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Title: A blood pressure-associated variant of the SLC39A8 gene influences cellular cadmium accumulation and toxicity
Authors: Zhang, Ruoxin
Witkowska, Kate
Guerra-Assunção, José Afonso
Ren, Meixia
Ng, Fu Liang
Mauro, Claudio
Tucker, Arthur T.
Caulfield, Mark J.
Ye, Shu
First Published: 27-Jul-2016
Publisher: Oxford University Press (OUP)
Citation: Human Molecular Genetics, 2016, 25 (18), pp. 4117-4126
Abstract: Genome-wide association studies have revealed a relationship between inter-individual variation in blood pressure and the single nucleotide polymorphism rs13107325 in the SLC39A8 gene. This gene encodes the ZIP8 protein which co-transports divalent metal cations, including heavy metal cadmium, the accumulation of which has been associated with increased blood pressure. The polymorphism results in two variants of ZIP8 with either an alanine (Ala) or a threonine (Thr) at residue 391. We investigated the functional impact of this variant on cadmium transport, protein conformation, activation of signalling pathways and cell viability in relation to blood pressure regulation. Following incubation with cadmium, higher intracellular cadmium was detected in cultured human embryonic kidney cells (HEK293) expressing heterologous ZIP8-Ala391, compared with HEK293 cells expressing heterologous ZIP8-Thr391. This Ala391-associated cadmium accumulation also increased the phosphorylation of the signal transduction molecule ERK2, activation of the transcription factor NFκB, and reduced cell viability. Similarly, vascular endothelial cells with the Ala/Ala genotype had higher intracellular cadmium concentration and lower cell viability than their Ala/Thr counterpart following cadmium exposure. These results indicate that the ZIP8 Ala391-to-Thr391 substitution has an effect on intracellular cadmium accumulation and cell toxicity, providing a potential mechanistic explanation for the association of this genetic variant with blood pressure.
DOI Link: 10.1093/hmg/ddw236
ISSN: 0964-6906
eISSN: 1460-2083
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © the authors, 2016. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-commercial License (, which permits unrestricted use, distribution, and reproduction in any medium non-commercially, provided the original author and source are credited.
Appears in Collections:Published Articles, Dept. of Cardiovascular Sciences

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