PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of envhperEnvironmental Health PerspectivesBrowse ArticlesAbout EHPGeneral InformationAuthorsMediaProgramsPartnerships
 
Environ Health Perspect. 2003 October; 111(13): 1613–1619.
PMCID: PMC1241683
Research Article

Associations of renal function with polymorphisms in the delta-aminolevulinic acid dehydratase, vitamin D receptor, and nitric oxide synthase genes in Korean lead workers.

Abstract

We analyzed data from 798 lead workers to determine whether polymorphisms in the genes encoding delta-aminolevulinic acid dehydratase (ALAD), endothelial nitric oxide synthase (eNOS), and the vitamin D receptor (VDR) were associated with or modified relations of lead exposure and dose measures with renal outcomes. Lead exposure was assessed with job duration, blood lead, dimercaptosuccinic acid (DMSA)-chelatable lead, and tibia lead. Renal function was assessed with blood urea nitrogen (BUN), serum creatinine, measured creatinine clearance, calculated creatinine clearance and urinary N-acetyl-beta-D-glucosaminidase (NAG), and retinol-binding protein. Mean (+/- SD) tibia lead, blood lead, and DMSA-chelatable lead levels were 37.2 +/- 40.4 microg/g bone mineral, 32.0 +/- 15.0 microg/dL, and 767.8 +/- 862.1 microg/g creatinine, respectively. After adjustment, participants with the ALAD(2) allele had lower mean serum creatinine and higher calculated creatinine clearance. We observed effect modification by ALAD on associations between blood lead and/or DMSA-chelatable lead and three renal outcomes. Among those with the ALAD(1-2) genotype, higher lead measures were associated with lower BUN and serum creatinine and higher calculated creatinine clearance. Participants with the eNOS variant allele were found to have higher measured creatinine clearance and BUN. In participants with the Asp allele, longer duration working with lead was associated with higher serum creatinine and lower calculated creatinine clearance and NAG; all were significantly different from relations in those with the Glu/Glu genotype except NAG (p = 0.08). No significant differences were seen in renal outcomes by VDR genotype, nor was consistent effect modification observed. The ALAD findings could be explained by lead-induced hyperfiltration.

