Glycolysis-related genes for bladder cancer: A Mendelian randomization analysis

Glycolysis contributes to tumor progression and treatment resistance in bladder cancer (BLCA). This study aims to identify glycolysis-related genes associated with BLCA risk.

We employed Mendelian randomization (MR) and summary-based MR (SMR) to explore glycolysis-related genes from MSigDB associated with BLCA risk. Genome-wide association study (GWAS) summary statistics for BLCA were obtained from FinnGen (R12) and UK Biobank. Lactate (LAC) and adenosine triphosphate (ATP) GWAS served as metabolic proxies. Inverse-variance weighted (IVW) was the primary MR method. Sensitivity analyses included Cochran's Q test, MR-PRESSO, radial MR, and leave-one-out analysis. SMR integrated expression quantitative trait loci (eQTL) and protein QTL (pQTL) data from eQTLGen/Fenland/UKB-PPP/deCODE to evaluate genetic associations. Colocalization analysis identified shared variants between gene/protein expression and BLCA risk.

In MR analysis, only AK3, PFKP, and ALDH2 had valid instrumental variables, among which only AK3-mediated LAC levels showed a nominal positive association with BLCA risk (IVW OR = 1.69, p = 0.026). eQTL-based SMR analysis revealed that AK3 exhibited a nominal inverse association with BLCA risk (OR = 0.89, p_SMR = 0.023), while PFKP showed a nominal positive association (OR = 1.11, p_SMR = 0.037). In pQTL-based SMR analysis, PFKM showed a nominal positive association (OR = 1.58, p_SMR = 0.01) and colocalization evidence, whereas CHST4 was negatively associated across multiple pQTL cohorts. However, colocalization analysis did not confirm shared genetic signals for AK3, PFKP, or CHST4, and none of the associations were replicated in the UKB cohort.

AK3, PFKM, PFKP, and CHST4 are genetically associated glycolysis-related candidates for BLCA risk, with PFKM showing colocalization support, warranting further functional and translational investigation.