Association between the PNPLA3 I148M (rs738409) polymorphism and risk of metabolic dysfunction-associated steatotic liver disease: a meta-analysis (2015-2025).
TL;DR
This updated meta-analysis confirms that the PNPLA3 rs738409 (I148M) polymorphism is a major genetic susceptibility factor for MASLD across diverse populations and supports the incorporation of PNPLA3 into multifactorial risk assessment models.
Abstract
Background
Metabolically-dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide and is strongly influenced by genetic susceptibility. Among the identified genetic variants, the patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 (I148M) polymorphism has been consistently associated with hepatic steatosis and disease progression. However, previous meta-analyses included fewer studies, limited ethnic diversity, and insufficient investigation of between-study heterogeneity. This study aimed to comprehensively evaluate the association between the PNPLA3 rs738409 polymorphism and MASLD susceptibility.
Methods
A systematic literature search was conducted in PubMed, Embase, Scopus, Web of Science, and Google Scholar to identify eligible case-control studies published between 2015 and 2025. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated under allelic, dominant, homozygous, heterozygous, and combined genotype models using random-effects meta-analysis. Between-study heterogeneity was assessed using the I² statistic, and ethnicity-based subgroup analyses were performed to investigate potential sources of heterogeneity.
Results
Forty-one studies comprising 9,064 patients with MASLD and 10,894 controls were included. The G allele was significantly associated with increased susceptibility to MASLD (OR = 1.70, 95% CI: 1.49-1.93). Individuals carrying the GG genotype had approximately a twofold higher risk of MASLD (OR = 2.00, 95% CI: 1.65-2.42), whereas the CC genotype showed a protective association (OR = 0.51, 95% CI: 0.44-0.59). Significant associations were also observed for the CG genotype (OR = 1.22, 95% CI: 1.08-1.38) and the dominant model (CG + GG vs. CC) (OR = 2.64, 95% CI: 1.86-3.75). Although substantial between-study heterogeneity was observed (I² = 66%-96%), ethnicity-based subgroup analyses explained part of the variability while demonstrating consistent associations across major ethnic populations.
Conclusions
This updated meta-analysis confirms that the PNPLA3 rs738409 (I148M) polymorphism is a major genetic susceptibility factor for MASLD across diverse populations. Although ethnicity contributes to between-study heterogeneity, the association remains robust across populations. These findings support the incorporation of PNPLA3 into multifactorial risk assessment models and provide an updated evidence base for future precision medicine approaches in MASLD.