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Mouse Model of Metabolic Dysfunction-Associated Steatotic Liver Disease with Fibrosis
Published on: July 18, 2025
Association between the PNPLA3 I148M (rs738409) polymorphism and risk of metabolic dysfunction-associated steatotic
Muteia'a Hamood1,2, Mohammed Ahmed Al-Salehi3, Ali F Hussein4
1Department of Biochemistry & Forensic Science, University School of Sciences, Gujarat University, Ahmedabad, Gujarat, 380009, India.
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.
Insights
The PNPLA3 rs738409 polymorphism significantly increases susceptibility to metabolically-dysfunction-associated steatotic liver disease (MASLD). This genetic factor is a major risk predictor across diverse ethnic populations, supporting its use in MASLD risk assessments.
Area of Science:
- Genetics and Genomics
- Hepatology
- Metabolic Diseases
Background:
- Metabolically-dysfunction-associated steatotic liver disease (MASLD) is a prevalent global liver condition.
- Genetic factors, particularly the PNPLA3 rs738409 (I148M) polymorphism, are known contributors to MASLD.
- Previous studies had limitations in scope and diversity, necessitating a comprehensive evaluation.
Purpose of the Study:
- To conduct an updated meta-analysis evaluating the association between the PNPLA3 rs738409 polymorphism and MASLD susceptibility.
- To address limitations of prior studies regarding sample size, ethnic diversity, and heterogeneity.
Main Methods:
- Systematic literature search across major databases (PubMed, Embase, Scopus, Web of Science, Google Scholar) for case-control studies (2015-2025).
- Random-effects meta-analysis to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs) for various genotype models.
- Assessment of between-study heterogeneity using I² statistic and performance of ethnicity-based subgroup analyses.
Main Results:
- Included 41 studies with 9,064 MASLD patients and 10,894 controls.
- The PNPLA3 G allele (OR=1.70) and GG genotype (OR=2.00) significantly increased MASLD risk; CC genotype was protective (OR=0.51).
- Consistent associations were found across ethnic groups, despite significant heterogeneity (I²=66%-96%).
Conclusions:
- The PNPLA3 rs738409 polymorphism is a robust genetic susceptibility factor for MASLD globally.
- Ethnicity influences heterogeneity, but the association remains significant across populations.
- Findings support integrating PNPLA3 into MASLD risk assessment and precision medicine strategies.
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