Mendelian Randomization Identified SLC2A9 as a Novel cis-eQTL-Mediated Susceptibility Gene in Suppressing Renal Cancer and Its Related Metabolic Mechanisms.

OBJECTIVE: Mendelian randomization (MR) analysis has currently been widely used in combination with expression quantitative trait loci (eQTLs) or cis-eQTLs for identifying novel drug targets in various diseases. Hence in this article, we first integrated MR analysis with eQTLs and cis-eQTLs to reveal the causal effects among SLC2A9 and renal cancer (RC), along with its related metabolic mechanisms.

METHODS: Related genome-wide association study (GWAS) data were obtained from online datasets. Two-sample MR and summary-data-based MR study (SMR) analyses were applied to assess the causal effects among SLC2A9 eQTL or cis-eQTLs and RC, respectively. Sensitivity analysis confirmed the robustness and heterogeneity of the results. Besides, 1400 metabolites were enrolled as mediators to further reveal the related metabolic mechanisms of SLC2A9 eQTL involved in RC.

RESULTS: Our results found that SLC2A9 eQTL was markedly associated with low risks of RC in the IEU OpenGWAS eQTLs dataset (discovering) (p = 0.030). The eQTLGEN and GTEx Whole Blood datasets validated the causal effects among SLC2A9 cis-eQTL and RC, reducing RC risks (both p  < 0.05). The TCGA-KIRC and the CPTAC-KIRC datasets validated the mRNA and protein expression levels of SLC2A9 in RC, confirming its antitumor roles in RC (both p  < 0.05). A total of five metabolites were finally identified to reveal the related metabolic mechanisms of SLC2A9 eQTL involved in RC (all p  < 0.05).

CONCLUSIONS: This study indicated that SLC2A9 eQTL or cis-eQTL was markedly associated with low risks of RC and played an antitumor role in RC, along with preliminary identification of five metabolic pathways for its potential mechanisms requiring further investigation.