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Byung-Kook Lee,¹ Gap-Soo Lee,¹ Walter F. Stewart,^2,3 Kyu-Dong Ahn,¹ David Simon,² Karl T. Kelsey,⁴ Andrew C. Todd,⁵ and Brian S. Schwartz^2,3,6

¹Institute of Industrial Medicine, Soonchunhyang University, Chonan, Korea; ²Department of Epidemiology, Johns Hopkins School of Hygiene and Public Health, Baltimore, Maryland, USA; ³Division of Occupational and Environmental Health, Department of Environmental Health Sciences, Johns Hopkins School of Hygiene and Public Health, Baltimore, Maryland, USA; ⁴Department of Cancer Cell Biology, Harvard School of Public Health, Boston, Massachusetts, USA; ⁵Department of Community and Preventive Medicine, Mount Sinai Medical Center, New York, New York, USA; ⁶Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA

Abstract

Evidence suggests that lead and selected genes known to modify the toxicokinetics of lead--namely, those for the vitamin D receptor (VDR) and -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 ALAD² allele, and there were no ALAD² 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 words: -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

Address correspondence to B.S. Schwartz, Division of Occupational and Environmental Health, Johns Hopkins School of Hygiene and Public Health, Room 7041, 615 N. Wolfe Street, Baltimore, MD, 21205 USA. Telephone: (410) 955-4158. Fax: (410) 955-1811 ; E-mail: bschwart@jhsph.edu

This research was supported by grants R01 ES07198 (B.S. Schwartz) and ES00002 (K.T. Kelsey) from the U.S. National Institute of Environmental Health Sciences (NIEHS) ; HMP-97-M-4-0047 from the Ministry of Health and Welfare, Republic of Korea ; and P42 ES05947 (K.T. Kelsey) from the NIEHS, with funding provided by the U.S. Environmental Protection Agency (U.S. EPA) . Its content is solely the responsibility of the authors and does not necessarily represent official views of the NIEHS or the U.S. EPA.

Received 3 October 2000 ; accepted 6 November 2000.