BackgroundRecent genome-wide association studies have revealed that nonalcoholic fatty liver disease (NAFLD) is correlated with genetic polymorphisms. However, the effects of genetic variation on nutritional metabolism and NAFLD are complex and further studies are still needed.ObjectivesThis study aimed to assess the nutritional characteristics interacting with the correlation between genetic predisposition and NAFLD.MethodsWe assessed the 2013–2017 health examination data of 1191 adults aged ≥40 y living in Shika town, Ishikawa Prefecture, Japan. Adults with moderate or heavy alcohol consumption and hepatitis were excluded, and 464 participants who underwent genetic analyses were included in the study. Abdominal echography was performed to diagnose fatty liver condition, and dietary intake and nutritional balance were evaluated using the brief self-administered diet history questionnaire. NAFLD-related gene polymorphisms were identified using Japonica Array v2 (Toshiba).ResultsAmong the 31 single nucleotide polymorphisms, only the polymorphism T-455C in the apolipoprotein C3 (APOC3) gene (rs2854116) was significantly associated with fatty liver condition. The condition was more common in participants with heterozygotes of theAPOC3gene (rs2854116) than in those with the TT and CC genotypes. Significant interactions were observed between NAFLD and the intake of fat, vegetable fat, MUFAs, PUFAs, cholesterol, n-3 FAs, and n-6 FAs. Moreover, participants with NAFLD who presented with the TT genotype had a significantly higher fat intake than those without NAFLD.ConclusionsThe polymorphism T-455C in theAPOC3gene (rs2854116) and fat intake are associated with the NAFLD risk in Japanese adults. Participants with a fatty liver who presented with the TT genotype of rs2854116 had a higher fat intake. Such nutrigenetic interaction can deepen our understanding of the NAFLD pathology. Moreover, in clinical settings, the correlation between genetic factors and nutrition intake should be considered in personalized nutritional interventions against NAFLD.Curr Dev Nutr2023;xx:xx.The study was registered in the University Hospital Medical Information Network Clinical Trials Registry as UMIN 000024915.