PNPLA3 Polymorphism Is Inversely Correlated with Aortic Stiffness in Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease Without Fibrosis

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) corresponds to the condition of increased hepatic fat levels, which is the leading cause of hepatic failure and carcinoma. It is also an independent risk factor for cardiovascular disease (CVD) and mortality. MASLD can be due to obesity with insulin resistance and/or genetic predisposition, i.e., polymorphism in the patatin-like phospholipase domain-containing 3 (PNPLA3) gene. PNPLA3 polymorphism has been associated with increased hepatic fat levels, fibrosis, cirrhosis, and hepatocellular carcinoma, while its association with CVD remains to be fully understood. The aim of the current study was to examine whether the vascular phenotype of patients with MASLD differed between carriers and noncarriers of the PNPLA3 polymorphism. Adult patients with MASLD underwent clinical assessment, PNPLA3 genotyping, arterial tonometry for aortic stiffness measurement, and ultrasound examination of carotid arteries. In total, 117 patients with MASLD and no fibrosis (median hepatic stiffness was 4.71 kPa) were recruited. Carriers of the PNPLA3 polymorphism were younger and exhibited higher levels of ALT and APRI, as compared to wild-type subjects. On the other hand, carriers of the PNPLA3 polymorphism had not only a better metabolic profile (i.e., lower glucose and glycated hemoglobin) but also lower blood pressure, carotid intima-media thickness (IMT), and cardiovascular risk. In addition, PNPLA3 polymorphism was negatively correlated with aortic stiffness, which is a marker of arteriolosclerosis and vascular ageing. Our data are consistent with previous observations that in case of genetically-driven MASLD, there is an inverse association with common predictors of CVD. Our data support the view that the main contributors to CVD risk in patients with MASLD remain conventional cardiometabolic risk factors (i.e., age, glucose) that are more likely to be found in metabolic syndrome-related MASLD rather than genetically-driven MASLD, at least in the first stages of the disease.

Keywords: CVD; MASLD; PNPLA3; aortic stiffness; arterial tonometry; cardiovascular risk; carotid intima-media thickness.

Figure 1

Metabolic differences between patients with and without PNPLA3 rs738409[G] allele. Variations in (A) age; (B) alanine aminotransferase (ALT); (C) aspartate aminotransferase to platelet ratio index (APRI); (D) systolic blood pressure (SBP); (E) glycaemia; (F) glycated hemoglobin (HbA1c). Results are reported as median (IQR). Comparison within groups was performed with the Wilcoxon test. p < 0.05 was considered statistically significant.

Figure 2

Cardiovascular phenotype of patients with and without PNPLA3 rs738409[G] allele. (A) central systolic blood pressure (cSBP); (B) pulse wave velocity (PWV); (C) mean intima-media thickness (IMT mean). Results are reported as median +IQR. Comparison within groups was performed with the t-test or the Wilcoxon test based on data distribution. p < 0.05 was considered statistically significant.