Patatin-Like Phospholipase Domain-Containing Protein 3 rs2896019 and MASLD Susceptibility and Severity in Adults: A Systematic Review and Meta-Analysis of Case–Control Studies

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of global liver morbidity. Genetic variants, particularly in the patatin-like phospholipase domain-containing 3 (PNPLA3) gene, are critical determinants of metabolic traits and disease progression. This study presents the first meta-analysis to clarify the association between the PNPLA3 rs2896019 polymorphism and MASLD susceptibility and severity. We systematically searched PubMed, Embase, Web of Science, and Google Scholar for relevant articles published up to February 12, 2026. Data were extracted, and summary estimates of the association between PNPLA3 rs2896019 and MASLD were assessed. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to measure the effect. Ten eligible case–control cohorts involving 15,028 participants (3118 cases and 11,910 controls) were included. Our results demonstrated that the G allele is significantly associated with a 51% increased risk of MASLD (OR: 1.5, CI: 1.23–1.85, P < 0.0001). A clear gene-dose effect was observed, with risks escalating in the homozygous model (OR: 2.32, 95% CI: 1.53–3.53, P < 0.0001). Subgroup analysis revealed that diagnostic modality was the primary source of heterogeneity, whereby restricting the analysis to biopsy-proven cohorts eliminated heterogeneity (I² = 0%) and strengthened the association (OR = 1.91). Furthermore, the G allele significantly increased the risk of severe MASLD/MASH (OR = 2.06) compared to mild steatosis (OR = 1.40). In conclusion, the PNPLA3 rs2896019 G allele is a robust, dose-dependent risk factor for both the development and severe progression of MASLD.