Markedly Low Prevalence of Fatty Liver Despite Obesity in Prader–Willi Syndrome: A Search for Protective Genetic Markers

Introduction and objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common liver disease across all age groups and is associated with significant morbidity and mortality. The pathogenesis of the disease is not fully understood, but genetic factors appear to play a major role in the development of MASLD. Prader–Willi syndrome (PWS) is a neurogenetic, multisystem disorder characterized primarily by hyperphagia, leading to uncontrolled eating and severe obesity. Despite the high prevalence of severe obesity in PWS, MASLD is relatively rare. The aim of this study was to assess whether single-nucleotide variants (SNVs) known to be associated with MASLD may play a role in the development of MASLD in individuals with PWS. Patients and methods: Using targeted amplicon-next-generation sequencing, we studied DNA from 142 individuals (69 females), with a median age of 17.5 years, with genetically confirmed PWS, and genotyped 13 SNVs that were previously associated with a high risk for MASLD. Results: Body mass index (BMI) z-score was 2.1 9IQR: 1.42, 2.490, and the median alanine aminotransferase and aspartate aminotransferase were 18 (IQR: 14, 25) units/L and 24 (IQR: 19, 32) units/L, respectively. Five of the 13 SNVs showed significantly lower frequencies of the risk allele in our cohort compared to frequencies reported in the general population. The cumulative risk score for all 13 SNVs was significantly lower in our cohort of PWS patients compared to the healthy population (FDR-adjusted P-value, 1.85 × 10⁻⁵). Conclusions: We identified genetic factors that may protect patients with PWS from developing MASLD. These findings may contribute to understanding the pathogenesis of MASLD in individuals with nonsyndromic obesity.