Maternal iron metabolism gene variants modify umbilical cord blood lead levels by gene-environment interaction: a birth cohort study

Abstract

BackgroundGiven the relationship between iron metabolism and lead toxicokinetics, we hypothesized that polymorphisms in iron metabolism genes might modify maternal-fetal lead transfer. The objective of this study was to determine whether maternal and/or infant transferrin (TF) and hemochromatosis (HFE) gene missense variants modify the association between maternal blood lead (MBL) and umbilical cord blood lead (UCBL).MethodsWe studied 476 mother-infant pairs whose archived blood specimens were genotyped for TF P570S, HFE H63D and HFE C282Y. MBL and UCBL were collected within 12 hours of delivery. Linear regression models were used to examine the association between log-transformed MBL and UCBL, examine for confounding and collinearity, and explore gene-environment interactions.ResultsThe geometric mean MBL was 0.61 μg/dL (range 0.03, 3.2) and UCBL 0.42 (<0.02, 3.9). Gene variants were common with carrier frequencies ranging from 12-31%; all were in Hardy-Weinberg equilibrium. In an adjusted linear regression model, log MBL was associated with log UCBL (β = 0.92, 95% CI: 0.82, 1.03; p < 0.01) such that a 1% increase in MBL was associated with a 0.92% increase in UCBL among infants born to wild-type mothers. In infants born to C282Y variants, however, a 1% increase in MBL is predicted to increase UCBL 0.65% (βMain Effect = −0.002, 95% CI: −0.09, −0.09; p = 0.97; βInteraction = −0.27, 95% CI: −0.52, −0.01; p = 0.04), representing a 35% lower placental lead transfer among women with MBL 5 μg/dL.ConclusionsMaternal HFE C282Y gene variant status is associated with greater reductions in placental transfer of lead as MBL increases. The inclusion of gene-environment interaction in risk assessment models may improve efforts to safeguard vulnerable populations.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-069X-13-77) contains supplementary material, which is available to authorized users.

Maternal hemochromatosis gene H63D single-nucleotide polymorphism and lead levels of placental tissue, maternal and umbilical cord blood

“…Taken together, it may be suggested that maternal HFE H63D polymorphism seems to have an effect not only on lead level in maternal blood but also on transfer of lead from placenta to fetus. In parallel line with our suggestion, Karwowski et al (2014) reported that maternal genotype primarily affects the lead's trans-placental transfer, whereas fetal HFE C282Y and H63D gene variants do not alter the lead transfer across the placenta (Karwowski et al, 2014). However, in contrast to Karwowski et al (2014), we found that maternal blood lead was linearly associated with umbilical cord blood in HFE H63D variant mother-infant pairs.…”

“…In parallel line with our suggestion, Karwowski et al (2014) reported that maternal genotype primarily affects the lead's trans-placental transfer, whereas fetal HFE C282Y and H63D gene variants do not alter the lead transfer across the placenta (Karwowski et al, 2014). However, in contrast to Karwowski et al (2014), we found that maternal blood lead was linearly associated with umbilical cord blood in HFE H63D variant mother-infant pairs. Unlike HFE C282Y polymorphism, how H63D polymorphism in the HFE gene modifies iron absorption has not been exactly understood.…”

“…In Turkish population, the frequency of HFE H63D polymorphism was studied in blood donors (Simsek et al, 2004;Bozkaya et al, 2004) and in women with breast cancer (GunelOzcan et al, 2006). On the other hand, the association between HFE gene variants (C282Y and H63D) and lead exposure in mother-infant pairs was first studied by Karwowski et al (2014) and maternal HFE C282Y gene variant status was found to be associated with placental lead transfer. Umbilical cord blood lead levels were detected to be lower in infants born to mothers with HFE C282Y variant than those with wild-type genotype.…”

“…HFE gene was selected since (a) HFE influences the expression of other metal transporters such as DMT1 and ferroportin; (b) HFE is one of the genes that are recognized to influence lead toxicokinetics and toxicodynamics; and, (c) HFE protein is expressed at the apical membrane of syncytiotrophoblasts and placental iron transfer occurs at this site. Previously, Karwowski et al (2014) studied the effect of maternal and/or infant hemochromatosis (both HFE C282Y and H63D) gene variants on maternal blood lead (MBL) and umbilical cord blood lead (UCBL). In this study, no statistically significant differences between geometric mean blood lead value and variant status was detected.…”

Variation in an Iron Metabolism Gene Moderates the Association Between Blood Lead Levels and Attention-Deficit/Hyperactivity Disorder in Children

“…For example, in a series of studies of older men, Wright and his colleagues reported that the association between lead level and cognitive decline was stronger for men who were carriers of HFE mutations (Wang et al, 2007) and that the association between blood lead level and disturbed cardiac function was greater for those with the C282Y variant of the HFE gene (Park et al, 2009). The C282Y variant also altered the association between lead and amyotrophic lateral sclerosis (Eum et al, 2014) and altered the rate of placental lead transfer (Karwowski et al, 2014); H63D variants altered lead’s association with low birth weight (Cantonwine et al, 2010). These findings are quite consistent, even though the strength of association among HFE variants and absolute blood lead level is modest and inconsistent in these studies.…”