Interaction of tissue inhibitor of metalloproteinase 3 gene polymorphism, blood cadmium and total urinary arsenic levels on clear cell renal cell carcinoma

In renal cell carcinoma (RCC), tissue inhibitor of metalloproteinase (TIMP) 3 expression is lost, suggesting that the TIMP3 gene may function as a tumor suppressor gene. Cadmium (Cd) and arsenic (As) exposure may affect the expression of TIMP3. Here we investigate the association of clear cell RCC with TIMP3 polymorphisms, and explore whether TIMP3 polymorphisms modify the relationship between blood Cd or total urinary As levels and clear cell RCC respectively. We recruited 281 clear cell RCC patients and 689 sex- and age-matched controls. The clear cell RCC was diagnosed by pathological evaluation after image-guided biopsy or surgical resection of the renal tumor. Concentrations of blood Cd and lead, and also total urinary As, were measured. We determined TIMP3 polymorphisms using the Agena Bioscience MassARRAY system. Odds ratio (OR) of clear cell RCC was significantly inversely correlated with TIMP3 rs9609643 GA/AA genotype, with OR = 0.63 (95% confidence interval, CI, 0.44-0.91). For TIMP3 rs715572 AA compared to the GG/GA genotype, the OR of clear cell RCC was 1.60 with 95% CI of 1.01-2.56. Individuals with high blood Cd concentrations and the TIMP3 rs9609643 GG genotype exhibited a higher OR of clear cell RCC than reference groups (OR = 4.48, 95% CI 2.09-9.60). This study presents a novel finding that the GA/AA genotype of TIMP3 rs9609643 significantly decreased the clear cell RCC risk, and AA genotype of TIMP3 rs715572 significantly increased the clear cell RCC risk. Furthermore, this study first identified that the TIMP3 rs9609643 risk genotypes appear to interact with high blood Cd levels to increase the OR of clear cell RCC.