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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 NF?B, 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.

SUBMITTER: Zhang R

PROVIDER: S-EPMC5291231 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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

Zhang Ruoxin R Witkowska Kate K Afonso Guerra-Assunção José J Ren Meixia M Ng Fu Liang FL Mauro Claudio C Tucker Arthur T AT Caulfield Mark J MJ Ye Shu S

Human molecular genetics 20160727 18

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 investigat ...[more]

PMID: 27466201

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Project description:AIMS:Activation of vascular GPER has been linked to vasodepressor effects in animals. However, the significance of GPER regulation on chronic blood pressure control in humans is unknown. METHODS:To examine this question we determined the functional significance of expression of a common missense single nucleotide variant of GPER, P16L in vascular smooth muscle cells, and its association with blood pressure in humans. Further, to validate the importance of carrying GPER P16L in the development of hypertension we assessed allele frequency in a cohort of hard-to-treat hypertensive patients referred to a tertiary care clinic. RESULTS:Expression of the GPER P16L variant (V) vs. wild type (WT) in rat aortic vascular smooth muscle cells, was associated with a significant decrease in G1 (1??m, a GPER agonist)-mediated ERK phosphorylation (slope of the function of G1-stimulated ERK phosphorylation: GPER content WT: 16.2, 95% CI 9.9, 22.6; V: 5.0, 95% CI 1.0, 9.0; P < 0.005) and apoptosis (slope of the function of G1-stimulated apoptosis: GPER content: WT: 4.4, 95% CI: 3.4, 5.4; V: 2.5, 95% CI 1.6, 2.3 P < 0.005). Normotensive female subjects, but not male subjects, carrying this hypofunctional variant (allele frequency 22%) have increased blood pressure [mean arterial pressure: P16/P16: 80 ± 1?mmHg (n = 204) vs.?P16L carriers: 82 ± 1?mmHg (n = 127), 95% CI for difference: 0.6, 4.0?mmHg, P < 0.05], [systolic blood pressure: P16/P16: 105 ± 1?mmHg vs. P16L carriers: 108 ± 1?mmHg, 95% CI for difference:1.0, 5.1?mmHg, P < 0.05], [diastolic blood pressure: P16/P16: 66 ± 0.5?mmHg vs. P16L carriers 68 ± 0.7, 95% CI for difference: 0.2, 3.6?mmHg, P < 0.05]. Further, the P16L allele frequency was almost two-fold higher in female vs. male hypertensive patients (31% vs. 16%, allele ratio 0.5, 95% CI 0.32, 0.76, P < 0.05). CONCLUSIONS:The common genetic variant, GPER P16L, is hypofunctional and female carriers of this allele have increased blood pressure. There was an increased prevalence in a population of hard-to-treat hypertensive female patients. Cumulatively, these data suggest that in females, impaired GPER function might be associated with increased blood pressure and risk of hypertension.

Dataset Information

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

Publications

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

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