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Polymorphisms in Arsenic(+III)methyltransferase (AS3MT) Predict Gene Expression of AS3MT as well as Arsenic Metabolism.

Författare:
Publiceringsår: 2011
Språk: Engelska
Sidor: 182-188
Publikation/Tidskrift/Serie: Environmental health perspectives
Volym: 119
Dokumenttyp: Artikel
Förlag: National Institute of Environmental Health Sciences (NIEHS)

Sammanfattning

Background: Arsenic is mono- (MMA) and dimethylated (DMA) in humans and the methylation pattern demonstrates large inter-individual differences. The fraction of urinary MMA is a marker for susceptibility to arsenic-related diseases. Objectives: The impact of polymorphisms in five methyltransferase genes on arsenic metabolism was evaluated in two populations, one in South America, one in southeast Asia. The methyltransferase genes were arsenic(+III)methyltransferase (AS3MT), DNAmethyltransferase 1a and 3b (DNMT1a, DNMT3b), phosphatidylethanolamine Nmethyltransferase (PEMT) and betaine-homocysteine methyltransferase (BHMT). AS3MT expression was analyzed in peripheral blood. Methods: Subjects were women, exposed to arsenic in drinking water in the Argentinean Andes (N=172; median urinary arsenic 200 μg/L) and in rural Bangladesh (N=361; 100 μg/L, all in early pregnancy). Urinary arsenic metabolites were measured by HPLC-ICPMS. Polymorphisms (N=22) were genotyped with Sequenom™. AS3MT expression was measured with qPCR using TaqMan® expression assays. Results: Six AS3MT polymorphisms were significantly associated with arsenic metabolite patterns in both populations (p-values ≤0.01). The most frequent AS3MT haplotype in Bangladesh was associated with higher %MMA, and the most frequent in Argentina with lower %MMA and higher %DMA. Four polymorphisms in the DNMTs were associated with metabolite patterns in Bangladesh. Non-coding AS3MT polymorphisms affected gene expression of AS3MT in peripheral blood, demonstrating that one functional impact of AS3MT polymorphisms may be altering 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.

Disputation

Nyckelord

  • Medicine and Health Sciences
  • AS3MT
  • arsenic
  • BHMT
  • DNMT1a
  • DNMT3b
  • gene expression
  • methylation
  • one-carbon metabolism
  • PEMT
  • polymorphism

Övriga

Published
Yes
  • ISSN: 1552-9924

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