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. 2025 Apr;82(4):571-581.
doi: 10.1016/j.jhep.2024.09.043. Epub 2024 Oct 9.

PNPLA3 rs738409, environmental factors and liver-related mortality in the US population

Eduardo Vilar-Gomez  1 , Samer Gawrieh  1 , Raj Vuppalanchi  1 , Carla Kettler  2 , Francis Pike  2 , Niharika Samala  1 , Naga Chalasani  3
Affiliations

PNPLA3 rs738409, environmental factors and liver-related mortality in the US population

Eduardo Vilar-Gomez et al. J Hepatol. 2025 Apr.

Abstract

Background & aims: Little is known about the interplay between patatin-like phospholipase domain-containing protein 3 (PNPLA3 rs738409 C>G), environmental factors, and the risk of liver-related death.

Methods: A total of 4,361 adults were selected from NHANES III, 1991-1994. All participants were linked to the National Death Index until 2019 (mean follow-up: 23.2 years). Liver-related death was the study outcome. Associations of PNPLA3, diet, light alcohol intake, smoking, and BMI (kg/m2) with liver-related death were examined using competing risk regression models.

Results: The PNPLA3 G-allele was significantly associated with liver-related death (adjusted subhazard ratio [adj.sHR] 2.9, 95% CI 1.4-5.8). Light alcohol intake (adj.sHR 2.2, 95% CI 1.1-4.5), top quartiles of monounsaturated fat (adj.sHR 0.43, 95% CI 0.12-0.99) and cholesterol (adj.sHR 2.6, 95% CI 1.00-8.8), coffee intake ≥3 cups/day (adj.sHR 0.05, 95% CI 0.06-0.10), former/current smoking (adj.sHR 1.8, 95% CI 1.2-2.6), BMI (adj.sHR 1.1, 95% CI 1.03-1.2), and healthy eating index (adj.sHR 0.96, 95% CI 0.93-0.98) were associated with liver-related death. Joint effects between PNPLA3 and environmental factors showed that the risk of liver-related death was significantly increased in carriers of the G-allele with light alcohol intake (adj.sHR 3.7), higher consumption (top quartile) of cholesterol (adj.sHR 4.1), former (adj.sHR 4.3) or current (adj.sHR 3.5) smoking, or BMI ≥30 (adj.sHR 4.0) kg/m2. The effects of the G-allele on the risk of LRD were significantly attenuated in those with top quartile consumption of monounsaturated fat (adj.sHR 0.5) or coffee intake ≥3 cups/day (adj.sHR 0.09). Healthy eating index was inversely associated with liver-related death across all PNPLA3 genotypes (adj.sHR 0.94, 0.96, and 0.97 for CC, CG, and GG, respectively).

Conclusions: PNPLA3 is associated with liver-related death and this relationship is significantly modified by anthropometric and environmental factors.

Impact and implications: Light alcohol intake, dietary factors (healthy eating index, monounsaturated fat, cholesterol), coffee intake, smoking status, and BMI are independently associated with the risk of liver-related death. The increased inherited risk of liver-related death associated with PNPLA3 rs738409 appears to be attenuated by healthy eating index, monounsaturated fat, and coffee intake, and exacerbated by light alcohol intake, smoking, and BMI. Reducing harmful environmental exposures and increasing healthy eating habits may help mitigate the risk of liver-specific mortality even in those with high genetic risk.

Keywords: PNPLA3 rs738409; alcohol; coffee; diet; liver-related mortality; obesity; smoking.

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Conflict of interest statement

Conflicts of interest Dr. Chalasani declares no COIs for this paper. For full disclosure, he has had paid consulting agreements with Madrigal, GSK, Galectin, Zydus, Altimune, Ventyx, Foresite, Merck, and Pfizer. He has research grants from DSM and Exact Sciences. He has equity ownership in Avant Sante Therapeutics, a contract research organization. Dr. Gawrieh discloses consulting for TransMedics, and Pfizer and receives research grant support from Zydus, Viking, and Sonic Incytes. Dr. Vuppalanchi receives research grant support from Zydus, Galectin Therapeutics, Gilead Sciences, Novo Nordisk, Eli Lilly, and also discloses consulting for Fortrea, Medpace, and GSK. Drs. Vilar-Gomez, Pike, Kettler, and Samala have no financial COIs to disclose. Please refer to the accompanying ICMJE disclosure forms for further details.

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