Lead-Related Genetic Loci, Cumulative Lead Exposure and Incident Coronary Heart Disease: The Normative Aging Study

Abstract

BackgroundCumulative 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.ObjectivesWe 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.MethodsWe 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.ResultsSignificant 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).ConclusionsOur 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.

Effect of Dietary Sodium and Potassium Intake on the Mobilization of Bone Lead among Middle-Aged and Older Men: The Veterans Affairs Normative Aging Study

“…Bone is the major storage site as well as endogenous source of lead in the human body [4,15]. The release of bone lead into the circulation is an important source of soft-tissue lead exposure and toxicity in older populations [5,6,7,8,18]. Dietary strategies provide the possibility of effective and affordable ways to deal with lasting adverse health effects related to bone lead resorption [32].…”

“…However, lead stemming from such environmental exposures remain in the body, specifically within bones, for decades, leading to adverse health impacts in aging populations [4]. Low-to-moderate chronic exposure to lead has been associated with age related conditions such as cognitive decline, hearing loss, kidney failure, and cardiovascular disease [5,6,7,8]. Recently, low-level environmental lead exposure has been further recognized as a largely overlooked risk factor for mortality, especially from cardiovascular disease, in the United States [9].…”

“…Given that an increase in bone resorption is a characteristic of aging, release of bone lead into the plasma is considered as an important source of lead toxicity in older adults [18]. This is supported by the superiority of bone lead over whole blood lead in predicting aging-related chronic health outcomes such as hypertension, coronary heart disease, and mortality [8,19,20].…”

Childhood Lead Exposure and Adult Neurodegenerative Disease

“…On the genetic front, a number of polymorphisms have been identified that are believed to influence susceptibility to lead, including those that alter lead uptake, retention, and bioavailability (Table 2) [166]. Evidence of these genes’ role in lead toxi-codynamics comes from experimental studies using animal and cellular models to test hypotheses about molecular mechanisms [166] and, additionally, from large, genome-wide association studies, which have provided confirmation of a significant relationship between many of these genes and blood-lead levels [167, 168]. Thus far, only a few studies on lead-disease risk have included measures of genetic susceptibility.…”

“…Thus far, only a few studies on lead-disease risk have included measures of genetic susceptibility. (Notable exceptions include studies of incident coronary heart disease [166], cognitive status [169, 170], and essential tremor [171] in older adults). Future studies on the long-term consequences of childhood lead exposure will be more informative for disease prevention if consideration can be given to also measuring genetic susceptibility.…”