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논문분류	춘계학술대회 초록집
제목	EHHADH Protects Against Diabetic Nephropathy through Improving Lipid Metabolism: Evidence from Mendelian Randomization
저자	Lei Chen
출판정보	2026; 2026(1):
키워드	Mendelian randomization, Diabetic nephropathy, Mitochondrial dysfunction
초록	Objectives: Mitochondrial dysfunction plays a critical role in diabetic microvascular complications, particularly diabetic nephropathy (DN) and diabetic retinopathy (DR). Although these complications often co-occur clinically, their shared pathogenic mechanisms remain unclear. Systematic investigation of mitochondria-related genes may identify key regulators for DN and allow independent validation in DR, providing potential targets for intervention. Methods: We obtained 1,136 human protein-coding genes with confirmed mitochondrial localization from the MitoCarta3.0 database. Using expression quantitative trait loci (eQTL) from the eQTLGen consortium and GWAS summary statistics for type 2 diabetes (T2D) from nine independent cohorts, we performed drug-target Mendelian randomization (MR) to identify genes causally associated with T2D. DN was analyzed as the discovery cohort, and the protective effects of key genes were subsequently replicated in DR using MR. Tissue-specific eQTL data from GTEx were used to assess potential gene expression effects across relevant tissues. Mediation MR explored potential pathogenic pathways, and phenome-wide MR evaluated the effects of key genes on other diseases. Finally, bulk RNA-seq data from DN and DR tissues were analyzed to validate differential expression and assess diagnostic and biological relevance. Results: EHHADH was identified as a protective gene for T2D and DN. Reduced expression of EHHADH, particularly in blood, may increase the risk of T2D and DN. Blood metabolites, including isovalerylcarnitine and methylpyridine sulfate, may mediate the protective effect of EHHADH on T2D. MR analysis in DR replicated the protective effect observed in DN. Phenome-wide MR did not reveal causal associations between EHHADH and other systemic diseases. Bulk RNA-seq confirmed significant downregulation of EHHADH in DN and DR tissues, suggesting that lipid metabolic dysregulation may be a shared pathogenic pathway linking EHHADH to both microvascular complications. Conclusion: EHHADH may play a key regulatory role in the pathogenesis of T2D and its microvascular complications.
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