Genetic variants in the death receptor 4 gene contribute to susceptibility to bladder cancer

Death receptor 4 (DR4) is an important mediator of apoptosis, and its dysfunction may be related to carcinogenesis and cancer development. We hypothesized that common variants in the DR4 gene are associated with risk of bladder cancer and test this hypothesis in a case-control study of 368 bladder cancer patients and 368 cancer-free controls. We genotyped six tagging single nucleotide polymorphisms (tagSNPs) in these subjects and found a significantly increased risk of bladder cancer associated with the SNP1−397GT/TT genotype (adjusted OR = 1.55; 95% CI = 1.15-2.09) compared with the GG genotype. This increased risk was more pronounced for superficial bladder cancer. A luciferase assay, performed in vitro, revealed that the −397T allele had a lower transcriptional activity than the −397G allele. Multifactor dimensionality reduction (MDR) analysis indicated that the two-factor model including −397G > T and pack-years of smoking was best for predicting bladder cancer risk. Moreover, a significant additive (but not multiplicative) interaction, was found between the −397G > T polymorphism and smoking on bladder cancer risk. In conclusion, genetic variants of the DR4 gene may be involved in the etiology of bladder cancer, and our findings need further validation by larger studies.