Interplay between PNPLA3 genotype, liver steatosis, and cardiac remodeling in young adults: A magnetic resonance imaging study

Steatotic liver disease (SLD) is associated with cardiovascular disease. The PNPLA3 rs738409C>G variant is a genetic determinant of liver fat accumulation. We investigated the association of the PNPLA3 rs738409C>G variant with cardiac structure and function in young adults, stratified by SLD status. Participants underwent genotyping at 17 years and liver and cardiac magnetic resonance imaging at 27 years. SLD was defined as volumetric liver fat fraction >3.55%. PNPLA3 rs738409 was analyzed primarily using a dominant genetic model (CC vs. CG/GG). Multivariable linear regression was used to evaluate the association between PNPLA3 rs738409C>G and cardiac parameters. Of 657 participants, 38.1% carried PNPLA3 rs738409C>G and 16.4% had SLD. Associations between PNPLA3 rs738409C>G and cardiac parameters were contingent on SLD status, with significant PNPLA3 × SLD interactions observed for left ventricular mass index (LVMi; p = 0.009), left ventricular end-diastolic volume index (LVEDVi; p = 0.015), and right ventricular end-diastolic volume index (RVEDVi; p = 0.049). PNPLA3 rs738409C>G was associated with greater LVMi (p = 0.014), LVEDVi (p = 0.005), and RVEDVi (p = 0.040) among individuals with SLD, but not without SLD. In this non-mechanistic observational study, PNPLA3 rs738409C>G was associated with subclinical cardiac remodeling only in the presence of SLD. These hypothesis-generating findings and any potential mechanisms require confirmation in future studies.