Genome-wide association study and Mendelian randomization analyses reveal insights into bladder cancer etiology
Menée à l'aide d'une méthode de randomisation mendélienne et de données européennes portant sur 708 432 témoins et 6 984 patients atteints d'un cancer de la vessie, cette méta-analyse d'association pangénomique identifie 17 loci de susceptibilité à la maladie ainsi que des facteurs de risque modifiables
The causes of bladder cancer are not completely understood. Our objective was to identify blood proteins and modifiable causal risk factors for bladder cancer by combining genome-wide association studies (GWAS) and Mendelian randomization (MR) analyses.We first performed a GWAS meta-analysis of 6984 bladder cancer cases and 708 432 controls from three European databases. Next, we conducted two-sample MR and colocalization analyses using data from the present GWAS and published GWAS meta-analyses on plasma proteins and modifiable factors.GWAS meta-analysis uncovered 17 bladder cancer susceptibility loci, of which 3 loci were novel. Genes were enriched in pathways related to the metabolic and catabolic processes of xenobiotics and cellular detoxification. Proteome-wide MR analysis based on cis-acting genetic variants revealed that higher plasma levels of glutathione S-transferases were strongly associated with a reduced risk of bladder cancer. There is strong evidence of colocalization between GSTM1 and bladder cancer. Finally, multivariable MR analyses of suspected risk factors for bladder cancer revealed independent causal associations between smoking and adiposity, particularly abdominal obesity, and risk of bladder cancer.Findings from this large-scale GWAS and multivariable MR analyses highlight the key role of detoxification processes, particularly glutathione S-transferase 1, as well as smoking and abdominal obesity in bladder cancer etiology.
JNCI Cancer Spectrum 2024