Interaction Between HFE Polymorphisms and Cumulative Lead Exposure on the Risk of Amyotrophic Lateral Sclerosis

Background We previously found an association between cumulative lead (Pb) exposure and risk of amyotrophic lateral sclerosis (ALS). Polymorphisms in the hemochromatosis (HFE) gene—involved in regulating iron uptake—have previously been associated with ALS. Oxidative stress may contribute to ALS pathophysiology, and excess iron can amplify toxic effects of Pb related to oxidative stress. No study has examined the possible modifying role of HFE on the association of cumulative Pb exposure with ALS risk. Aim To determine whetherHFEpolymorphisms alter the association of cumulative Pb exposure with ALS risk. Methods We measured bone Pb—a biomarker of cumulative Pb exposure—using K-shell-X-Ray Fluorescence in 100 neurologist-confirmed ALS cases and 192 controls from New England. We genotyped H63D and C282YHFE polymorphisms; participants were considered variant carriers or not for each. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) for ALS using logistic regression adjusted for age, sex, education, and smoking. To assess effect modification by HFE polymorphism, we included in one model terms for Pb (continuous), H63D and C282Y genotypes (separately), and separate cross-product terms between Pb and the polymorphisms. Results We found an elevated OR for ALS among H63D variant carriers (OR: 5.30; 95% CI: 1.81-15.52), but not C282Y carriers, as seen in other studies. The cross-products terms indicated that the OR for association of patella lead with ALS among C282Y variant carriers was 15 times larger (15.48; 95% CI: 1.54-155.9) than that among those without C282Y variants, while the OR among H63D variant carriers was about half as large (0.43; 95% CI: 0.20-0.93) as that among those without H63D variants. Conclusion Our results suggest that the H63D and C282Y HFE genotypes modify the association of Pb with ALS risk, but in opposite directions. Thus effects on iron are unlikely to explain the findings since both H63D and C282Y increase labile iron.