PNPLA3 rs738409, age, diabetes, sex, and advanced fibrosis jointly contribute to the risk of major adverse liver outcomes in metabolic-associated steatotic liver disease

Naga Chalasani; Eduardo Vilar-Gomez; Rohit Loomba; Katherine P Yates; Anna Mae Diehl; Brent A Neuschwander-Tetri; Srinivasan Dasarathy; Kris V Kowdley; Norah Terrault; Laura A Wilson; James Tonascia; Arun Sanyal

doi:10.1097/HEP.0000000000000896

PNPLA3 rs738409, age, diabetes, sex, and advanced fibrosis jointly contribute to the risk of major adverse liver outcomes in metabolic-associated steatotic liver disease

Hepatology. 2024 Apr 23. doi: 10.1097/HEP.0000000000000896. Online ahead of print.

Authors

Affiliations

¹ Division of Gastroenterology, and Hepatology, Indiana University School of Medicine Indiana University Health, Indianapolis, IN.
² MASLD Research Center, Division of Gastroenterology, and Hepatology, University of California, San Diego School of Medicine, La Jolla, CA.
³ Department of Epidemiology, Johns Hopkins University, Baltimore, MD.
⁴ Division of Gastroenterology, Duke University Medical Center, Durham, North Carolina.
⁵ Division of Gastroenterology, and Hepatology, Saint Louis University, St Louis, MO.
⁶ Division of Gastroenterology, and Hepatology, Cleveland Clinic, Cleveland, Ohio.
⁷ Liver Institute Northwest, Seattle, Washington.
⁸ Division of Gastrointestinal and Liver Diseases, University of Southern California, Los Angeles, California.
⁹ Department of Biostatistics and Epidemiology, Johns Hopkins University, Baltimore, MD.
¹⁰ Division of Gastroenterology, and Hepatology, Virginia Commonwealth University, Richmond, VA.

PMID: 38652636
DOI: 10.1097/HEP.0000000000000896

Abstract

Background and aims: The patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 variant is associated with Steatotic Liver Disease (SLD) and its progression. We examined the association between PNPLA3 and the development of major adverse liver outcomes (MALO) and how non-modifiable and modifiable conditions modify this relationship.

Approach and results: 2,075 adults with biopsy-confirmed Metabolic-Associated SLD (MASLD) were enrolled in the MASLD CRN studies and followed prospectively until death, transplant, or withdrawal of consent. 104 MALOs were recorded during an average of 4.3 years. PNPLA3 G-allele (Adj. SubHazard ratio (sHR): 1.4, 95% confidence interval (CI): 1.07-1.8), advanced fibrosis (AF) (Adj. sHR: 7.8, 95% CI: 4.4-13.8), age >60 years (Adj. sHR: 2.9, 95% CI: 1.3-6.8), and type 2 diabetes mellitus (T2DM) (Adj. sHR: 2.8, 95% CI: 1.8-4.2) were associated with MALO. Among participants with AF, those carrying the G-allele displayed the highest cumulative incidence of MALO (85%) vs. noncarriers (53%), p=0.03, and p value for interaction<0.01. The strength of the association between PNPLA3 and MALO was statistically significantly greater among older than 60 years (sHR: 2.1, 95% CI: 1.5-2.8), women (sHR: 1.4, 95% CI: 1.1-1.9), and those with AF (sHR: 1.9, 95% CI: 1.5-2.4) or T2DM (sHR: 2.1, 95% CI: 1.5-2.8) as compared with their counterparts, p value for interaction between PNPLA3 and each factor<0.01.

Conclusions: The deleterious effects of PNPLA3 rs738409 on the risk of MALO are significantly worsened by advanced fibrosis, age, T2DM, and sex.