Developmentally restricted genetic determinants of human arsenic metabolism: association between urinary methylated arsenic and CYT19 polymorphisms in children

Abstract

We report the results of a screen for genetic association with urinary arsenic metabolite levels in three arsenic metabolism candidate genes, PNP, GSTO, and CYT19, in 135 arsenic-exposed subjects from the Yaqui Valley in Sonora, Mexico, who were exposed to drinking water concentrations ranging from 5.5 to 43.3 ppb. We chose 23 polymorphic sites to test in the arsenic-exposed population. Initial phenotypes evaluated included the ratio of urinary inorganic arsenic(III) to inorganic arsenic(V) and the ratio of urinary dimethylarsenic(V) to monomethylarsenic(V) (D:M). In the initial association screening, three polymorphic sites in the CYT19 gene were significantly associated with D:M ratios in the total population. Subsequent analysis of this association revealed that the association signal for the entire population was actually caused by an extremely strong association in only the children (7-11 years of age) between CYT19 genotype and D:M levels. With children removed from the analysis, no significant genetic association was observed in adults (18-79 years). The existence of a strong, developmentally regulated genetic association between CYT19 and arsenic metabolism carries import for both arsenic pharmacogenetics and arsenic toxicology, as well as for public health and governmental regulatory officials.

Figure 1. Summary of frequency and gene context of polymorphisms discovered in CYT19 in EA (Europe) and IA (America) ancestry subjects. ID column indicates the polymorphism identification number relative to the location in the consensus sequence, with the first base of the consensus numbered 1. ATG offset column indicates the polymorphism location relative to the first base “A” of the ATG methionine initiation codon. Freq % columns are the minor allele frequency, graphically displayed in the column to the right. SNP, single nucleotide polymorphism.

Figure 2. D:M ratio, stratified by genotype and age group at three CYT19 polymorphic positions in unrelated Mexican subjects. Log-transformed D:M ratio for each group is shown as geometric mean, with error bars delineating the 95% CI of the geometric mean values. Genotype groups are depicted on the abscissa. p-Values (unadjusted for multiple comparisons) are from a two-tailed t-test comparing the geometric means of the genotype groups, and shown only when p < 0.05. Graphs are presented for CYT19 sites 2393, 7388, and 30585.

Figure 3. 3:M ratio, stratified by genotype at CYT19 site 30585 in the group of children analyzed in Figure 2. 3:M ratio for each genotype group is shown as geometric mean, with error bars delineating the 95% CI of the geometric mean values. Genotype groups are depicted on the abscissa. p-Value (unadjusted for multiple comparisons) = 0.023, two-tailed t-test comparing the geometric means of the genotype groups.