Modification of the association between lead exposure and amyotrophic lateral sclerosis by iron and oxidative stress related gene polymorphisms

Our objective was to examine whether functional polymorphisms in hemochromatosis (HFE; H63D and C282Y), transferrin (TfC2), and glutathione-s-transferase Pi1 (GSTP1; Ile105Val) genes modify any lead-ALS association. We measured blood lead using atomic absorption spectroscopy and bone lead – a biomarker of cumulative lead exposure – using K-shell-X-ray fluorescence in 100 neurologist-confirmed ALS cases and 194 controls, the latter recruited as part of two separate studies; all subjects lived in New England. Participants were considered variant carriers or wild-type for each polymorphism. To assess effect modification, we included cross-product terms between lead biomarkers and each polymorphism in separate adjusted polytomous logistic regression models. Compared with wild-type, the odds ratio (OR) per 15.6 μg/g patella lead (interquartile range; IQR) was 8.24 (95% CI 0.94–72.19) times greater among C282Y variant carriers, and 0.34 (95% CI 0.15–0.78) times smaller among H63D variant carriers. Results were weaker for tibia lead. Compared with wild-type the OR per 2 μg/dl blood lead (IQR) was 0.36 (95% CI 0.19–0.68) times smaller among H63D variant carriers, and 1.96 (95% CI 0.98–3.92) times greater among GSTP1 variant carriers. In conclusion, we found that HFE and GSTP1 genotypes modified the association between lead biomarkers and ALS. Contrasting modification by the HFE polymorphisms H63D and C282Y may suggest that the modification is not simply the result of increased iron.