The Impact of Omega Fatty Acids on DKD: A Multimodal Study Integrating Mendelian Randomization, Proteomic Mediation Analysis, and Meta‐Analysis

Abstract

Diabetic kidney disease (DKD), a significant microvascular complication of diabetes, is escalating the global disease burden. Research suggests free fatty acids, particularly specific polyunsaturated fatty acids, may influence DKD development and progression through anti‐inflammatory and antioxidant mechanisms. However, existing evidence remains controversial, and the precise underlying mechanisms are still unclear. We performed a two‐sample Mendelian randomization (MR) analysis leveraging genome‐wide association study data and plasma proteomic panels. A two‐step protein‐mediated MR framework and Reactome pathway enrichment were employed to identify mediators and elucidate biological pathways. Subsequently, we conducted a meta‐analysis of clinical studies to comprehensively evaluate the impact of omega‐3 supplementation on DKD patients. Genetically predicted higher plasma omega‐3 fatty acid levels were causally associated with reduced DKD risk (odds ratio [OR] = 0.869, 95% confidence interval [CI]: 0.772–0.978, p = 0.020), while omega‐6 fatty acids showed no significant causal association (OR = 0.895, 95% CI: 0.731–1.096, p = 0.283). Fourteen plasma proteins showed nominally significant evidence of partial mediation, with consistent mediation directions and mediation proportions ranging from 2.10% to 29.80%. Potential mediators included neuronal pentraxin‐2, hemoglobin subunit theta‐1, and periostin. Enrichment analysis highlighted Notch signaling, apoptosis regulation, and chronic inflammatory pathways as core processes. Meta‐analysis of 12 randomized controlled trials (474 participants) showed that omega‐3 supplementation significantly reduced triglycerides (mean difference [MD] = −0.27 mmol/L, 95% CI: −0.35 to −0.20, p < 0.00001), systolic blood pressure (MD = −4.50 mmHg, 95% CI: −7.57 to −1.42, p = 0.004), and kidney injury molecule‐1 (MD = −1.74 pg/mL, 95% CI: −2.58 to −0.89, p < 0.0001), while increasing high‐density lipoprotein cholesterol (MD = 0.14 mmol/L, 95% CI: 0.04–0.23, p = 0.004). No significant improvements in albumin‐to‐creatinine ratio or estimated glomerular filtration rate were observed. Genetic evidence demonstrates that elevated omega‐3 fatty acid levels may causally reduce DKD risk, with this protective effect possibly partially mediated by plasma proteins. The meta‐analysis findings confirm that omega‐3 supplementation effectively ameliorates lipid profiles, systolic blood pressure, and early renal impairment in DKD cases. Dietary omega‐3 supplementation may offer a protective effect against DKD, though this association requires further validation.