Genetic polymorphisms of catechol-O-methyltransferase modify the neurobehavioral effects of mercury in children

Abstract

Mercury (Hg) is neurotoxic and children may be particularly susceptible to this effect. A current major challenge is identification of children who may be uniquely susceptible to Hg toxicity because of genetic disposition. This study examined the hypothesis that genetic variants of catechol-O-methyltransferase (COMT) that are reported to alter neurobehavioral functions that are also affected by Hg in adults might modify the adverse neurobehavioral effects of Hg exposure in children. Five hundred and seven children, 8-12 yr of age at baseline, participated in a clinical trial to evaluate the neurobehavioral effects of Hg from dental amalgam tooth fillings. Subjects were evaluated at baseline and at seven subsequent annual intervals for neurobehavioral performance and urinary Hg levels. Following the clinical trial, genotyping assays were performed for single-nucleotide polymorphisms (SNPs) of COMT rs4680, rs4633, rs4818, and rs6269 on biological samples provided by 330 of the trial participants. Regression-modeling strategies were employed to evaluate associations between allelic status, Hg exposure, and neurobehavioral test outcomes. Similar analysis was performed using haplotypes of COMT SNPs. Among girls, few interactions for Hg exposure and COMT variants were found. In contrast, among boys, numerous gene-Hg interactions were observed between individual COMT SNPs, as well as with a common COMT haplotype affecting multiple domains of neurobehavioral function. These findings suggest increased susceptibility to the adverse neurobehavioral effects of Hg among children with common genetic variants of COMT, and may have important implications for strategies aimed at protecting children from the potential health risks associated with Hg exposure.

FIGURE 1.

Haplotype block structure of the COMT gene in study subjects. Linkage disequilibrium (LD) plot statistics of rs6269, rs4633, rs4818, and 4680. L1 = Locus 1; L2 = Locus 2; D′ = D prime, a measure of pairwise LD; LOD (logarithm of odds) = LOD score; r² = goodness of fit. Haplotype block structure is as depicted by Haploview. Values for D′ (×100) are shown in shaded cells; cells with D′ = 1.00 are shaded without values indicated.

FIGURE 2.

Associations between performance on the Rey Auditory Verbal Learning Test (RAVLT) Trials 1–5: Sum of Learning & Memory and acute Hg exposure among boys. Scatter plots and simple linear regression fit lines of RAVLT Trials 1–5: Sum test scores by acute Hg exposure (ln[HgU + 1]) are plotted to distinguish boys with the COMT Group B haplotype Mut (ATCA_met-ATCA_met) (open circles, solid line) versus those with Not Group B haplotype status (closed circles, dashed line). The linear slope r² values for Group B and Not Group B are .126 and 2.562E-4, respectively (p < .02). Thus, while acute Hg exposure explains 12.6% of the performance variation among boys with the Group B haplotype, Hg explains virtually no variation among those with Not Group B status.

FIGURE 3.

Associations between performance on the WAIS-III Digit Symbol test of Visual-Spatial acuity and chronic cumulative Hg exposure among boys. Scatter plots and simple linear regression fit lines of WAIS-III Digit Symbol test scores by chronic cumulative Hg exposure (ln[(ΣHgU) + 1]) are plotted to distinguish boys with the COMT Group B haplotype Mut (ATCA_met-ATCA_met) (open circles, solid line) versus those with Not Group B haplotype status (closed circles, dashed line). Linear slope r² values for Group B and Not Group B are .270 and .007, respectively (p < .006). Thus, while chronic Hg exposure explains 27% of the performance variation among boys with the Group B haplotype, it explains less than 1% of variation among those with Not Group B status.