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

• Published in: Clinical gastroenterology and hepatology Vol. 21; no. 13; pp. 3314 - 3321.e3
• Main Authors: Rosso, Chiara, Caviglia, Gian Paolo, Birolo, Giovanni, Armandi, Angelo, Pennisi, Grazia, Pelusi, Serena, Younes, Ramy, Liguori, Antonio, Perez-Diaz-del-Campo, Nuria, Nicolosi, Aurora, Govaere, Olivier, Castelnuovo, Gabriele, Olivero, Antonella, Abate, Maria Lorena, Ribaldone, Davide Giuseppe, Fariselli, Piero, Valenti, Luca, Miele, Luca, Petta, Salvatore, Romero-Gomez, Manuel, Anstee, Quentin M., Bugianesi, Elisabetta
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2023
• Subjects: Carcinoma, Hepatocellular - complications; Carcinoma, Hepatocellular - epidemiology; Carcinoma, Hepatocellular - genetics; Esophageal and Gastric Varices - complications; Female; Gastroenterology and Hepatology; Gastrointestinal Hemorrhage - complications; Genetic Predisposition to Disease; Genotype; Humans; Liver Neoplasms - complications; Liver Neoplasms - epidemiology; Liver Neoplasms - genetics; Liver-Related Outcomes; Male; Middle Aged; NAFLD; NASH; Non-alcoholic Fatty Liver Disease - complications; Non-alcoholic Fatty Liver Disease - epidemiology; Non-alcoholic Fatty Liver Disease - genetics; PNPLA3; Polymorphism, Single Nucleotide; Retrospective Studies; NAFLD; SNP; Liver-Related Outcomes; PNPLA3; HCC; NASH; BMI; nonalcoholic steatohepatitis; nonalcoholic fatty liver disease; single nucleotide polymorphism; body mass index; hepatocellular carcinoma
• ISSN: 1542-3565; 1542-7714; 1542-7714
• DOI: 10.1016/j.cgh.2023.04.024

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. 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. 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). 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. [Display omitted]