title: A blood pressure-associated variant of the SLC39A8 gene influences cellular cadmium accumulation and toxicity.
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 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.
authors.affiliation: William Harvey Research Institute.
authors.forename: Ruoxin
authors.initials: R
authors.lastname: Zhang
authors.affiliation: William Harvey Research Institute.
authors.forename: Kate
authors.initials: K
authors.lastname: Witkowska
authors.affiliation: Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: José
authors.initials: J
authors.lastname: Afonso Guerra-Assunção
authors.affiliation: William Harvey Research Institute.
authors.forename: Meixia
authors.initials: M
authors.lastname: Ren
authors.affiliation: William Harvey Research Institute.
authors.forename: Fu Liang
authors.initials: FL
authors.lastname: Ng
authors.affiliation: William Harvey Research Institute.
authors.forename: Claudio
authors.initials: C
authors.lastname: Mauro
authors.affiliation: William Harvey Research Institute.
authors.forename: Arthur T
authors.initials: AT
authors.lastname: Tucker
authors.affiliation: William Harvey Research Institute sy127@leicester.ac.uk m.j.caulfield@qmul.ac.uk.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Caulfield
authors.affiliation: William Harvey Research Institute sy127@leicester.ac.uk m.j.caulfield@qmul.ac.uk.|Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK.|NIHR Biomedical Research Centre in Cardiovascular Disease, Leicester LE3 9QP, UK.|Shantou University Medical College, Shantou 515041, People's Republic of China.
authors.forename: Shu
authors.initials: S
authors.lastname: Ye
mesh_terms: D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics*; D002104:Cadmium / Q000633:toxicity*; D027682:Cation Transport Proteins / Q000235:genetics*; D002470:Cell Survival / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects; D055106:Genome-Wide Association Study; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000187:drug effects; D008297:Male; D013737:Testis / Q000187:drug effects
chemical_list: D027682:Cation Transport Proteins; C530151:SLC39A8 protein, human; D002104:Cadmium