Academic journal article Environmental Health Perspectives

Associations of Blood Pressure and Hypertension with Lead Dose Measures and Polymorphisms in the Vitamin D Receptor and [Delta]-Aminolevulinic Acid Dehydratase Genes

Academic journal article Environmental Health Perspectives

Associations of Blood Pressure and Hypertension with Lead Dose Measures and Polymorphisms in the Vitamin D Receptor and [Delta]-Aminolevulinic Acid Dehydratase Genes

Article excerpt

Evidence suggests that lead and selected genes known to modify the toxicokinetics of lead--namely, those for the vitamin D receptor (VDR) and [Delta]-aminolevulinic acid dehydratase (ALAD)--may independently influence blood pressure and hypertension risk. We report the relations among ALAD and VDR genotypes, three lead dose measures, and blood pressure and hypertension status in 798 Korean lead workers and 135 controls without occupational exposure to lead. Lead dose was assessed by blood lead, tibia lead measured by X-ray fluorescence, and dimercaptosuccinic acid (DMSA)-chelatable lead. Among lead workers, 9.9% (n = 79) were heterozygous for the [ALAD.sup.2] allele, and there were no [ALAD.sup.2] homozygotes; 11.2% (n = 89) had at least one copy of the VDR B allele, and 0.5% (n = 4) had the BB genotype. In linear regression models to control for covariates, VDR genotype (BB and Bb vs. bb), blood lead, tibia lead, and DMSA-chelatable lead were all positive predictors of systolic blood pressure. On average, lead workers with the VDR B allele, mainly heterozygotes, had systolic blood pressures that were 2.7-3.7 mm Hg higher than did workers with the bb genotype. VDR genotype was also associated with diastolic blood pressure; on average, lead workers with the VDR B allele had diastolic blood pressures that were 1.9-2.5 mm Hg higher than did lead workers with the VDR bb genotype (p = 0.04). VDR genotype modified the relation of age with systolic blood pressure; compared to lead workers with the VDR bb genotype, workers with the VDR B allele had larger elevations in blood pressure with increasing age. Lead workers with the VDR B allele also had a higher prevalence of hypertension compared to lead workers with the bb genotype [adjusted odds ratio (95% confidence interval) = 2.1 (1.0, 4.4), p = 0.05]. None of the lead biomarkers was associated with diastolic blood pressure, and tibia lead was the only lead dose measure that was a significant predictor of hypertension status. In contrast to VDR, ALAD genotype was not associated with the blood pressure measures and did not modify associations of the lead dose measures with any of the blood pressure measures. To our knowledge, these are the first data to suggest that the common genetic polymorphism in the VDR is associated with blood pressure and hypertension risk. We speculate that the BsmI polymorphism may be in linkage disequilibrium with another functional variant at the VDR locus or with a nearby gene. Key word: [Delta]-aminolevulinic acid dehydratase, blood pressure, hypertension, lead, polymorphisms, vitamin D receptor, X-ray fluorescence. Environ Health Perspect 109:383-389 (2001). [Online 22 March 2001]

http://ehpnet1.niehs.nih.gov/docs/2001/109p383-389lee/abstract.html

Lead absorption increases blood pressure, especially systolic blood pressure, at blood lead levels as low as 5 [micro]g/dL (1,2). Little is known; however, about genetic variation in risk of elevated blood pressure from lead. In particular, two polymorphic genes known to modify the toxicokinetics of lead--those for the vitamin D receptor (VDR) (3-5) and [Delta]-aminolevulinic acid dehydratase (ALAD) (5-17)--could influence the effect of lead on blood pressure and hypertension.

ALAD is a principal erythrocytic binding site for lead, and such binding differs for the three isoforms of the ALAD protein (17). Thus, the polymorphism could influence the effect of lead on blood pressure by, for example, modifying the deposition of lead at the critical cellular or molecular targets through which lead acts to cause elevations in blood pressure. VDR genotype is also of particular interest not only because it has been implicated to modify the absorption of lead and the uptake and release of lead from bone (3,4), but also because alterations in calcium metabolism have been implicated in the risk of elevations in blood pressure and essential hypertension. These alterations include such factors as calcium intake, calcium absorption, bone calcium metabolism, serum calcium levels, and cytosolic free calcium (18-21). …

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