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Environ Health Perspect. 2001 April; 109(4): 383–389.
PMCID: PMC1240279
Research Article

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.

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Selected References

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  • Schwartz BS, Stewart WF. Different associations of blood lead, meso 2,3-dimercaptosuccinic acid (DMSA)-chelatable lead, and tibial lead levels with blood pressure in 543 former organolead manufacturing workers. Arch Environ Health. 2000 Mar-Apr;55(2):85–92. [PubMed]
  • Schwartz BS, Lee BK, Lee GS, Stewart WF, Simon D, Kelsey K, Todd AC. Associations of blood lead, dimercaptosuccinic acid-chelatable lead, and tibia lead with polymorphisms in the vitamin D receptor and [delta]-aminolevulinic acid dehydratase genes. Environ Health Perspect. 2000 Oct;108(10):949–954. [PMC free article] [PubMed]
  • Schwartz BS, Stewart WF, Kelsey KT, Simon D, Park S, Links JM, Todd AC. Associations of tibial lead levels with BsmI polymorphisms in the vitamin D receptor in former organolead manufacturing workers. Environ Health Perspect. 2000 Mar;108(3):199–203. [PMC free article] [PubMed]
  • Onalaja AO, Claudio L. Genetic susceptibility to lead poisoning. Environ Health Perspect. 2000 Mar;108 (Suppl 1):23–28. [PMC free article] [PubMed]
  • Potluri VR, Astrin KH, Wetmur JG, Bishop DF, Desnick RJ. Human delta-aminolevulinate dehydratase: chromosomal localization to 9q34 by in situ hybridization. Hum Genet. 1987 Jul;76(3):236–239. [PubMed]
  • Battistuzzi G, Petrucci R, Silvagni L, Urbani FR, Caiola S. delta-Aminolevulinate dehydrase: a new genetic polymorphism in man. Ann Hum Genet. 1981 Jul;45(Pt 3):223–229. [PubMed]
  • Schwartz BS, Lee BK, Stewart W, Ahn KD, Springer K, Kelsey K. Associations of delta-aminolevulinic acid dehydratase genotype with plant, exposure duration, and blood lead and zinc protoporphyrin levels in Korean lead workers. Am J Epidemiol. 1995 Oct 1;142(7):738–745. [PubMed]
  • Wetmur JG, Lehnert G, Desnick RJ. The delta-aminolevulinate dehydratase polymorphism: higher blood lead levels in lead workers and environmentally exposed children with the 1-2 and 2-2 isozymes. Environ Res. 1991 Dec;56(2):109–119. [PubMed]
  • Ziemsen B, Angerer J, Lehnert G, Benkmann HG, Goedde HW. Polymorphism of delta-aminolevulinic acid dehydratase in lead-exposed workers. Int Arch Occup Environ Health. 1986;58(3):245–247. [PubMed]
  • Schwartz BS, Lee BK, Stewart W, Sithisarankul P, Strickland PT, Ahn KD, Kelsey K. delta-Aminolevulinic acid dehydratase genotype modifies four hour urinary lead excretion after oral administration of dimercaptosuccinic acid. Occup Environ Med. 1997 Apr;54(4):241–246. [PMC free article] [PubMed]
  • Sithisarankul P, Schwartz BS, Lee BK, Kelsey KT, Strickland PT. Aminolevulinic acid dehydratase genotype mediates plasma levels of the neurotoxin, 5-aminolevulinic acid, in lead-exposed workers. Am J Ind Med. 1997 Jul;32(1):15–20. [PubMed]
  • Smith CM, Wang X, Hu H, Kelsey KT. A polymorphism in the delta-aminolevulinic acid dehydratase gene may modify the pharmacokinetics and toxicity of lead. Environ Health Perspect. 1995 Mar;103(3):248–253. [PMC free article] [PubMed]
  • Fleming DE, Chettle DR, Wetmur JG, Desnick RJ, Robin JP, Boulay D, Richard NS, Gordon CL, Webber CE. Effect of the delta-aminolevulinate dehydratase polymorphism on the accumulation of lead in bone and blood in lead smelter workers. Environ Res. 1998 Apr;77(1):49–61. [PubMed]
  • Alexander BH, Checkoway H, Costa-Mallen P, Faustman EM, Woods JS, Kelsey KT, van Netten C, Costa LG. Interaction of blood lead and delta-aminolevulinic acid dehydratase genotype on markers of heme synthesis and sperm production in lead smelter workers. Environ Health Perspect. 1998 Apr;106(4):213–216. [PMC free article] [PubMed]
