Abstract
Choline metabolism alteration is considered as a metabolic hallmark in cancer, reflecting the complex interactions between carcinogenic signaling pathways and cancer metabolism, but little is known about whether genetic variants in the metabolism pathway contribute to the susceptibility of bladder cancer. Herein, a case–control study comprising 580 patients and 1,101 controls was carried out to analyze the association of bladder cancer with genetic variants on candidate genes involved in the choline metabolism pathway using unconditional logistic regression. Gene expression data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database were applied for differential gene expression analysis. Cox regression was also applied to estimate the role of candidate genes on bladder cancer prognosis. Our results demonstrated that C allele of rs6810830 in ENPP6 was a significant protective allele of bladder cancer, compared to the T allele [Odds ratio (OR) = 0.74, 95% confidence interval (CI) = 0.64–0.86, P = 7.14 × 10–5 in additive model]. Besides, we also found that the expression of ENPP6 remarkably decreased in bladder tumors compared with normal tissues. Moreover, high expression of ENPP6 was associated with worse overall survival (OS) in bladder cancer patients [hazard ratio (HR) with their 95% CI 1.39 (1.02–1.90), P = 0.039]. In conclusion, our results suggested that SNP rs6810830 (T > C) in ENPP6 might be a potential susceptibility loci for bladder cancer, and these findings provided novel insights into the underlying mechanism of choline metabolism in cancers.
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Abbreviations
- BCa:
-
Bladder cancer
- CI:
-
Confidence interval
- DEGs:
-
Differentially expressed genes
- ENPP6 :
-
Ectonucleotide pyrophosphatase/phosphodiesterase 6
- eQTL:
-
Expression quantitative trait loci
- FC:
-
Fold change
- FDR:
-
False discovery rate
- GEO:
-
Gene Expression Omnibus
- GWAS:
-
Genome-wide association study
- HR:
-
Hazard ratio
- HWE:
-
Hardy–Weinberg equilibrium
- LD:
-
Linkage disequilibrium
- LSECs:
-
Liver sinusoidal endothelial cells
- MAF:
-
Minor allele frequency
- MRS:
-
Magnetic resonance spectroscopy
- OR:
-
Odds ratio
- OS:
-
Overall survival
- PCho:
-
Phosphocholine
- SNPs:
-
Single-nucleotide polymorphisms
- TCGA:
-
The Cancer Genome Atlas
- tCho:
-
Total choline
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This study was supported by the National Natural Science Foundation of China (82130096), the Collaborative Innovation Center for Cancer Personalized Medicine and Priority Academic Program Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine).
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ZZ and YL conceived and designed the experiments. MD and HC contributed reagents/materials/analysis tools. ZH and JG wrote the paper. HL, JX, and YW revised the paper. All authors reviewed the manuscript.
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Han, Z., Gu, J., Xin, J. et al. Genetic variants in choline metabolism pathway are associated with the risk of bladder cancer in the Chinese population. Arch Toxicol 96, 1729–1737 (2022). https://doi.org/10.1007/s00204-022-03258-6
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DOI: https://doi.org/10.1007/s00204-022-03258-6