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

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.

The two levels of care for diabetes in a developing country: Mechanisms for improved intermediate health outcomes.

India has over 70 million citizens with diabetes, the second-most of any country worldwide. Disparities in learning skills, resources, education, and physician practices make it difficult to practically implement the diabetes management guidelines recommended by international scientific organizations. In its guidelines, the International Diabetes Federation advocates for three different levels of care based on availability of resources. This study investigates the differences in intermediate health outcomes between two diabetes care programs: one a comprehensive diabetes centre, the other a limited care setting. The comprehensive centre offers telemedicine and periodic diabetes education, empowering patients and providing 24-hour advice on lifestyle modifications, diet, and exercise. All patients of this centre practice self-monitoring of blood glucose. The subjects in the limited care setting receive minimal investigations and periodic physical follow-ups, and few patients have access to home glucose monitoring. The results showed that HbA1c (7.62 vs. 8.58, p=0.003), cholesterol (134.4 vs. 173.4, p<0.001), and diastolic blood pressure (72.9 vs. 77.0, p=0.016) were significantly lower in patients receiving comprehensive care, while the reductions in systolic blood pressure (134.6 vs. 138.7, p=0.202) did not achieve statistical significance. These reductions, which remained significant after correcting for confounding factors, could be attributed to more aggressive treatment regimens in the comprehensive care centre, as well as the real-time, frequent communication with medical professionals in the telemedicine program.

Modification of neurobehavioral effects of mercury by genetic polymorphisms of metallothionein in children.

Mercury (Hg) is neurotoxic, and children may be particularly susceptible to this effect. A current major challenge is the identification of children who may be uniquely susceptible to Hg toxicity because of genetic disposition. We examined the hypothesis that genetic variants of metallothionein (MT) that are reported to affect Hg toxicokinetics in adults would modify the neurotoxic effects of Hg in children. Five hundred seven children, 8-12 years 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 7 subsequent annual intervals for neurobehavioral performance and urinary Hg levels. Following the completion of the clinical trial, we performed genotyping assays for variants of MT isoforms MT1M (rs2270837) and MT2A (rs10636) 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. Among girls, few significant interactions or independent main effects for Hg exposure and either of the MT gene variants were observed. In contrast, among boys, numerous significant interaction effects between variants of MT1M and MT2A, alone and combined, with Hg exposure were observed spanning multiple domains of neurobehavioral function. All dose-response associations between Hg exposure and test performance were restricted to boys and were in the direction of impaired performance. These findings suggest increased susceptibility to the adverse neurobehavioral effects of Hg among children with relatively common genetic variants of MT, and may have important public health implications for future strategies aimed at protecting children and adolescents from the potential health risks associated with Hg exposure. We note that because urinary Hg reflects a composite exposure index that cannot be attributed to a specific source, these findings do not support an association between Hg in dental amalgams specifically and the adverse neurobehavioral outcomes observed.