Impact of PNPLA3 rs738409 Polymorphism on the Development of Liver-Related Events in Patients With Nonalcoholic Fatty Liver Disease

Chiara Rosso ¹, Gian Paolo Caviglia ¹, Giovanni Birolo ¹, Angelo Armandi ², Grazia Pennisi ³, Serena Pelusi ⁴, Ramy Younes ⁵, Antonio Liguori ⁶, Nuria Perez-Diaz-Del-Campo ¹, Aurora Nicolosi ¹, Olivier Govaere ⁷, Gabriele Castelnuovo ¹, Antonella Olivero ¹, Maria Lorena Abate ¹, Davide Giuseppe Ribaldone ¹, Piero Fariselli ¹, Luca Valenti ⁸, Luca Miele ⁹, Salvatore Petta ³, Manuel Romero-Gomez ¹⁰, Quentin M Anstee ¹¹, Elisabetta Bugianesi ¹²

PMID: 37149016 DOI: 10.1016/j.cgh.2023.04.024

Abstract

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/m²) 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.

Keywords: Liver-Related Outcomes; NAFLD; NASH; PNPLA3.