ArticleHepatology (Baltimore, Md.)2022
PNPLA3 rs738409 and risk of fibrosis in NAFLD: Exploring mediation pathways through intermediate histological features.
Article in Hepatology (Baltimore, Md.), 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 25 citations in OpenAlex.
- Epidemiological features of pediatric nonalcoholic fatty liver disease in China.Diabetology & metabolic syndrome · 2026Article
- Genetic and non-genetic drivers of histological progression and regression in MASLD.Journal of hepatology · 2026Article
- Genome-wide association study identifies three PNPLA3/SAMM50 SNPs associated with HCC development in non-viral liver disease.JHEP reports : innovation in hepatology · 2026Article
- Metabolic dysfunction-associated steatotic liver disease in Egypt: Epidemiology, risk factors and management challenges.World journal of gastroenterology · 2025Review
- The PNPLA3 I148M variant is associated with immune cell infiltration and advanced fibrosis in MASLD: a prospective genotype-phenotype study.Journal of gastroenterology · 2025Article
- Impact of PNPLA3 I148M on Clinical Outcomes in Patients With MASLD.Liver international : official journal of the International Association for the Study of the Liver · 2025Review
- Global Epidemiological Impact of PNPLA3 I148M on Liver Disease.Liver international : official journal of the International Association for the Study of the Liver · 2025Review
- The emerging phenotype of nonalcoholic fatty liver disease in lean individuals: what's different?Frontiers in endocrinology · 2025Review
- Insulin resistance is an integral feature of MASLD even in the presence of PNPLA3 variants.JHEP reports : innovation in hepatology · 2024Article
- Age, BMI, and Type 2 Diabetes Modify the Relationship Between PNPLA3 and Advanced Fibrosis in Children and Adults With NAFLD.Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association · 2024Article
- Genetic and Metabolic Characteristics of Lean Nonalcoholic Fatty Liver Disease in a Korean Health Examinee Cohort.Gut and liver · 2024Article
- Article
- Genetics in non-alcoholic fatty liver disease: The role of risk alleles through the lens of immune response.Clinical and molecular hepatology · 2023Review
- The I148MFrontiers in nutrition · 2023Article
- Article
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
BACKGROUND AND
aimsIt is unclear whether rs738409 (p.I148M) missense variant in patatin-like phospholipase domain-containing 3 rs738409 promotes fibrosis development by triggering specific fibrogenic pathways or by creating an unfavorable microenvironment by promoting steatosis, inflammation, and ultimately fibrosis. We tested the hypothesis that intermediate histologic traits, including steatosis, lobular and portal inflammation, and ballooning may determine the effect of rs738409 on liver fibrosis among individuals with biopsy-proven NAFLD. APPROACH AND
resultsCausal mediation models including multiple mediators in parallel or sequentially were performed to examine the effect of rs738409, by decomposing its total effect on fibrosis severity into direct and indirect effects, mediated by histology traits in 1153 non-Hispanic White patients. Total effect of rs738409 on fibrosis was β = 0.19 (95% CI: 0.09-0.29). The direct effect of rs738409 on fibrosis after removing mediators' effects was β = 0.09 (95% CI: 0.01-0.17) and the indirect effect of rs738409 on fibrosis through all mediators' effects were β = 0.010 (95% CI: 0.04-0.15). Among all mediators, the greatest estimated effect size was displayed by portal inflammation (β = 0.09, 95% CI: 0.05-0.12). Among different sequential combinations of histology traits, the path including lobular inflammation followed by ballooning degeneration displayed the most significant indirect effect (β = 0.023, 95% CI: 0.011-0.037). Mediation analysis in a separate group of 404 individuals with biopsy-proven NAFLD from other races and ethnicity showed similar results.
conclusionsIn NAFLD, nearly half of the total effect of the rs738409 G allele on fibrosis severity could be explained by a direct pathway, suggesting that rs738409 may promote fibrosis development by activating specific fibrogenic pathways. A large proportion of the indirect effect of rs738409 on fibrosis severity is mediated through portal inflammation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.