clinical course of steatotic liver disease (SLD).
• Understanding these genetic associations is crucial for predicting disease progression and outcomes.

Purpose of the Study:

• To systematically review and meta-analyze the impact of SLD-associated genetic variants (PNPLA3, TM6SF2, MBOAT7, HSD17B13, GCKR) on hepatic and extrahepatic complications.
• To determine the association between specific genotypes and outcomes such as cirrhosis, major adverse liver outcomes (MALO), cardiovascular disease, malignancy, and mortality.

Main Methods:

• Comprehensive literature search of PubMed, Embase, and Medline databases up to July 4th, 2024.
• Inclusion of studies on adult SLD patients reporting effects of key genetic variants on defined clinical outcomes.
• Meta-analysis of pooled hazard ratios and 95% confidence intervals for comparative analysis.

Main Results:

• PNPLA3-rs738409-GG genotype strongly associated with increased MALO, liver-related mortality, and all-cause mortality.
• TM6SF2-rs58542926-CT/TT genotypes linked to higher incidence of hepatocellular carcinoma.
• MBOAT7-rs641738-TT genotype showed a significant association with MALO.

Conclusions:

• Genetic variants in PNPLA3, TM6SF2, and MBOAT7 significantly influence hepatic outcomes, particularly in advanced liver disease.
• These variants have a more modest effect on extrahepatic complications.
• Routine genotyping could enhance risk stratification for SLD patients with advanced liver disease.