Homozygosity for the patatin‐like phospholipase‐3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease†
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UNLABELLED: Inherited factors play a major role in the predisposition to nonalcoholic fatty liver disease (NAFLD), and the rs738409 C-->G polymorphism of PNPLA3/adiponutrin, encoding for the isoleucine-to-methionine substitution at residue 148 (I148M) protein variant, has recently been recognized as a major determinant of liver fat content. However, the effect of the rs738409 polymorphism on the severity of liver fibrosis in patients with NAFLD is still unknown. In this study, we considered 253 Italian patients, 179 healthy controls, and 71 family trios with an affected child with NAFLD. Analyses were replicated in 321 patients from the United Kingdom. The rs738409 polymorphism was determined by TaqMan assays. Liver histology was scored according to Kleiner et al. Hepatic expression of genes regulating liver damage was assessed by real-time polymerase chain reaction in 52 patients. The rs738409 GG genotype was more prevalent in patients than in controls (14% versus 3%, adjusted odds ratio [OR] = 3.29, 95% confidence interval [CI] = 1.8-6.9), and in the family study, the G allele was overtransmitted to affected children (P = 0.001). In Italian and United Kingdom patients, adiponutrin genotype influenced alanine aminotransferase levels and the severity of steatosis. Adiponutrin genotype was associated with the expression of genes involved in the steatosis-related liver damage, including the proapoptotic molecule Fas ligand. In the whole series combined, adiponutrin genotype was associated with steatosis grade >1 (OR = 1.35, 95% CI = 1.04-1.76), nonalcoholic steatohepatitis (OR = 1.5, 95% CI = 1.12-2.04), and fibrosis stage >1 (OR = 1.5, 95% CI = 1.09-2.12), independent of age, body mass index, and diabetes. Adiponutrin genotype demonstrated a dose effect with heterozygote risk intermediate between CC and GG homozygotes. CONCLUSION: In patients with NAFLD, adiponutrin rs738409 C-->G genotype, encoding for I148M, is associated with the severity of steatosis and fibrosis and the presence of nonalcoholic steatohepatitis.
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PNPLA3, CPEB4, and ASPG are linked to hepatic steatosis, steatohepatitis, and/or fibrosis.
“PNPLA3, CPEB4, and ASPG, which are linked to hepatic steatosis, steatohepatitis, and/or fibrosis33,39–41”
From Spatial transcriptomics of healthy and fibrotic human liver at single-cell resolution (2025) · cites this paper as [39]
PNPLA3 rs6006460[T] (S453I) carriers, enriched in African Americans, are associated with decreased MASLD.
“Conversely, carriers of the PNPLA3 allele rs6006460[T] (encoding S453I), enriched in African Americans, are associated with decreased MASLD (132-134).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [133]
PNPLA3 rs738409[G] (I148M) carriers are most prevalent in Hispanics and have increased susceptibility to MASLD and MASH.
“Among these polymorphisms, carriers of the Patatin Like Phospholipase Domain Containing 3 (PNPLA3) allele rs738409[G] (encoding I148M) are most prevalent in Hispanics and display an increased susceptibility to MASLD and MASH.”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [133]
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- Authors
- Valenti, L., Al‐Serri, A., Daly, A. K., Galmozzi, E., Rametta, R., Dongiovanni, P., Nobili, V., Mozzi, E., Roviaro, G., Vanni, E., Bugianesi, E., Maggioni, M., Fracanzani, A. L., Fargion, S., & Day, C. P.
- Affiliations
- University of Milan (IT)
- Newcastle University (GB)
- University of Turin (IT)
- Ospedale San Paolo (IT)
- Corresponding author
- Fargion, Silvia
- ORCID
- Venue
- Hepatology
- Published
- 2010-04
- Volume
- 51
- Issue
- 4
- Pages
- 1209-1217
- ISSN
- 0270-9139 (ISSN-L)
- OpenAlex
- W1979443397
- Cited by
- 651
- References
- 36
- Citations by year
- 2026: 13 · 2025: 22 · 2024: 28 · 2023: 32 · 2022: 45 · 2021: 45 · 2020: 54 · 2019: 26 · 2018: 32 · 2017: 46 · 2016: 60 · 2015: 57 · 2014: 37 · 2013: 39 · 2012: 43
- FWCI
- 35.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Keywords
- non-alcoholic fatty liver disease, liver fibrosis, PNPLA3, I148M polymorphism, rs738409, genetic susceptibility, nonalcoholic steatohepatitis, hepatic steatosis, Fas ligand, family trios, dose-dependent effects
- MeSH terms
- Acyltransferases, Adult, Aged, Fatty Liver, Female, Genotype, Homozygote, Humans, Lipase, Liver Cirrhosis, Male, Membrane Proteins, Middle Aged, Polymorphism, Genetic, Phospholipases A2, Calcium-Independent
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