title: N-6-adenine-specific DNA methyltransferase 1 (N6AMT1) polymorphisms and arsenic methylation in Andean women.
abstract: BACKGROUND
  In humans, inorganic arsenic is metabolized to methylated metabolites mainly by arsenic (+3 oxidation state) methyltransferase (AS3MT). AS3MT polymorphisms are associated with arsenic metabolism efficiency. