A blood pressure-associated variant of theSLC39A8gene 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.

Hepatic metal ion transporter ZIP8 regulates manganese homeostasis and manganese-dependent enzyme activity

“…The lead variant in SLC39A8 associated with lower wholeblood Mn levels and other pleiotropic traits is the coding variant rs13107325 (Ala391Thr), which is associated with lower hepatic SLC39A8 expression (4, 6) and may encode a protein with reduced function (10,11). We examined the N-glycan profile in the plasma of rs13107325 A391T homozygotes and matched major allele homozygotes.…”

“…Importantly, the lead variant for blood Mn and all of the other traits is a coding variant, rs13107325 (Ala391Thr), that has an 8% minor allele frequency in people of European ancestry (9) and has been reported to encode a protein with reduced function (10,11). This variant is also an expression quantitative trait locus (eQTL) for SLC39A8 in human liver and is associated with lower hepatic SLC39A8 expression (4,6).…”

Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank

“…rs13107325 (osteoarthritis, PPC 0.99) is a missense variant located in SLC39A8 and demonstrates significantly increased expression in degraded compared to intact articular cartilage (logFC=0.522, FDR=5.80x10 -5 ) (Table1; Supplementary Table 2), consistent with previously-reported increased levels of SLC39A8 in osteoarthritis compared to healthy chondrocytes 30,31 . rs13107325 is also associated with obesity 32 , hypertension 33 , Crohn's disease and altered microbiome composition 34 . SLC39A8 functions in the cellular import of zinc at the onset of inflammation.…”

Functional variant of MTOR rs2536 and survival of Chinese gastric cancer patients

“…It is not surprising that such variants have only moderate contribution to risk and progression of cancers, if any, particularly compared to germline mutations that are associated with some distinct disease phenotypes. This is particularly true for a single locus change such as the MTOR rs2536 T > C change, which is similar to other functional studies focused on single germline variant . The effect of such germline variants on gene expression is also likely to be affected by other molecular events that govern gene expression regulation, such as long coding RNAs and circular RNAs that are competing endogenous RNAs (ceRNAs), which may disrupt the binding of miRNA to 3′UTR of the genes.…”

“…This is particularly true for a single locus change such as the MTOR rs2536 T > C change, which is similar to other functional studies focused on single germline variant. [43][44][45] The effect of such germline variants on gene expression is also likely to be affected by other molecular events that govern gene expression regulation, such as long coding RNAs and circular RNAs that are competing endogenous RNAs (ceRNAs), 46,47 which may disrupt the binding of miRNA to 3 0 UTR of the genes. This might be the reason for the relatively less strong impact of miRNA-150 on modulating the MTOR expression associated with the MTOR rs2536 T > C change.…”