Effect modification by delta-aminolevulinic acid dehydratase, vitamin D receptor, and nitric oxide synthase gene polymorphisms on associations between patella lead and renal function in lead workers.
Genetic polymorphisms that affect lead toxicokinetics or toxicodynamics may be important modifiers of risk for adverse outcomes in lead-exposed populations. We recently reported associations between higher patella lead, which is hypothesized to represent a lead pool that is both bioavailable and cumulative, and adverse renal outcomes in current and former Korean lead workers. In the present study, we assessed effect modification by polymorphisms in the genes encoding for delta-aminolevulinic acid dehydratase (ALAD), the vitamin D receptor (VDR), and endothelial nitric oxide synthase on those associations. Similar analyses were conducted with three other lead biomarkers. Renal function was assessed via blood urea nitrogen, serum creatinine, measured and calculated creatinine clearances, urinary N-acetyl-beta-D-glucosaminidase, and retinol-binding protein. Mean (SD) blood, patella, tibia, and dimercaptosuccinic acid-chelatable lead values were 30.9 (16.7) microg/dl, 75.1 (101.1)and 33.6 (43.4) microg Pb/g bone mineral, and 0.63 (0.75) microg Pb/mg creatinine, respectively, in 647 lead workers. Little evidence of effect modification by genotype on associations between patella lead and renal outcomes was observed. The VDR polymorphism did modify associations between the other lead biomarkers and the serum creatinine and calculated creatinine clearance. Higher lead dose was associated with worse renal function in participants with the variant B allele. Models in two groups, dichotomized by median age, showed that this effect was present in the younger half of the population. Limited evidence of effect modification by ALAD genotype was observed; higher blood lead levels were associated with higher calculated creatinine clearance among participants with the ALAD(1-2) genotype. In conclusion, VDR and/or ALAD genotypes modified associations between all the lead biomarkers, except patella lead, and the renal outcomes.
Division of Occupational and Environmental Health, Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA. vweaver@jhsph.edu
Virginia M
VM
Weaver
Byung-Kook
BK
Lee
Andrew C
AC
Todd
Kyu-Dong
KD
Ahn
Weiping
W
Shi
Bernard G
BG
Jaar
Karl T
KT
Kelsey
Mark E
ME
Lustberg
Ellen K
EK
Silbergeld
Patrick J
PJ
Parsons
Jiayu
J
Wen
Brian S
BS
Schwartz
D000118:Acetylglucosaminidase / Q000097:blood; D000328:Adult; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D003430:Cross-Sectional Studies; D004247:DNA / Q000737:chemistry / Q000235:genetics; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced* / Q000453:epidemiology / Q000378:metabolism; D007723:Korea / Q000453:epidemiology; D007854:Lead / Q000493:pharmacokinetics*; D007855:Lead Poisoning / Q000235:genetics* / Q000378:metabolism; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000235:genetics* / Q000378:metabolism; D016273:Occupational Exposure / Q000009:adverse effects*; D010329:Patella / Q000378:metabolism*; D011110:Polymorphism, Genetic; D000623:Porphobilinogen Synthase / Q000235:genetics* / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000235:genetics* / Q000378:metabolism; D012177:Retinol-Binding Proteins / Q000378:metabolism
D018167:Receptors, Calcitriol; D012177:Retinol-Binding Proteins; D007854:Lead; D004247:DNA; D003404:Creatinine; D052250:Nitric Oxide Synthase Type III; D000118:Acetylglucosaminidase; D000623:Porphobilinogen Synthase