Effect modification by transferrin C2 polymorphism on lead exposure, hemoglobin levels, and IQ

Abstract

Background Iron deficiency and lead exposure remain significant public health issues in many parts of the world and are both independently associated with neurocognitive deficits. Polymorphisms in iron transport pathways have been shown to modify the absorption and toxicity of lead. Objective We hypothesized that the transferrin (TF) C2 polymorphism modifies the effects of lead and hemoglobin on intelligence. Methods Children aged 3–7 years (N=708) were enrolled from 12 primary schools in Chennai, India. The Binet-Kamat Scale of Intelligence were administered to ascertain intelligence quotient (IQ). Venous blood was analyzed for lead and hemoglobin levels. Genotyping for the TF C2 polymorphism (rs1049296) was carried out using a MassARRAY iPLEXTM platform. Stratified analyses and interaction models, using generalized estimating equations, were examined to explore interactions between lead, hemoglobin, and TF C2 categories. Results A one-unit increase in log blood lead and 1 g/dl higher hemoglobin was associated with −7.7 (95% CI: −13.6, −1.8) and 1.7 (95% CI 1.4, 2.1) IQ points, respectively, among children carrying the C2 variant. In comparison, among children who had the homozygous wildtype allele, the same increment of lead and hemoglobin were associated with -−2.1(95% CI: −6.5, 2.4) and 2.8(95% CI:1.5, 4.0) IQ points, respectively. There was a significant interaction between lead (p=0.04) and hemoglobin (p=0.07) with the C2 variant. Conclusion Children who carry the TF C2 variant may be more susceptible to the neurotoxic effects of lead exposure and less protected by higher levels of hemoglobin.

Maternal iron metabolism gene variants modify umbilical cord blood lead levels by gene-environment interaction: a birth cohort study

“…Other research in this area has shown that genetic polymorphisms in iron metabolism genes not only modify lead kinetics, but also confer variable host response to lead exposure. Carriers of the TF P570S gene variant, for example, lose significantly more IQ points per unit of blood lead than children with wild-type genotypes [ 27 ]. Lead-related decreases in birth weight [ 28 ], advancement of cognitive decline [ 24 ], widening of pulse pressure [ 29 ], and prolongation of the QT-interval [ 25 ] have been shown to be amplified in HFE gene variant carriers.…”

Exposure to Mixtures of Metals and Neurodevelopmental Outcomes: A Multidisciplinary Review Using an Adverse Outcome Pathway Framework

“…Nonchemical stressors (e.g., nutritional and socioeconomic status), genetic polymorphisms, and epigenetic changes are also likely to impact responses to chemical mixtures. For example, genetic factors may influence metal uptake and metabolism and modify associations of metals with health outcomes, which could partially explain variability across populations and susceptibility in certain subpopulations.…”

Blood lead levels, iron metabolism gene polymorphisms and homocysteine: a gene-environment interaction study

“…Interactions between lead exposure and the TF gene, possibly resulting from changes in iron distribution and oxidative stress status, have been reported previously. Genetic polymorphisms in the TF gene have been reported to modify the association of lead exposure with prolonged QT intervals, which serve as an indicator of electrocardiographic conduction30 and reduced intelligence quotients 31. Although three SNPs which showed interactions with lead levels are located in the non-functional elements of the TF gene, rs8649, which is in the functional region of the TF gene, is in complete linkage with rs2715632, rs2715631 and rs2715627 (|D′|=1, r 2 =1).…”