Full Text

The Full Text of this article is available as a PDF (304K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • 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]
  • Allon M. Renal abnormalities in sickle cell disease. Arch Intern Med. 1990 Mar;150(3):501–504. [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]
  • Bellinger D, Hu H, Titlebaum L, Needleman HL. Attentional correlates of dentin and bone lead levels in adolescents. Arch Environ Health. 1994 Mar-Apr;49(2):98–105. [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]
  • Brenner BM, Lawler EV, Mackenzie HS. The hyperfiltration theory: a paradigm shift in nephrology. Kidney Int. 1996 Jun;49(6):1774–1777. [PubMed]
  • Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31–41. [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]
  • 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]
  • Hibi K, Ishigami T, Tamura K, Mizushima S, Nyui N, Fujita T, Ochiai H, Kosuge M, Watanabe Y, Yoshii Y, et al. Endothelial nitric oxide synthase gene polymorphism and acute myocardial infarction. Hypertension. 1998 Sep;32(3):521–526. [PubMed]
  • Hu H. A 50-year follow-up of childhood plumbism. Hypertension, renal function, and hemoglobin levels among survivors. Am J Dis Child. 1991 Jun;145(6):681–687. [PubMed]
  • Hu H, Wu MT, Cheng Y, Sparrow D, Weiss S, Kelsey K. The delta-aminolevulinic acid dehydratase (ALAD) polymorphism and bone and blood lead levels in community-exposed men: the Normative Aging Study. Environ Health Perspect. 2001 Aug;109(8):827–832. [PMC free article] [PubMed]
  • Kelada SN, Shelton E, Kaufmann RB, Khoury MJ. Delta-aminolevulinic acid dehydratase genotype and lead toxicity: a HuGE review. Am J Epidemiol. 2001 Jul 1;154(1):1–13. [PubMed]
  • Khalil-Manesh F, Gonick HC, Cohen AH, Alinovi R, Bergamaschi E, Mutti A, Rosen VJ. Experimental model of lead nephropathy. I. Continuous high-dose lead administration. Kidney Int. 1992 May;41(5):1192–1203. [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]
  • Klahr S. The role of nitric oxide in hypertension and renal disease progression. Nephrol Dial Transplant. 2001;16 (Suppl 1):60–62. [PubMed]
  • Lee BK, Lee GS, Stewart WF, Ahn KD, Simon D, Kelsey KT, Todd AC, Schwartz BS. Associations of blood pressure and hypertension with lead dose measures and polymorphisms in the vitamin D receptor and delta-aminolevulinic acid dehydratase genes. Environ Health Perspect. 2001 Apr;109(4):383–389. [PMC free article] [PubMed]
  • Lee SS, Lee BK, Lee GS, Stewart WF, Simon D, Kelsey K, Todd AC, Schwartz BS. Associations of lead biomarkers and delta-aminolevulinic acid dehydratase and vitamin D receptor genotypes with hematopoietic outcomes in Korean lead workers. Scand J Work Environ Health. 2001 Dec;27(6):402–411. [PubMed]
  • Marco MP, Craver L, Betriu A, Fibla J, Fernández E. Influence of vitamin D receptor gene polymorphisms on mortality risk in hemodialysis patients. Am J Kidney Dis. 2001 Nov;38(5):965–974. [PubMed]
  • Miyamoto Y, Saito Y, Kajiyama N, Yoshimura M, Shimasaki Y, Nakayama M, Kamitani S, Harada M, Ishikawa M, Kuwahara K, et al. Endothelial nitric oxide synthase gene is positively associated with essential hypertension. Hypertension. 1998 Jul;32(1):3–8. [PubMed]
  • Müller D, Sievers E, Eggert P. Influence of hyperfiltration on the measurement of urinary N-acetyl-beta-D-glucosaminidase. Pediatr Nephrol. 1999 Aug;13(6):519–523. [PubMed]
  • Nenov VD, Taal MW, Sakharova OV, Brenner BM. Multi-hit nature of chronic renal disease. Curr Opin Nephrol Hypertens. 2000 Mar;9(2):85–97. [PubMed]
  • Noiri Eisei, Satoh Hiroaki, Taguchi Jun-ichi, Brodsky Sergey V, Nakao Akihide, Ogawa Yumiko, Nishijima Satomi, Yokomizo Takehiko, Tokunaga Katsushi, Fujita Toshiro. Association of eNOS Glu298Asp polymorphism with end-stage renal disease. Hypertension. 2002 Oct;40(4):535–540. [PubMed]
  • Ozaki Y, Nomura S, Nagahama M, Yoshimura C, Kagawa H, Fukuhara S. Vitamin-D receptor genotype and renal disorder in Japanese patients with systemic lupus erythematosus. Nephron. 2000 May;85(1):86–91. [PubMed]
  • Persu A, Stoenoiu MS, Messiaen T, Davila S, Robino C, El-Khattabi O, Mourad M, Horie S, Feron O, Balligand J-L, et al. Modifier effect of ENOS in autosomal dominant polycystic kidney disease. Hum Mol Genet. 2002 Feb 1;11(3):229–241. [PubMed]
  • Roels H, Lauwerys R, Konings J, Buchet JP, Bernard A, Green S, Bradley D, Morgan W, Chettle D. Renal function and hyperfiltration capacity in lead smelter workers with high bone lead. Occup Environ Med. 1994 Aug;51(8):505–512. [PMC free article] [PubMed]
  • Schwartz BS, Lee BK, Lee GS, Stewart WF, Lee SS, Hwang KY, Ahn KD, Kim YB, Bolla KI, Simon D, et al. Associations of blood lead, dimercaptosuccinic acid-chelatable lead, and tibia lead with neurobehavioral test scores in South Korean lead workers. Am J Epidemiol. 2001 Mar 1;153(5):453–464. [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, 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]
  • 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]
  • Schwartz BS, Stewart WF, Todd AC, Links JM. Predictors of dimercaptosuccinic acid chelatable lead and tibial lead in former organolead manufacturing workers. Occup Environ Med. 1999 Jan;56(1):22–29. [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]
  • Todd AC, McNeill FE. In vivo measurements of lead in bone using a 109Cd 'spot' source. Basic Life Sci. 1993;60:299–302. [PubMed]
  • Todd AC, McNeill FE, Palethorpe JE, Peach DE, Chettle DR, Tobin MJ, Strosko SJ, Rosen JC. In vivo X-ray fluorescence of lead in bone using K X-ray excitation with 109Cd sources: radiation dosimetry studies. Environ Res. 1992 Apr;57(2):117–132. [PubMed]
  • Topping MD, Forster HW, Dolman C, Luczynska CM, Bernard AM. Measurement of urinary retinol-binding protein by enzyme-linked immunosorbent assay, and its application to detection of tubular proteinuria. Clin Chem. 1986 Oct;32(10):1863–1866. [PubMed]
  • Vaziri ND, Ding Y, Ni Z, Gonick HC. Altered nitric oxide metabolism and increased oxygen free radical activity in lead-induced hypertension: effect of lazaroid therapy. Kidney Int. 1997 Oct;52(4):1042–1046. [PubMed]
  • Weaver VM, Buckley T, Groopman JD. Lack of specificity of trans,trans-muconic acid as a benzene biomarker after ingestion of sorbic acid-preserved foods. Cancer Epidemiol Biomarkers Prev. 2000 Jul;9(7):749–755. [PubMed]
  • Weaver VM, Lee B-K, Ahn K-D, Lee G-S, Todd AC, Stewart WF, Wen J, Simon DJ, Parsons PJ, Schwartz BS. Associations of lead biomarkers with renal function in Korean lead workers. Occup Environ Med. 2003 Aug;60(8):551–562. [PMC free article] [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]
  • Yuen CT, Kind PR, Price RG, Praill PF, Richardson AC. Colorimetric assay for N-acetyl-beta-D-glucosaminidase (NAG) in pathological urine using the omega-nitrostyryl substrate: the development of a kit and the comparison of manual procedure with the automated fluorimetric method. Ann Clin Biochem. 1984 Jul;21(Pt 4):295–300. [PubMed]
  • Zanchi A, Moczulski DK, Hanna LS, Wantman M, Warram JH, Krolewski AS. Risk of advanced diabetic nephropathy in type 1 diabetes is associated with endothelial nitric oxide synthase gene polymorphism. Kidney Int. 2000 Feb;57(2):405–413. [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]

Articles from Environmental Health Perspectives are provided here courtesy of National Institute of Environmental Health Science