A blood pressure-associated variant of the SLC39A8 gene influences cellular cadmium accumulation and toxicity

Ruoxin Zhang, Claudio Mauro, Kate Witkowska, José Afonso Guerra-assunção, Meixia Ren, Fu Liang Ng, Arthur T. Tucker, Mark J. Caulfield, Shu Ye

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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 protein conformation, cadmium transport, 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.
Original languageEnglish
Pages (from-to)4117-4126
Number of pages10
JournalHuman Molecular Genetics
Issue number18
Early online date27 Jul 2016
Publication statusPublished - 15 Sept 2016


  • Hypertension
  • Signal transduction
  • Plasmids
  • Endothelial cells
  • Polymorphism
  • Blood pressure
  • Alanine
  • Cations
  • Cell survival
  • Embryo
  • Genes
  • Genotype
  • Metals
  • Metals, heavy
  • Mitogen activated protein kinase 1
  • Phosphorylation
  • Single nucleotide polymorphism
  • Protein conformation
  • Threonine
  • Cadmium
  • Genetics
  • Kidney
  • Transcription factor
  • Signal pathway
  • Arterial pressure, increased
  • Toxic effect
  • Signal transduction pathways
  • Blood pressure regulation
  • Genome-wide association study
  • hek293 cells
  • Molecule


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