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

Background: & Aims. Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in all ages that may cause significant morbidity and mortality. The pathogenesis of the disease is not fully elucidated but genetic factors have a major role in the development of NAFLD. Prader-Willi syndrome (PWS) is a neurogenetic, multisystemic disorder in which the main symptom is lack of satiety with uncontrolled eating and severe obesity. Despite obesity, NAFLD is relatively rare in PWS. The aim of this study was to assess whether known NAFLD-associated small nucleotide variants (SNVs) play a role in the protection from NAFLD in PWS. Approach & Results. Using targeted amplicon next generation sequencing, we studied DNA from patients with PWS and genotyped 13 SNVs that were previously associated with high risk for NAFLD. The study population included 142 (69 females) individuals with genetically confirmed PWS. Median age was 17.5 years, BMI z-score was 2.13 ± 1.9 and mean ALT and AST were 22 ± 20 units/L and 29 ± 17 units/L, respectively. Five of the 13 SNVs showed significantly lower frequency of the risk allele in our cohort compared to healthy population frequencies. Cumulative risk score for all 13 SNVs was also significantly lower in our cohort of PWS patients compared to the healthy population (adjusted p-value, 1.85E-5). Furthermore, it was found that Ashkenazi Jews have lower frequency of the risk alleles of NAFLD. Conclusions. Our results show that genetic factors may protect patients with PWS from developing NAFLD. Larger scale studies should be performed to confirm our findings.