Journal Article

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

Schwartz, Joel, Ding, Ning, Weisskopf, Marc G., Wang, Xin, Sparrow, David, Hu, Howard, Park, Sung Kyun

2016

Overview

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. 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. 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. 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). 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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Aged / Aging / Aging - physiology / Aminolevulinic acid / Analysis / Angina pectoris / Angiotensin / Angiotensin II / Angiotensinogen / Angiotensins / Apolipoprotein E / Biology and Life Sciences / Bone and Bones - chemistry / Cardiovascular disease / Cardiovascular diseases / Care and treatment / Coronary artery disease / Coronary Disease - chemically induced / Coronary Disease - genetics / Coronary heart disease / Dehydration / Endocrine system / Environmental Exposure / Environmental health / Enzymes / Epidemiology / Exposure / Female / Fluorescence / Gene loci / Gene polymorphism / Genes / Genetic aspects / Genetic Predisposition to Disease / Glutathione / Glutathione transferase / GSTM1 protein / GSTT1 protein / Health aspects / Health hazards / Health risk assessment / Health sciences / Heart attacks / Heart diseases / Heavy metals / Heme oxygenase (decyclizing) / Hemochromatosis / Humans / Hypertension / Lead - analysis / Lead - pharmacokinetics / Lead - toxicity / Lead content / Male / Medicine and Health Sciences / Middle Aged / Oxidative stress / Physical Sciences / Polymorphism, Genetic / Public health / Risk factors / Single nucleotide polymorphisms / Statistical analysis / Statistical models / Veterans / Vitamin D / Vitamin D receptors / X ray fluorescence