Effect Modification by Transferrin C2 Polymorphism on Lead Exposure, Hemoglobin Levels, and IQ

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-Kamath 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 1g/dl higher hemoglobin was associated with -77 (95% CI: -136, -18) and 17 (95% CI 14, 21) 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 -21(95% CI: -65, 24) and 28 (95% CI: 15, 40) 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.