|
|
|
|
|
|
fact sheet
ALAD Genotype and Lead Toxicity
Samir
Kelada and Erin Haynes
print version
HuGE Review
Published June, 2001
|
|
|
ALAD
Gene |
|
The
ALAD gene (chromosome 9q34) codes for d
-aminolevulinic acid |
|
|
dehydratase
(ALAD), which catalyzes the asymmetric addition of two molecules
of aminolevulinic acid (ALA) to form porphobilinogen --
the second step of heme synthesis. |
Prevalence of
Gene Variants |
|
Eight ALAD variants have been described in the literature.
Most attention has been paid to the G177C polymorphism,
which yields two alleles, designated ALAD-1 and ALAD-2.
The ALAD-2 allele contains a G --->
C transversion at position 177 of the coding region, resulting
in the substitution of asparagine for lysine at amino acid
59. These two
alleles determine three isozymes, designated 1-1, 1-2, and
2-2, all of which display similar activities but have different
charges. The
prevalence of the ALAD-2 allele ranges from 0 to 20 percent depending on the population.
Generally, Caucasians have the highest frequency
of ALAD-2 allele,
with approximately 18 percent of the population being ALAD
1-2 heterozygotes and 1 percent being 2-2 homozygotes.
Some studies used hospital-based study samples, while
others used samples comprised of occupationally exposed
individuals with relatively high blood lead levels.
|
Disease
Burden |
|
Studies
have shown relations between ALAD
G177C genotype and several features of lead toxicity.
The evidence surrounding this ALAD
polymorphism and lead poisoning can be summarized as
follows: at high levels of exposure and in comparison to
ALAD 1-1 genotype individuals, ALAD
1-2/2-2 genotype individuals have increased blood lead
levels, lower concentrations of ALA in the plasma (ALAP),
lower zinc protoporphyrin levels, lower cortical bone lead
concentrations, higher concentrations of trabecular (spongy)
bone lead, and lower amounts of chelatable lead (1,2,3,
5).
These differences are only clearly evident at blood
lead concentrations greater than 25 mg/dL.
The data also suggest that lead exposed ALAD-1
homozygotes may be at greater risk of neurotoxicity than
exposed ALAD 1-2
individuals, as ALAD-1
homozygotes have higher levels of ALAP.
One study gave preliminary evidence that ALAD
1-2 individuals may have better neuropsychological performance
than ALAD-1 homozygotes
of similar lead exposure history (4).
|
Interactions |
|
Schwartz
et al. (5) have evaluated interactions
between ALAD
and VDR, which
codes for the Vitamin D Receptor.
VDR is polymorphic and evidence suggests that alone it may influence
the effect of lead exposure, but no evidence for gene-gene
interaction was found. |
|
|
|
Laboratory
Tests |
|
Whereas
early studies used an electrophoretic technique to distinguish
ALAD protein variants (due to charge differences), most
studies have used a PCR-based genotyping technique in which
the polymorphic site is amplified and then cleaved with
the MspI restriction
enzyme. The
cleavage products are then visualized on an agarose gel.
There is complete concordance between the genotyping
and phenotyping techniques.
|
Population
Testing |
|
At
this time, there is inadequate evidence to support population-based
testing.
|
References |
|
-
Wetmur
JG. Influence of the common human delta-aminolevulinate
dehydratase polymorphism on lead body burden. Environ
Health Perspect 1994;102 Suppl 3:215-9.
-
Fleming
DE, Chettle DR, Wetmur JG, et al. Effect of the
delta-aminolevulinate dehydratase polymorphism on
the accumulation of lead in bone and blood in lead
smelter workers. Environ Res 1998;77(1):49-61.
-
Schwartz
BS, Lee BK, Stewart W, et al. delta-Aminolevulinic
acid dehydratase genotype modifies four hour urinary
lead excretion after oral administration of dimercaptosuccinic
acid. Occup Environ Med 1997;54(4):241-6.
-
Bellinger
D, Hu H, Titlebaum L, et al. Attentional correlates
of dentin and bone lead levels in adolescents. Arch
Environ Health 1994;49:98-105.
-
Schwartz
BS, Lee B-L, Lee G-S, et al. Associations of Blood
Lead, Dimercaptosuccinic Acid-Chelatable Lead, and
Tibia Lead with Polymorphisms in the Vitamin D Receptor
and d-Aminolevulinic
Acid Dehydratase Genes.
Environ Health Perspect 2000;108(10):949-54.
|
|
Web
sites |
|
OMIM
The National Institute for
Occupational Safety and Health (NIOSH)
Occupational Safety
and Health Administration
CDC
Childhood Lead Poisoning Prevention Program
|
|
|
|
|
|
|
You will need
for the print
version
|
|
|