06 (95% CI − 0.8 to 0.6) compared
to heterozygotes (ß-coefficient 0.18; 95% CI 0.04 to 0.3). The threshold for having affected kidney function was based on 95th percentile of UB2M and concentrations of the individuals in the control area (corresponding to 1.49 mg/gCr UB2M and 20.3 U/gCr UNAG) for persons younger than 80 years. With this threshold 12.3% (N = 46) of the individuals in the medium and highly polluted areas had affected kidney function measured as UB2M and 15% (N = 56) measured as UNAG. Carriers of rs11076161 variant GKT137831 genotypes (AA/AG) had an odds ratio of 2.8 (95% CI 1.4–5.8; P = 0.004) for UB2M above threshold compared to carriers of the GG genotype (adjusted for U-Cd; odds ratio = 3.3 (95% CI 1.5–7.2; P = 0.003, adjusted for U-Cd, sex, age, and smoking). None of the other SNPs affected
the risk of having affected kidney function measured as increased levels of UB2M or UNAG. Despite the known individual susceptibility of Cd toxicity, strikingly little is known about the role of our genetic background for Cd sensitivity. Here we have identified a genetic marker that modifies Cd-associated renal toxicity: with elevating Cd concentration the MT1A rs11076161 AA carriers demonstrated http://www.selleckchem.com/products/AZD2281(Olaparib).html the highest concentrations of UNAG and UB2M in urine. Also, we found a relationship between the MT1A rs11076161 AA genotype and B-Cd at high Cd exposures. One major strength is that the Cd exposure varies widely within this study: B-Cd ranged between 0.11 and 21, U-Cd between 0.05 and 75 μg/L. We analyzed UNAG and UB2M,
which are very sensitive biomarkers of renal tubular damage (Bernard, 2004). Furthermore, the study population was ethnically homogenous, and the study participants were recruited so that living PLEKHM2 conditions, social and economic conditions and lifestyles were similar in the different areas. The genotyping was done with Taqman assays that are less prone to errors compared to restriction fragment length polymorphism analysis and quality control was strict. To our knowledge no other studies were performed of an appropriate study size suitable for genetic association studies with both well-defined exposure and kidney toxicity assessments. Initially, we kept the classification in exposure groups in the statistical analyses. However, as there was an overlap of B-Cd concentrations between the groups, the subjects were also grouped by B-Cd tertiles and in each tertile the associations between genotype and B-Cd, U-Cd, UNAG and UB2M were evaluated. This strengthened the associations for rs11076161. In this study multiple testing was performed: 3 polymorphisms and 4 outcomes were included in several multivariate regression models. Thus, there might problems with false positive findings. According to Wacholder et al. (2004) the false positive report probability is influenced by the significance level, statistical power and prior probability of the association tested.