PNPLA3 Gene Polymorphisms Affect MASLD Progression Severity Assessed by MRE in a Large Cohort of Clinical Patients

Motivation: Understanding how liver stiffness (LS), which indicates liver disease severity, varies across PNPLA3 alleles and polygenic risk scores (PRS) may improve MASLD patient management. Goal(s): To analyze the association between PNPLA3 variants/PRS and LS distribution, and to assess their role in LS-based risk stratification for liver outcomes. Approach: Logistic regression analyzed PNPLA3 genotype associations with MRE-defined liver outcomes, while linear regression evaluated continuous LS with PNPLA3 alleles or PRS. Results: For genotypes CG and GG versus CC, the odds ratios were 1.9 and 2.4 for advanced fibrosis, 1.6 and 3.0 for cirrhosis, and 2.2 and 3.1 for decompensated cirrhosis, respectively. Impact: Genotype impacts liver stiffness, thus understanding their association is essential for improving MASLD prevention, prognosis, and treatment. Integrating genetic risk and LS assessment could enhance risk prediction for liver complications.