Author information

¹Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine Indiana University Health, Indianapolis, Indiana, USA.

²Division of Gastroenterology and Hepatology, Department of Medicine, MASLD Research Center, University of California, San Diego School of Medicine, La Jolla, California, USA.

³Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland.

⁴Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.

⁵Division of Gastroenterology and Hepatology, Saint Louis University, St Louis, Missouri.

⁶Division of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio, USA.

⁷Liver Institute Northwest, Seattle, Washington, USA.

⁸Division of Gastrointestinal and Liver Diseases, Department of Medicine, University of Southern California, Los Angeles, California, USA.

⁹Department of Biostatistics and Epidemiology, Johns Hopkins University, Baltimore, Maryland, USA.

¹⁰Division of Gastroenterology and Hepatology, Department of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA.

Abstract

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

Approach and results: A total of 2075 adults with biopsy-confirmed metabolic dysfunction-associated steatotic liver disease (MASLD) were enrolled in the metabolic dysfunction-associated steatohepatitis Clinical Research Network (MASH CRN) studies and followed prospectively until death, transplant, or withdrawal of consent. One hundred four MALOs were recorded during an average of 4.3 years. PNPLA3 G-allele (Adj. sub-hazard ratio (sHR): 1.4, 95% 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 (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%) versus 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 type 2 diabetes mellitus (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 AF, age, type 2 diabetes mellitus, and sex.