title: Lead-Related Genetic Loci, Cumulative Lead Exposure and Incident Coronary Heart Disease: The Normative Aging Study.
abstract: BACKGROUND
  Cumulative exposure to lead is associated with cardiovascular outcomes. Polymorphisms in the δ-aminolevulinic acid dehydratase (ALAD), hemochromatosis (HFE), heme oxygenase-1 (HMOX1), vitamin D receptor (VDR), glutathione S-transferase (GST) supergene family (GSTP1, GSTT1, GSTM1), apolipoprotein E (APOE),angiotensin II receptor-1 (AGTR1) and angiotensinogen (AGT) genes, are believed to alter toxicokinetics and/or toxicodynamics of lead.
  
  
  OBJECTIVE
  We assessed possible effect modification by genetic polymorphisms in ALAD, HFE, HMOX1, VDR, GSTP1, GSTT1, GSTM1, APOE, AGTR1 and AGT individually and as the genetic risk score (GRS) on the association between cumulative lead exposure and incident coronary heart disease (CHD) events.
  
  
  METHODS
  We used K-shell-X-ray fluorescence to measure bone lead levels. GRS was calculated on the basis of 22 lead-related loci. We constructed Cox proportional hazard models to compute adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident CHD. We applied inverse probability weighting to account for potential selection bias due to recruitment into the bone lead sub-study.
  
  
  RESULTS
  Significant effect modification was found by VDR, HMOX1, GSTP1, APOE, and AGT genetic polymorphisms when evaluated individually. Further, the bone lead-CHD associations became larger as GRS increases. After adjusting for potential confounders, a HR of CHD was 2.27 (95%CI: 1.50-3.42) with 2-fold increase in patella lead levels, among participants in the top tertile of GRS. We also detected an increasing trend in HRs across tertiles of GRS (p-trend = 0.0063).
  
  
  CONCLUSIONS
  Our findings suggest that lead-related loci as a whole may play an important role in susceptibility to lead-related CHD risk. These findings need to be validated in a separate cohort containing bone lead, lead-related genetic loci and incident CHD data.
authors: Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, United States of America.
authors: Ning
authors: http://orcid.org/0000-0001-5244-2909
authors: N
authors: Ding
authors: Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, United States of America.
authors: Xin
authors: X
authors: Wang
authors: Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America.
authors: Marc G
authors: MG
authors: Weisskopf
authors: Veterans Affairs Normative Aging Study, Veterans Affairs Boston Healthcare System, Boston, Massachusetts, United States of America.|Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors: David
authors: D
authors: Sparrow
authors: Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America.
authors: Joel
authors: J
authors: Schwartz
authors: Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.|Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, Michigan, United States of America.
authors: Howard
authors: H
authors: Hu
authors: Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, United States of America.|Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, Michigan, United States of America.
authors: Sung Kyun
authors: SK
authors: Park
mesh_terms: D000368:Aged; D000375:Aging / Q000502:physiology*; D001842:Bone and Bones / Q000737:chemistry; D003327:Coronary Disease / Q000139:chemically induced* / Q000235:genetics; D004781:Environmental Exposure; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007854:Lead / Q000032:analysis / Q000493:pharmacokinetics / Q000633:toxicity*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic
chemical_list: D007854:Lead