title: Amyotrophic lateral sclerosis, lead, and genetic susceptibility: polymorphisms in the delta-aminolevulinic acid dehydratase and vitamin D receptor genes.
abstract: Previous studies have suggested that lead exposure may be associated with increased risk of amyotrophic lateral sclerosis (ALS). Polymorphisms in the genes for delta-aminolevulinic acid dehydratase (ALAD) and the vitamin D receptor (VDR) may affect susceptibility to lead exposure. We used data from a case-control study conducted in New England from 1993 to 1996 to evaluate the relationship of ALS to polymorphisms in ALAD and VDR and the effect of these polymorphisms on the association of ALS with lead exposure. The ALAD 2 allele (177G to C; K59N) was associated with decreased lead levels in both patella and tibia, although not in blood, and with an imprecise increase in ALS risk [odds ratio (OR) = 1.9; 95% confidence interval (95% CI), 0.60-6.3]. We found a previously unreported polymorphism in ALAD at an Msp1 site in intron 2 (IVS2+299G>A) that was associated with decreased bone lead levels and with an imprecise decrease in ALS risk (OR = 0.35; 95% CI, 0.10-1.2). The VDR B allele was not associated with lead levels or ALS risk. Our ability to observe effects of genotype on associations of ALS with occupational exposure to lead or with blood or bone lead levels was limited. These findings suggest that genetic susceptibility conferred by polymorphisms in ALAD may affect ALS risk, possibly through a mechanism related to internal lead exposure.
authors.affiliation: National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA. kamel@niehs.nih.gov
authors.forename: Freya
authors.initials: F
authors.lastname: Kamel
authors.forename: David M
authors.initials: DM
authors.lastname: Umbach
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Lehman
authors.forename: Lawrence P
authors.initials: LP
authors.lastname: Park
authors.forename: Theodore L
authors.initials: TL
authors.lastname: Munsat
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Shefner
authors.forename: Dale P
authors.initials: DP
authors.lastname: Sandler
authors.forename: Howard
authors.initials: H
authors.lastname: Hu
authors.forename: Jack A
authors.initials: JA
authors.lastname: Taylor
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000139:chemically induced* / Q000235:genetics; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007854:Lead / Q000009:adverse effects* / Q000032:analysis / Q000097:blood; D011110:Polymorphism, Genetic; D000623:Porphobilinogen Synthase / Q000187:drug effects / Q000235:genetics*; D018167:Receptors, Calcitriol / Q000187:drug effects / Q000235:genetics*
chemical_list: D018167:Receptors, Calcitriol; D007854:Lead; D004247:DNA; D000623:Porphobilinogen Synthase