Associations of blood pressure and hypertension with lead dose measures and polymorphisms in the vitamin D receptor and delta-aminolevulinic acid dehydratase genes.

Abstract

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(2) allele, and there were no ALAD(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.

Association of Blood Lead and Tibia Lead with Blood Pressure and Hypertension in a Community Sample of Older Adults

“…Studies have compared associations of blood lead and bone lead with blood pressure and/ or hypertension in two populations with current or former occupational lead exposure (2,4,5) and three populations whose lead exposure was mainly from nonoccupational sources (6-9) (table 1). In the latter studies, only bone lead was associated with blood pressure or hypertension status, despite a large number of studies that have reported strong and consistent relations of blood lead and blood pressure when blood lead was the only lead biomarker measured (10)(11)(12)(13)(14)(15)(16).…”

The G894-T894 Polymorphism in the Gene for Endothelial Nitric Oxide Synthase and Blood Pressure in Lead-Exposed Workers From Korea

“…The associations of lead with systolic and diastolic blood pressure and hypertension have been previously reported in this population. 54 Many mechanisms have been proposed for how lead could increase blood pressure; it is important to evaluate gene-environment interaction, like we have here, because if eNOS genotype does not modify the relation of lead dose with blood pressure, this provides evidence that lead is unlikely to act through the eNOS gene product to influence blood pressure. Such studies thus have relevance for understanding the mechanism of lead toxicity.…”

“…54 A polymerase chain reaction (PCR)-based assay was adapted from Hibi et al to genotype individuals for the polymorphism. 58 The primer sequences were 5Ј-TCCCTGAGGAGGGCAT-GAGGC T-3Ј and 5Ј-TGAGGGT-CACACAGGTTCCT-3Ј.…”

Low-Level Exposure to Lead as a Cardiovascular Risk Factor

“…VDR genotype was also associated with diastolic blood pressure; lead workers with the VDR B allele had diastolic blood pressures that were 1.9-2.5 mm Hg higher than in lead workers with the VDR bb genotype (p = 0.04). In addition, compared to lead workers with the VDR bb genotype, workers with the VDR B allele had a higher prevalence of hypertension (adjusted odds ratio (95% confidence interval) = 2.1 (1.0, 4.4), p = 0.05) and a larger increase in blood pressure with age (Lee et al, 2001). …”