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Randomized Controlled Trial
. 2011 Feb;119(2):182-8.
doi: 10.1289/ehp.1002471. Epub 2010 Sep 24.

Polymorphisms in arsenic(+III oxidation state) methyltransferase (AS3MT) predict gene expression of AS3MT as well as arsenic metabolism

Karin Engström  1 , Marie Vahter, Simona Jurkovic Mlakar, Gabriela Concha, Barbro Nermell, Rubhana Raqib, Alejandro Cardozo, Karin Broberg
Affiliations
Randomized Controlled Trial

Polymorphisms in arsenic(+III oxidation state) methyltransferase (AS3MT) predict gene expression of AS3MT as well as arsenic metabolism

Karin Engström et al. Environ Health Perspect. 2011 Feb.

Abstract

Background: Arsenic (As) occurs as monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) in humans, and the methylation pattern demonstrates large interindividual differences. The fraction of urinary MMA is a marker for susceptibility to As-related diseases.

Objectives: We evaluated the impact of polymorphisms in five methyltransferase genes on As metabolism in two populations, one in South America and one in Southeast Asia. The methyltransferase genes were arsenic(+III oxidation state) methyltransferase (AS3MT), DNA-methyltransferase 1a and 3b (DNMT1a and DNMT3b, respectively), phosphatidylethanolamine N-methyltransferase (PEMT), and betaine-homocysteine methyltransferase (BHMT). AS3MT expression was analyzed in peripheral blood.

Methods: Subjects were women exposed to As in drinking water in the Argentinean Andes [n = 172; median total urinary As (U-As), 200 µg/L] and in rural Bangladesh (n = 361; U-As, 100 µg/L; all in early pregnancy). Urinary As metabolites were measured by high-pressure liquid chromatography/inductively coupled plasma mass spectrometry. Polymorphisms (n = 22) were genotyped with Sequenom, and AS3MT expression was measured by quantitative real-time polymerase chain reaction using TaqMan expression assays.

Results: Six AS3MT polymorphisms were significantly associated with As metabolite patterns in both populations (p ≤ 0.01). The most frequent AS3MT haplotype in Bangladesh was associated with a higher percentage of MMA (%MMA), and the most frequent haplotype in Argentina was associated with a lower %MMA and a higher percentage of DMA. Four polymorphisms in the DNMT genes were associated with metabolite patterns in Bangladesh. Noncoding AS3MT polymorphisms affected gene expression of AS3MT in peripheral blood, demonstrating that one functional impact of AS3MT polymorphisms may be altered levels of gene expression.

Conclusions: Polymorphisms in AS3MT significantly predicted As metabolism across these two very different populations, suggesting that AS3MT may have an impact on As metabolite patterns in populations worldwide.

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Figures

Figure 1
Figure 1
Box plots depicting relative AS3MT gene expression according to genotype in women from Argentina; expression for the reference genotype (associated with low %MMA and high %DMA) is set to 1. (A) Relative gene expression based on assay 1 (covering exons 1–2) according to rs3740400 genotype. (B) Relative gene expression based on assay 4 (covering part of the 3′ untranslated region) according to rs1046778 genotype. Numbers below the boxes indicate the number of individuals with that genotype. The bottom and top of each box indicate 25th and 75th percentiles, respectively; the line inside the box is the median; whiskers represent the smallest and the largest values that are not outliers. Circles and asterisks indicate outliers; squares indicate outliers outside the range of the y-axis, which had a gene expression of 25 (CT genotype) and 23 (TT genotype).
See this image and copyright information in PMC

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