An epigenetic–metabolic framework linking genetically prioritized LDHA to clear cell renal cell carcinoma susceptibility

Introduction Lactate dehydrogenase A (LDHA) is implicated in clear cell renal cell carcinoma (ccRCC), but the genetic, epigenetic, and metabolic context of this association remains incompletely characterized. Methods We integrated whole-blood eQTLGen data and FinnGen ccRCC summary statistics using two-sample Mendelian randomization and summary-data-based Mendelian randomization. LDHA-related DNA methylation and circulating metabolite signals were evaluated in exploratory analyses. Expression and pathway associations were examined in renal transcriptomic datasets. LDHA was knocked down using two independent siRNAs in 786-O and CAKI-1 cells, followed by measurements of cellular lactate and NAD content, migration, colony formation, and EMT-associated proteins. Results Genetically predicted LDHA expression was associated with higher ccRCC susceptibility (inverse-variance weighted OR = 2.04, 95% CI 1.34–3.10, P = 8.09 × 10), with supportive SMR evidence. LDHA expression was higher in ccRCC than in normal kidney tissue. Three CpG sites were prioritized, but the confidence intervals for their product-of-coefficients estimates included zero. Deoxycarnitine was nominated as a hypothesis-generating metabolic correlate, with a descriptive pathway proportion of 12.46%. LDHA-high tumors were associated with glycolysis, hypoxia, EMT, MYC targets, mTORC1 signaling, and oxidative phosphorylation. In both cell lines, LDHA knockdown reduced cellular lactate and NAD content, migration, and clonogenic growth and altered EMT-associated protein expression. Discussion Convergent genetic, transcriptomic, and cellular findings support LDHA as a ccRCC-relevant gene. The CpG and deoxycarnitine results remain exploratory and do not establish epigenetic regulation, causal mediation, or a validated CpG–LDHA–deoxycarnitine pathway.