Genetic susceptibility to environmental toxicants in ALS.

Environmental toxicants such as heavy metals, pesticides, and chemicals appear to be risk factors for sporadic amyotrophic lateral sclerosis (SALS). An impaired ability to break down these toxicants because of differences in detoxification genes could underlie some cases of this disease. We therefore examined the frequencies of single nucleotide polymorphisms (SNPs) in 186 SALS patients and 186 controls at the allele, genotype, and haplotype levels for the metallothionein (MT) family of genes, metal transcription factor-1 (MTF-1), and glutathione synthetase (GSS). Exposure to heavy metals, solvents/chemicals, and pesticides/herbicides was assessed by questionnaire, and gene-toxicant interactions were analyzed. An intronic SNP upstream of MT-Ie differed in SALS patients and controls at the allele and genotype levels. Haplotypes covering MT-I isoforms also differed between the two groups. Alleles and genotypes of one MTF-1 SNP differed in female SALS patients. One GSS haplotype interacted with both metals and solvents/chemicals to increase the risk of the disease. Differences in genes involved in handling toxicants, and interactions between toxicants and these genes, appear to be present in some patients with SALS. This suggests that impaired detoxification mechanisms play a role in SALS. (c) 2007 Wiley-Liss, Inc.