Global Epidemiology and Implications of PNPLA3 I148M Variant in Metabolic Dysfunction–Associated Steatotic Liver Disease: A Systematic Review and Meta-analysis

Abstract

Background & Aims

PNPLA3 rs738409 variant is a risk factor for onset and progression of metabolic dysfunction–associated steatotic liver disease (MASLD). We aimed to assess its global prevalence, clinical and histological characteristics, and long-term outcomes in patients with MASLD.

Methods

PubMed and Embase databases were searched until December 30, 2023, for observational studies on PNPLA3 genotyped adults with MASLD. Proportions were pooled using a generalized linear mixed model with Clopper–Pearson intervals. Continuous and dichotomous variables were analyzed using the DerSimonian–Laird method. International Prospective Register of Systematic Reviews registration number: CRD42023449838.

Results

A total of 109 studies involving 118,302 individuals with MASLD were identified. The overall minor allele frequency of the G allele [MAF(G)] at PNPLA3 was 0.45 (95% confidence interval [CI]: 0.43; 0.48) with high heterogeneity (I² = 98%). The highest MAF(G) was found in Latin America (0.63) and the lowest in Europe (0.38). No African countries were identified. Carriers of the PNPLA3 variant had reduced adiposity, altered fat metabolism, and worse liver damage/histology than noncarriers. There was significant heterogeneity in the clinical/histological analyses (I² > 50%). Only the PNPLA3 GG genotype was associated with higher mortality and liver-related events with no heterogeneity (I² = 0%). Metaregressions showed the influence of adiposity, age, diabetes mellitus, and glucose on some PNPLA3 expression parameters. Overall, there was a moderate risk of bias in the included studies.

Conclusions

This study reveals the global pattern of PNPLA3 and its clinical, histological, and outcome implications in MASLD. Patients with MASLD and PNPLA3 variant have different clinical features and worse liver severity, and only PNPLA3 GG has a higher risk of mortality and liver outcomes. Our findings highlight the importance of PNPLA3 genotyping in clinical trials and advocate for personalized medicine approaches.