Impact of PNPLA3 rs738409 polymorphism on the development of liver-related events in patients with nonalcoholic fatty liver disease
Open accessAbstract
Background and aims Nonalcoholic fatty liver disease (NAFLD) is a complex disease, resulting from the interplay between environmental determinants and genetic variations. Single nucleotide polymorphism rs738409 C>G in the PNPLA3 gene is associated with hepatic fibrosis and with higher risk of developing hepatocellular carcinoma. Here, we analyzed a longitudinal cohort of biopsy-proven NAFLD subjects with the aim to identify individuals in whom genetics may have a stronger impact on disease progression.Methods We retrospectively analyzed 756 consecutive, prospectively enrolled biopsy-proven NAFLD subjects from Italy, United Kingdom, and Spain who were followed for a median of 84 months (interquartile range, 65-109 months). We stratified the study cohort according to sex, body mass index (BMI) </≥30 kg/m 2) and age (</≥50 years). Liver-related events (hepatic decompensation, hepatic encephalopathy, esophageal variceal bleeding, and hepatocellular carcinoma) were recorded during the follow-up and the log-rank test was used to compare groups.Results Overall, the median age was 48 years and most individuals were men (64.7%). The PNPLA3 rs738409 genotype was CC in 235 (31.1%), CG in 328 (43.4%), and GG in 193 (25.5%) patients. At univariate analysis, the PNPLA3 GG risk genotype was associated with female sex and inversely related to BMI (odds ratio, 1.6; 95% confidence interval, 1.1-2.2; P = .006; and odds ratio, 0.97; 95% confidence interval, 0.94-0.99; P = .043, respectively). Specifically, PNPLA3 GG risk homozygosis was more prevalent in female vs male individuals (31.5% vs 22.3%; P = .006) and in nonobese compared with obese NAFLD subjects (50.0% vs 44.2%; P = .011). Following stratification for age, sex, and BMI, we observed an increased incidence of liver-related events in the subgroup of nonobese women older than 50 years of age carrying the PNPLA3 GG risk genotype (log-rank test, P = .0047).Conclusions Nonobese female patients with NAFLD 50 years of age and older, and carrying the PNPLA3 GG risk genotype, are at higher risk of developing liver-related events compared with those with the wild-type allele (CC/CG). This finding may have implications in clinical practice for risk stratification and personalized medicine.
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The impact of the PNPLA3 variant is larger in post-menopausal women than in men.
“Notably, the impact of the PNPLA3 variant is larger in post-menopausal women than in men. 197,198”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [198]
The Discussion reports that the PNPLA3 GG variant was associated with the highest risk of liver-related outcomes in nonobese women with NAFLD aged 50 or older, compared with other subgroups. It also states that menopausal status was not recorded and age 50 was used as a surrogate. The claim therefore overstates the evidence for post-menopausal women generally and does not specify that the reported impact concerns liver-related events in this subgroup. (LLM, conf=0.86)
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Research works printed but not linked: 4
- Nuria Pérez Diaz-del-Campo (Data curation: Supporting; Visualization: Supporting) Aurora Nicolosi (Data curation: Supporting; Visualization: Supporting) Olivier Govaere (Data curation: Lead; Visualization: Supporting) Gabriele Castelnuovo (Data curation: Supporting; Visualization: Supporting) Antonella Olivero (Visualization: Supporting) Maria Lorena Abate (Visualization: Supporting) Davide Giuseppe Ribaldone (Visualization: Supporting) Piero Fariselli (Data curation: Supporting; Formal analysis: Supporting; Methodology: Supporting; Software: Supporting; Visualization: Supporting) Luca Valenti (Data curation: Supporting; Resources: Lead; Supervision: Equal; Validation: Equal; Visualization: Equal; Writing -review & editing: Equal)
- Luca Miele (Data curation: Supporting; Supervision: Supporting; Validation: Supporting; Visualization: Supporting; Writing -review & editing: Supporting) Salvatore Petta (Data curation: Supporting; Methodology: Supporting; Su- pervision: Supporting; Validation: Supporting; Visualization: Supporting; Writing -review & editing: Supporting)
- Manuel Romero-Gomez (Data curation: Lead; Supervision: Equal; Validation: Supporting; Visualization: Supporting; Writing -review & editing: Supporting)
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- Authors
- Rosso, C., Caviglia, G. P., Birolo, G., Armandi, A., Pennisi, G., Pelusi, S., Younes, R., Liguori, A., Perez-Diaz-del-Campo, N., Nicolosi, A., Govaere, O., Castelnuovo, G., Olivero, A., Abate, M. L., Ribaldone, D. G., Fariselli, P., Valenti, L., Miele, L., Petta, S., Romero-Gomez, M., Anstee, Q. M., & Bugianesi, E.
- Affiliations
- University of Turin (IT)
- Johannes Gutenberg University Mainz (DE)
- University of Palermo (IT)
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
- Boehringer Ingelheim (Germany) (DE)
- Università Cattolica del Sacro Cuore (IT)
- Newcastle University (GB)
- University of Milan (IT)
- Newcastle upon Tyne Hospital (GB)
- Corresponding author
- Bugianesi, Elisabetta
- ORCID
- Rosso, Chiara
- Caviglia, Gian Paolo
- Birolo, Giovanni
- Armandi, Angelo
- Pennisi, Grazia
- Pelusi, Serena
- Younes, Ramy
- Liguori, Antonio
- Govaere, Olivier
- Castelnuovo, Gabriele
- Olivero, Antonella
- Abate, Maria Lorena
- Ribaldone, Davide Giuseppe
- Fariselli, Piero
- Valenti, Luca
- Miele, Luca
- Petta, Salvatore
- Anstee, Quentin M.
- Bugianesi, Elisabetta
- Venue
- Clinical Gastroenterology and Hepatology
- Publisher
- Elsevier BV
- Published
- 2023-12
- Volume
- 21
- Issue
- 13
- Pages
- 3314-3321.e3
- ISSN
- 1542-3565 (ISSN-L)
- OpenAlex
- W4368373786
- Cited by
- 59
- References
- 23
- Citations by year
- 2026: 11 · 2025: 22 · 2024: 20 · 2023: 6
- FWCI
- 11.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Clinical Gastroenterology and Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Nova Science Publishers (Nova Science Publishers, Inc.) (submittedVersion)
- Lirias (KU Leuven) (submittedVersion)
- Funders
- Horizon 2020 (634413)
- European Commission
- Ministero della Salute (RF-2016-02364358)
- Ministero dell’Istruzione, dell’Università e della Ricerca (D15D18000410001)
- Horizon 2020 Framework Programme (101016726)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- non-alcoholic fatty liver disease, PNPLA3, rs738409, single nucleotide polymorphisms, liver-related events, hepatocellular carcinoma, hepatic decompensation, hepatic encephalopathy, esophageal variceal bleeding, liver fibrosis, genetic susceptibility, obesity, sex differences, disease progression, longitudinal cohort
- MeSH terms
- Esophageal and Gastric Varices, Female, Genotype, Gastrointestinal Hemorrhage, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Male, Middle Aged, Retrospective Studies, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Non-alcoholic Fatty Liver Disease
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