  • Bergdahl IA, Gerhardsson L, Schütz A, Desnick RJ, Wetmur JG, Skerfving S. Delta-aminolevulinic acid dehydratase polymorphism: influence on lead levels and kidney function in humans. Arch Environ Health. 1997 Mar-Apr;52(2):91–96. [PubMed]
  • Bergdahl IA, Grubb A, Schütz A, Desnick RJ, Wetmur JG, Sassa S, Skerfving S. Lead binding to delta-aminolevulinic acid dehydratase (ALAD) in human erythrocytes. Pharmacol Toxicol. 1997 Oct;81(4):153–158. [PubMed]
  • Oshima T, Young EW. Systemic and cellular calcium metabolism and hypertension. Semin Nephrol. 1995 Nov;15(6):496–503. [PubMed]
  • Resnick LM. The role of dietary calcium in hypertension: a hierarchical overview. Am J Hypertens. 1999 Jan;12(1 Pt 1):99–112. [PubMed]
  • Grobbee DE, van Hooft IM, Hofman A. Calcium metabolism and familial risk of hypertension. Semin Nephrol. 1995 Nov;15(6):512–518. [PubMed]
  • Bell PD, Mashburn N, Unlap MT. Renal sodium/calcium exchange; a vasodilator that is defective in salt-sensitive hypertension. Acta Physiol Scand. 2000 Jan;168(1):209–214. [PubMed]
  • Hatton DC, Yue Q, McCarron DA. Mechanisms of calcium's effects on blood pressure. Semin Nephrol. 1995 Nov;15(6):593–602. [PubMed]
  • Resnick L. The cellular ionic basis of hypertension and allied clinical conditions. Prog Cardiovasc Dis. 1999 Jul-Aug;42(1):1–22. [PubMed]
  • Zmuda JM, Cauley JA, Ferrell RE. Recent progress in understanding the genetic susceptibility to osteoporosis. Genet Epidemiol. 1999;16(4):356–367. [PubMed]
  • Cooper GS, Umbach DM. Are vitamin D receptor polymorphisms associated with bone mineral density? A meta-analysis. J Bone Miner Res. 1996 Dec;11(12):1841–1849. [PubMed]
  • Nelson DA, Vande Vord PJ, Wooley PH. Polymorphism in the vitamin D receptor gene and bone mass in African-American and white mothers and children: a preliminary report. Ann Rheum Dis. 2000 Aug;59(8):626–630. [PMC free article] [PubMed]
  • Kikuchi R, Uemura T, Gorai I, Ohno S, Minaguchi H. Early and late postmenopausal bone loss is associated with BsmI vitamin D receptor gene polymorphism in Japanese women. Calcif Tissue Int. 1999 Feb;64(2):102–106. [PubMed]
  • Lim SK, Park YS, Park JM, Song YD, Lee EJ, Kim KR, Lee HC, Huh KB. Lack of association between vitamin D receptor genotypes and osteoporosis in Koreans. J Clin Endocrinol Metab. 1995 Dec;80(12):3677–3681. [PubMed]
  • Todd AC, Lee BK, Lee GS, Ahn KD, Moshier EL, Schwartz BS. Predictors of DMSA chelatable lead, tibial lead, and blood lead in 802 Korean lead workers. Occup Environ Med. 2001 Feb;58(2):73–80. [PMC free article] [PubMed]
  • Thomas WJ, Collins TM. Comparison of venipuncture blood counts with microcapillary measurements in screening for anemia in one-year-old infants. J Pediatr. 1982 Jul;101(1):32–35. [PubMed]
  • Heinegård D, Tiderström G. Determination of serum creatinine by a direct colorimetric method. Clin Chim Acta. 1973 Feb 12;43(3):305–310. [PubMed]
  • Blumberg WE, Eisinger J, Lamola AA, Zuckerman DM. Zinc protoporphyrin level in blood determined by a portable hematofluorometer: a screening device for lead poisoning. J Lab Clin Med. 1977 Apr;89(4):712–723. [PubMed]
  • Todd AC. Contamination of in vivo bone-lead measurements. Phys Med Biol. 2000 Jan;45(1):229–240. [PubMed]
  • Kim R, Aro A, Rotnitzky A, Amarasiriwardena C, Hu H. K x-ray fluorescence measurements of bone lead concentration: the analysis of low-level data. Phys Med Biol. 1995 Sep;40(9):1475–1485. [PubMed]
  • Lee BK, Schwartz BS, Stewart W, Ahn KD. Provocative chelation with DMSA and EDTA: evidence for differential access to lead storage sites. Occup Environ Med. 1995 Jan;52(1):13–19. [PMC free article] [PubMed]
  • Morrison NA, Yeoman R, Kelly PJ, Eisman JA. Contribution of trans-acting factor alleles to normal physiological variability: vitamin D receptor gene polymorphism and circulating osteocalcin. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):6665–6669. [PubMed]
