Genetic variation in arsenic (+3 oxidation state) methyltransferase (AS3MT), arsenic metabolism and risk of basal cell carcinoma in a European population. (25th August 2014)

• Record Type: Journal Article
• Authors: Engström, Karin S.; Vahter, Marie; Fletcher, Tony; Leonardi, Giovanni; Goessler, Walter; Gurzau, Eugen; Koppova, Kvetoslava; Rudnai, Peter; Kumar, Rajiv; Broberg, Karin
• Is Part Of: Environmental and molecular mutagenesis. Volume 56:Number 1(2015:Jan.)
• Page Start: 60
• Page End: 69
• Publication Date: 2014-08-25
• Subjects: Mutagenesis -- Periodicals; Molecular genetics -- Periodicals; Mutagenèse -- Périodiques; Mutagenèse chimique -- Périodiques; Mutation -- Périodiques; Maladies de l'environnement -- Périodiques; Génétique moléculaire -- Périodiques; 576.542
• DOI: 10.1002/em.21896
• Languages: English
• ISSNs: 0893-6692

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Exposure to inorganic arsenic increases the risk of basal cell carcinoma (BCC). Arsenic metabolism is a susceptibility factor for arsenic toxicity, and specific haplotypes in arsenic (+3 oxidation state) methyltransferase <italic>(AS3MT)</italic> have been associated with increased urinary fractions of the most toxic arsenic metabolite, methylarsonic acid (MMA). The aim of this study is to elucidate the association of <italic>AS3MT</italic> haplotypes with arsenic metabolism and the risk of BCC. Four <italic>AS3MT</italic> polymorphisms were genotyped in BCC cases (<italic>N</italic> = 529) and controls (<italic>N</italic> = 533) from Eastern Europe with low to moderate arsenic exposure (lifetime average drinking water concentration: 1.3 µg/L, range 0.01–167 µg/L). Urinary metabolites [inorganic arsenic (iAs), MMA, dimethylarsinic acid (DMA)] were analyzed by HPLC‐ICPMS. Five <italic>AS3MT</italic> haplotypes (based on rs3740400 <italic>A/C</italic>, rs3740393 <italic>G/C</italic>, rs11191439 <italic>T/C</italic> and rs1046778 <italic>T/C</italic>) had frequencies >5%. Individuals with the <italic>CCTC</italic> haplotype had lower %iAs (<italic>P</italic> = 0.032) and %MMA (<italic>P</italic> = 0.020) in urine, and higher %DMA (<italic>P</italic> = 0.033); individuals with the <italic>CGCT</italic> haplotype had higher %MMA (<italic>P</italic> < 0.001) and lower %DMA (<italic>P</italic> < 0.001). All haplotypes showed increased risk of BCC with increasing arsenic exposure through drinking water (ORs 1.1–1.4, <italic>P</italic> values from <0.001 to 0.082), except for the <italic>CCTC</italic> haplotype (OR 1.0, CI 0.9–1.2, <italic>P</italic> value 0.85). The results suggest that carriage of <italic>AS3MT</italic> haplotypes associated with less‐efficient arsenic methylation, or lack of <italic>AS3MT</italic> haplotypes associated with a more‐efficient arsenic methylation, results in higher risk of arsenic‐related BCC. The fact that <italic>AS3MT</italic> haplotype status modified arsenic metabolism, and in turn the arsenic‐related BCC risk, supports a causal relationship between low‐level arsenic exposure and BCC. Environ. Mol. Mutagen. 56:60–69, 2015. © 2014 The Authors. Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society</p> </abstract>