Academic journal article Environmental Health Perspectives

Association between Hemochromatosis Genotype and Lead Exposure among Elderly Men: The Normative Aging Study

Academic journal article Environmental Health Perspectives

Association between Hemochromatosis Genotype and Lead Exposure among Elderly Men: The Normative Aging Study

Article excerpt

Because body iron burden is inversely associated with lead absorption, genes associated with hemochromatosis may modify body lead burden. Our objective was to determine whether the C282Y and/or H63D hemochromatosis gene (HFE) is associated with body lead burden. Patella and tibia lead levels were measured by K X-ray fluorescence in subjects from the Normative Aging Study. DNA samples were genotyped for C282Y and H63D using polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP). A series of multivariate linear regression models were constructed with bone or blood lead as dependent variables; age, smoking, and education as independent variables; and C282Y or H63D as independent risk factors and/or effect modifiers. Of 730 subjects, 94 (13%) carried the C282Y variant and 183 (25%) carried the H63D variant. In the crude analysis, mean tibia, patella, and blood lead levels were consistently lower in carriers of either HFE variant compared with levels in subjects with wild-type genotypes. In multivariate analyses that adjusted for age, smoking, and education, having an HFE variant allele was an independent predictor of significantly lower patella lead levels (p < 0.05). These data suggest that HFE variants have altered kinetics of lead accumulation after exposure. Among elderly men, subjects with HFE variants had lower patella lead levels. These effects may be mediated by alterations in lead toxicokinetics via iron metabolic pathways regulated by the HFE gene product and body iron stores. Key words: aging, hemochromatosis, lead, men, metals. Environ Health Perspect 112:746-750 (2004). doi:10.1289/ehp.6581 available via[Online 29 January 2004]


There is considerable variability in the development of toxicity in response to lead exposure in the general population. Genetic factors that modify the absorption, metabolism, or excretion of lead may influence lead toxicity. Genetic variants that predispose individuals to accumulation of lead could occur in enzymes known to influence or regulate lead metabolism. For example, lead is known to bind to the enzyme aminolevulinic acid dehydratase (ALAD), and the absorption of lead is inversely related to calcium stores and dietary vitamin D intake (Chisolm et al. 1985; Mahaffey et al. 1986). Genetic variants in the ALAD and vitamin D receptor genes have been associated with lead exposure biomarkers (Hu et al. 2001; Schwartz et al. 2000a, 2000b; Smith et al. 1995; Wetmur et al. 1997).

Another potential candidate gene for susceptibility to lead exposure

is the gene that is altered in hemochromatosis (Onalaja and Claudio 2000; Wright 1999). Hemochromatosis is an autosomal recessive genetic disease that produces an increase in the absorption of ingested iron. Affected subjects may develop iron overload, leading to diabetes, heart disease, and liver disease, but generally do not present until mid- to late adulthood. A hemochromatosis gene (HFE) variant (C282Y) accounts for most cases (Feder et al. 1996). The HFE variant H63D is also associated with hemochromatosis but with a lower penetrance (Waheed et al. 1997).

Both polymorphisms are very common in the U.S. population. Approximately 7-17% of the U.S. general population are heterozygous for C282Y (Bradley et al. 1998; Cox and Kelly 1998; Jouanolle et al. 1997; Phatak et al. 1998), and the prevalence of the H63D heterozygous genotype in the general population has been estimated to be 10-32% (Beutler 1997; Jouanolle et al. 1997). The recent cloning of the HFE gene has made available rapid screening tests using polymerase chain reaction (PCR) techniques to identify subjects who carry either the C282Y or the H63D allele (Burke et al. 1998; Merryweather-Clarke et al. 1999). The high combined prevalence of the two alleles suggests that these two polymorphisms could play a major role in the general population in both the distribution of body iron and the distribution of any metals that share absorptive pathways with iron, such as lead. …

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