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. 2015 Dec 15;289(3):381-8.
doi: 10.1016/j.taap.2015.10.024. Epub 2015 Oct 31.

Genetic variation in metallothionein and metal-regulatory transcription factor 1 in relation to urinary cadmium, copper, and zinc

Scott V Adams  1 , Brian Barrick  2 , Emily P Christopher  3 , Martin M Shafer  4 , Karen W Makar  5 , Xiaoling Song  5 , Johanna W Lampe  3 , Hugo Vilchis  6 , April Ulery  2 , Polly A Newcomb  3
Affiliations

Genetic variation in metallothionein and metal-regulatory transcription factor 1 in relation to urinary cadmium, copper, and zinc

Scott V Adams et al. Toxicol Appl Pharmacol. .

Abstract

Background: Metallothionein (MT) proteins play critical roles in the physiological handling of both essential (Cu and Zn) and toxic (Cd) metals. MT expression is regulated by metal-regulatory transcription factor 1 (MTF1). Hence, genetic variation in the MT gene family and MTF1 might influence excretion of these metals.

Methods: 321 women were recruited in Seattle, WA and Las Cruces, NM and provided demographic information, urine samples for measurement of metal concentrations by mass spectrometry and creatinine, and blood or saliva for extraction of DNA. Forty-one single nucleotide polymorphisms (SNPs) within the MTF1 gene region and the region of chromosome 16 encoding the MT gene family were selected for genotyping in addition to an ancestry informative marker panel. Linear regression was used to estimate the association of SNPs with urinary Cd, Cu, and Zn, adjusted for age, urinary creatinine, smoking history, study site, and ancestry.

Results: Minor alleles of rs28366003 and rs10636 near the MT2A gene were associated with lower urinary Cd, Cu, and Zn. Minor alleles of rs8044719 and rs1599823, near MT1A and MT1B, were associated with lower urinary Cd and Zn, respectively. Minor alleles of rs4653329 in MTF1 were associated with lower urinary Cd.

Conclusions: These results suggest that genetic variation in the MT gene region and MTF1 influences urinary Cd, Cu, and Zn excretion.

Keywords: Cadmium; Copper; Metal-regulatory transcription factor 1; Metallothionein; Zinc.

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Conflict of interest statement

Conflict of interest statement. The authors state that they have no real or potential conflicts of interest that could have influenced this research.

Figures

Figure 1
Figure 1
Mean difference in urinary Cd, Cu, and Zn concentrations (μg/L) associated with selected metallothionein (MT) gene region and metal-regulatory transcription factor 1 (MTF1) single nucleotide polymorphisms. Shading is for clarity. a Approximate relative location of MT genes (chromosome 16) and MTF1 gene (chromosome 1). The MT region is ~125 kbp. The MTF1 region is ~50 kbp. b Mean difference in urinary metal comparing homozygote minor to homozygote major alleles (referent), adjusted for age, study site, urinary creatinine, smoking (never/ever), and the largest three principal components of the ancestry informative marker panel. Difference >0 indicates homozygote minor alleles is associated with higher mean urinary metal. c P(mm) is P-value for comparison of mean urinary metal between homozygote major to homozygote minor alleles. d P-value for trend in urinary metals with number of minor alleles. e Comparing heterozygotes to homozygotes because no homozygotes with minor alleles were included in the study sample.
Figure 2
Figure 2
Pooled results and results from each study (Equol, Breast and Bone (EBB) and New Mexico Metals (NMM)), showing the association of trend in minor alleles with urinary metals (β(trend)), for SNPs significantly associated with one or more urinary metal concentrations in the primary analysis (Figure 1). Pint(study) is the P-value of the interaction between study and the SNP, in association with urinary metals; Pint(study)>0.05 indicates no significant difference between studies. Shading is for clarity. a Results for heterozygotes are plotted because of small number of homozygotes of the minor allele
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