Effect modification by vitamin D receptor genetic polymorphisms in the association between cumulative lead exposure and pulse pressure: a longitudinal study.

Min A Jhun,Howard Hu,Joel Schwartz,David Sparrow,Pantel S Vokonas,Marc G Weisskopf,Linda H Nie,Sung Kyun Park

doi:10.1186/1476-069x-14-5

Abstract

BackgroundAlthough the association between lead and cardiovascular disease is well established, potential mechanisms are still poorly understood. Calcium metabolism plays a role in lead toxicity and thus, vitamin D receptor (VDR) polymorphisms have been suggested to modulate the association between lead and health outcomes. We investigated effect modification by VDR genetic polymorphisms in the association between cumulative lead exposure and pulse pressure, a marker of arterial stiffness.MethodsWe examined 727 participants (3,100 observations from follow-ups from 1991 to 2011) from the Normative Aging Study (NAS), a longitudinal study of aging. Tibia and patella bone lead levels were measured using K-x-ray fluorescence. Four single nucleotide polymorphisms (SNPs) in the VDR gene, Bsm1, Taq1, Apa1, and Fok1, were genotyped. Linear mixed effects models with random intercepts were implemented to take into account repeated measurements.ResultsAdjusting for potential confounders, pulse pressure was 2.5 mmHg (95% CI: 0.4-4.7) and 1.9 mmHg (95% CI: 0.1-3.8) greater per interquartile range (IQR) increase in tibia lead (15 μg/g) and patella lead (20 μg/g), respectively, in those with at least one minor frequency allele in Bsm1 compared with those with major frequency allele homozygotes. The observed interaction effect between bone lead and the Bsm1 genotype persists over time during the follow-up. Similar results were observed in effect modification by Taq1.ConclusionsThis study suggests that subjects with the minor frequency alleles of VDR Bsm1 or Taq1 may be more susceptible to cumulative lead exposure-related elevated pulse pressure.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-069X-14-5) contains supplementary material, which is available to authorized users.

Highlights

The association between lead and cardiovascular disease is well established, potential mechanisms are still poorly understood
We investigate effect modification by the vitamin D receptor (VDR) gene in the association between cumulative lead exposure measured by bone lead levels and pulse pressure, a marker of arterial stiffness
Using longitudinal observations, we found a stronger association between cumulative bone lead levels and pulse pressure in participants with at least one minor frequency allele on Bsm1 or Taq1

Summary

Introduction

The association between lead and cardiovascular disease is well established, potential mechanisms are still poorly understood. We investigated effect modification by VDR genetic polymorphisms in the association between cumulative lead exposure and pulse pressure, a marker of arterial stiffness. Lead (Pb) is known to increase the risk of cardiovascular diseases (CVD). Several studies have identified a positive associated with increased risk of pregnancy-induced hypertension [5]. The association between lead exposure and the risk of hypertension in pregnant women was demonstrated even in those with blood lead levels less than 2 μg/dL [6]. The study by Perlstein et al [10] suggests that lead accumulation may contribute to the increase in pulse pressure, a measure of arterial stiffness, and with clinical cardiovascular events. Zhang et al [11] reported a deleterious impact of cumulative lead on pulse pressure with effect modification by hemochromatosis genetic polymorphism in the NAS

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