Amyotrophic Lateral Sclerosis, Lead, and Genetic Susceptibility: Polymorphisms in the [Delta]-Aminolevulinic Acid Dehydratase and Vitamin D Receptor Genes

By Kamel, Freya; Umbach, David M. et al. | Environmental Health Perspectives, August 2003 | Go to article overview

Amyotrophic Lateral Sclerosis, Lead, and Genetic Susceptibility: Polymorphisms in the [Delta]-Aminolevulinic Acid Dehydratase and Vitamin D Receptor Genes


Kamel, Freya, Umbach, David M., Lehman, Teresa A., Park, Lawrence P., Munsat, Theodore L., Shefner, Jeremy M., Sandler, Dale P., Hu, Howard, Taylor, Jack A., Environmental Health Perspectives


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. Key words: [delta]-aminolevulinic acid dehydratase, amyotrophic lateral sclerosis, genetic susceptibility, lead, vitamin D receptor.

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the motor neurons of the brain and spinal cord. The disease is characterized by muscular atrophy and weakness due to degeneration of spinal motor neurons and by hyperreflexia after loss of cerebral cortical motor neurons. Approximately 5-10% of ALS cases have a family history of ALS. The etiology of ALS remains largely unknown, although genetic factors are likely involved in the familial form (Al-Chalabi and Leigh 2000). Environmental exposures have also been considered as potential causes of ALS (Nelson 1995-1996). We reported that increased risk of ALS was associated with occupational exposure to lead and with higher levels of both bone and blood lead, suggesting a potential role for lead exposure in the etiology of ALS (Kamel et al. 2002).

Genetic susceptibility may modify the relationship of ALS to lead exposure. A potentially relevant gene is ALAD, found on chromosome 9q34 (Kelada et al. 2001), which codes for [delta]-aminolevulinic acid dehydratase (ALAD), an enzyme involved in heme synthesis in red blood cells. A G to C transversion at position 177 of the coding region of ALAD replaces a lysine with an asparagine at position 59 of the ALAD protein, creating a variant allele ALAD 2 as opposed to the wild-type allele ALAD 1 (Wetmur et al. 1991a). The frequency of ALAD 2 is approximately 10% in Caucasian populations (Kelada et al. 2001). The ALAD enzyme is the principal lead-binding site in erythrocytes, and the ALAD 2 protein binds lead more tightly than does the ALAD 1 protein (Bergdahl et al. 1997b). This change alters the toxicokinetics of lead and may modify risk associated with lead exposure (Kelada et al. 2001).

VDR, another gene potentially affecting susceptibility to lead, is found on chromosome 12q and codes for the vitamin D receptor (VDR). One polymorphism in this gene is found at a BsmI restriction site in the intron separating exons VIII and IX (Zmuda et al. 2000). Presence of the site is denoted by b and absence by B. The BB genotype is found in 10-20% of Caucasians (Cooper and Umbach 1996). The BB genotype may be associated with a less functional receptor, thereby affecting calcium absorption and distribution in the body (Zmuda et al. 2000). Vitamin D can also influence lead absorption and distribution (Fullmer 1992), suggesting that the BB genotype might also be associated with uptake of lead or susceptibility to lead toxicity. …

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