  • Hu H, Aro A, Payton M, Korrick S, Sparrow D, Weiss ST, Rotnitzky A. The relationship of bone and blood lead to hypertension. The Normative Aging Study. JAMA. 1996 Apr 17;275(15):1171–1176. [PubMed]
  • Barger-Lux MJ, Heaney RP, Hayes J, DeLuca HF, Johnson ML, Gong G. Vitamin D receptor gene polymorphism, bone mass, body size, and vitamin D receptor density. Calcif Tissue Int. 1995 Aug;57(2):161–162. [PubMed]
  • Morrison NA, Qi JC, Tokita A, Kelly PJ, Crofts L, Nguyen TV, Sambrook PN, Eisman JA. Prediction of bone density from vitamin D receptor alleles. Nature. 1994 Jan 20;367(6460):284–287. [PubMed]
  • Taymans SE, Pack S, Pak E, Orban Z, Barsony J, Zhuang Z, Stratakis CA. The human vitamin D receptor gene (VDR) is localized to region 12cen-q12 by fluorescent in situ hybridization and radiation hybrid mapping: genetic and physical VDR map. J Bone Miner Res. 1999 Jul;14(7):1163–1166. [PubMed]
  • Gómez C, Naves ML, Barrios Y, Díaz JB, Fernández JL, Salido E, Torres A, Cannata JB. Vitamin D receptor gene polymorphisms, bone mass, bone loss and prevalence of vertebral fracture: differences in postmenopausal women and men. Osteoporos Int. 1999;10(3):175–182. [PubMed]
  • Brown AJ, Dusso A, Slatopolsky E. Vitamin D. Am J Physiol. 1999 Aug;277(2 Pt 2):F157–F175. [PubMed]
  • Carling T, Kindmark A, Hellman P, Lundgren E, Ljunghall S, Rastad J, Akerström G, Melhus H. Vitamin D receptor genotypes in primary hyperparathyroidism. Nat Med. 1995 Dec;1(12):1309–1311. [PubMed]
  • Ferrari S, Manen D, Bonjour JP, Slosman D, Rizzoli R. Bone mineral mass and calcium and phosphate metabolism in young men: relationships with vitamin D receptor allelic polymorphisms. J Clin Endocrinol Metab. 1999 Jun;84(6):2043–2048. [PubMed]
  • Kontula K, Välimäki S, Kainulainen K, Viitanen AM, Keski-Oja J. Vitamin D receptor polymorphism and treatment of psoriasis with calcipotriol. Br J Dermatol. 1997 Jun;136(6):977–978. [PubMed]
  • Ruggiero M, Pacini S, Amato M, Aterini S, Chiarugi V. Association between vitamin D receptor gene polymorphism and nephrolithiasis. Miner Electrolyte Metab. 1999 May-Jun;25(3):185–190. [PubMed]
  • Hamet P, Daignault-Gélinas M, Lambert J, Ledoux M, Whissell-Cambiotti L, Bellavance F, Mongeau E. Epidemiological evidence of an interaction between calcium and sodium intake impacting on blood pressure. A Montréal study. Am J Hypertens. 1992 Jun;5(6 Pt 1):378–385. [PubMed]
  • Jorde R, Bonaa KH. Calcium from dairy products, vitamin D intake, and blood pressure: the Tromso Study. Am J Clin Nutr. 2000 Jun;71(6):1530–1535. [PubMed]
  • Osborne CG, McTyre RB, Dudek J, Roche KE, Scheuplein R, Silverstein B, Weinberg MS, Salkeld AA. Evidence for the relationship of calcium to blood pressure. Nutr Rev. 1996 Dec;54(12):365–381. [PubMed]
  • Miller GD, DiRienzo DD, Reusser ME, McCarron DA. Benefits of dairy product consumption on blood pressure in humans: a summary of the biomedical literature. J Am Coll Nutr. 2000 Apr;19(2 Suppl):147S–164S. [PubMed]
  • Sowers MR, Wallace RB, Lemke JH. The association of intakes of vitamin D and calcium with blood pressure among women. Am J Clin Nutr. 1985 Jul;42(1):135–142. [PubMed]
  • Kristal-Boneh E, Froom P, Yerushalmi N, Harari G, Ribak J. Calcitropic hormones and occupational lead exposure. Am J Epidemiol. 1998 Mar 1;147(5):458–463. [PubMed]
  • Mason HJ, Somervaille LJ, Wright AL, Chettle DR, Scott MC. Effect of occupational lead exposure on serum 1,25-dihydroxyvitamin D levels. Hum Exp Toxicol. 1990 Jan;9(1):29–34. [PubMed]
  • Jorde R, Sundsfjord J, Haug E, Bonaa KH. Relation between low calcium intake, parathyroid hormone, and blood pressure. Hypertension. 2000 May;35(5):1154–1159. [PubMed]
  • Gross C, Musiol IM, Eccleshall TR, Malloy PJ, Feldman D. Vitamin D receptor gene polymorphisms: analysis of ligand binding and hormone responsiveness in cultured skin fibroblasts. Biochem Biophys Res Commun. 1998 Jan 26;242(3):467–473. [PubMed]

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