Abstract
Introduction: Cumulative exposure to lead is associated with cardiovascular outcomes. Polymorphisms in the aminolevulinic acid dehydratase (ALAD), hemochromatosis (HFE), heme oxygenase-1 (HMOX-1), vitamin D receptor (VDR), glutathione S-transferase (GST) supergene family (GSTP-1, GSTT-1, GSTM-1), apolipoprotein E (APOE) and angiotensinogen (AGT) genes, are believed to alter toxicokinetics and/or toxicodynamics of lead. We assessed possible effect modification by genetic polymorphisms in ALAD, HFE, HMOX-1, VDR, GSTP-1, GSTT-1, GSTM-1, APOE, AGTR-1 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 weightin...
Highlights
Incident coronary heart disease (CHD) is a major health problem, and the leading cause of mortality worldwide [1]
Significant effect modification was found by vitamin D receptor (VDR), heme oxygenase-1 (HMOX1), GSTP1, apolipoprotein E (APOE), and AGT genetic polymorphisms when evaluated individually
The bone lead-CHD associations became larger as genetic risk score (GRS) increases
Summary
Incident coronary heart disease (CHD) is a major health problem, and the leading cause of mortality worldwide [1]. A number of genes and gene encoding proteins have been identified to play important roles in lead toxicokinetics and/or toxicodynamics: δ-aminolevulinic acid dehydratase (ALAD), an enzyme on the heme-biosynthetic pathway that binds over 80% of lead in erythrocytes [9]; hemochromatosis (HFE), a membrane protein that regulates uptake of cellular iron and other divalent metals including lead [10]; heme oxygenase-1 (HMOX1), a heme-degrading enzyme that plays an important role in the inflammation and oxidative stress induced by lead [11,12,13,14]; vitamin D receptor (VDR) that plays a role in calcium homeostasis that influences the absorption and retention of lead into blood and bone [15]; apolipoprotein E (APOE) that affects lipid metabolism, down-regulates blood lead concentrations, and possesses antioxidative property [16,17,18]; glutathione S-transferases (GSTs), a family of phase-II detoxification isozymes involved in catalyzing the conjugation of lead and glutathione to form a thermodynamically stable complex, which decreases lead bioavailability and protects against lead toxicity through reduced oxidative stress [19,20,21,22]; and the renin-angiotensin system involved in the development of hypertension where lead exposure may enhance blood angiotensin I levels by increasing plasma renin activity, which in turn contribute to production and activation of substrate-induced angiotensin converting enzyme [23,24]. 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
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