The impact of BMI on the causal relationship between NAFLD and OA: A 2-sample Mendelian randomization study exploring gene interactions and metabolic pathways.

This study aims to investigate the role of body mass index (BMI) in modulating the causal relationship between nonalcoholic fatty liver disease (NAFLD) and osteoarthritis (OA), focusing on the impact of BMI on metabolic pathways. Two-sample Mendelian randomization analysis was conducted using genome-wide association study data to assess how BMI affects the relationship between NAFLD and OA. The study was divided into 3 BMI groups: BMI < 25, BMI 25 to 30, and BMI > 30. Additionally, gene expression differences between damaged and undamaged cartilage samples from individuals in these BMI categories were validated through qPCR. Mendelian randomization analysis revealed a negative association between NAFLD and OA in individuals with BMI < 25 (OR: 0.7215, 95% CI [0.5214-0.9984], P = .048), while a positive association was found in individuals with BMI > 30 (OR: 1.0956, 95% CI [1.0294-1.1661], P = .0029). Gene expression analysis showed significant downregulation of ULK3 in damaged cartilage in the BMI < 25 group, while ACER3, RAB14, ZNF600, and ADARB1 exhibited significant upregulation in the BMI > 30 group. Our findings highlight the critical role of BMI in the relationship between NAFLD and OA. In the low BMI group, enhanced autophagy and lower systemic inflammation may protect joint health, while obesity-related metabolic dysfunction and chronic low-grade inflammation contribute to OA progression in the high BMI group. The differential expression of ULK3, ACER3, RAB14, ZNF600, and ADARB1 genes across BMI categories provides potential clinical therapeutic targets for BMI-specific interventions in NAFLD and OA.