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…
How strong is the evidence?
Evidence Hub reads this as a meta-analysis, done in people. Its evidence level is 1 of 5 (Highest · pooled evidence). Pooled evidence from several studies sits at the top of the evidence pyramid. Reported size: 474 participants or records.
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