There were 32.8% men and 66.2% women in the total study population, and 83% of the subjects were non-smokers,

3% former smokers, and 14% smokers. The median age of the subjects from the control area was 7–10 years higher than the median age from the other two areas (p-value Kruskal–Wallis-test < 0.001). Median levels of B-Cd and U-Cd increased from low to high exposure groups, and the same trends were seen for all kidney markers apart from UNAG, where low and moderate exposure groups demonstrated similar median levels. Thus, the genetic association MAPK Inhibitor high throughput screening studies were based on exposure groups. However, as there was an overlap between the B-Cd values among the groups, in an alternative approach the subjects were grouped by B-Cd tertiles. The cut-off values were 1.7 μg/L and 3.2 μg/L. Thus, there were N = 174 in the lowest, N = 164 in the middle, and N = 173 in the highest tertile. The genotype and allele frequencies of MT1A rs11076161, MT2A rs10636 and MT2A rs28366003 were tabulated in Table 2.

All three SNPs demonstrated allele frequencies Bafetinib in vitro > 5%. The Chi square (χ2) test showed that the genotypic distributions of all three SNPs did not deviate from the Hardy–Weinberg equilibrium (p > 0.05). First, the impact of genotype on the B-Cd concentration was evaluated in each exposure group. For MT1A rs11076161 and MT2A rs10636, an allele-dosage effect could be observed ( Fig. 1, and Supplementary Fig. 1) where variant genotypes showed slightly higher B-Cd levels in the moderate and the high exposure groups. There were very few (≤ 10) variant Fossariinae homozygotes for MT2A rs28366003 and the variant genotypes (GG and AG) were thus combined. The variant genotypes for MT2A rs28366003 demonstrated higher B-Cd levels as well, also in the low exposure group (Supplementary

Fig. 2). The trend for higher B-Cd with increasing number of variant alleles was significant for MT1A rs11076161 in the high exposure group (p-value = 0.032 unadjusted; p-value = 0.033 adjusted for sex, age and smoking). P-values for trend in the other exposure groups were p > 0.1. A non-significant trend was also seen for MT2A rs28366003 in the low exposure group (unadjusted p-value = 0.099; adjusted p-value = 0.075). In the analysis grouped by B-Cd tertiles, the trend for increased B-Cd with increasing number of variant alleles of rs11076161 became more pronounced in the middle tertile (p-value for trend = 0.001 both, unadjusted and adjusted for age, sex, and smoking). The trends for rs10636 and rs28366003 disappeared. In the analyses grouped by B-Cd tertiles, there was very little difference between the adjusted R2 for rs11076161 only (0.06) compared to the model including age, sex and smoking as well (0.07). Secondly, the same analysis was performed for U-Cd, but no clear allele dosage effect for MT1A rs11076161 or MT2A rs10636 was found (data not shown).