title: Modification of the association between lead exposure and amyotrophic lateral sclerosis by iron and oxidative stress related gene polymorphisms.
abstract: 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.
authors.affiliation: Department of Environmental Health, Harvard School of Public Health , Boston, Massachusetts , USA.
authors.forename: Ki-Do
authors.initials: KD
authors.lastname: Eum
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Seals
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Taylor
authors.forename: Matthew
authors.initials: M
authors.lastname: Grespin
authors.forename: David M
authors.initials: DM
authors.lastname: Umbach
authors.forename: Howard
authors.initials: H
authors.lastname: Hu
authors.forename: Dale P
authors.initials: DP
authors.lastname: Sandler
authors.forename: Freya
authors.initials: F
authors.lastname: Kamel
authors.forename: Marc G
authors.initials: MG
authors.lastname: Weisskopf
mesh_terms: D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000453:epidemiology / Q000235:genetics*; D001842:Bone and Bones / Q000378:metabolism; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000235:genetics; D006432:Hemochromatosis / Q000235:genetics; D006801:Humans; D007501:Iron; D007854:Lead / Q000378:metabolism; D020263:Lead Poisoning, Nervous System / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D013054:Spectrophotometry, Atomic; D014168:Transferrin / Q000235:genetics
chemical_list: D014168:Transferrin; D007854:Lead; D007501:Iron; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi
keywords: Amyotrophic lateral sclerosis; epidemiology; hemochromatosis; iron metabolism; oxidative stress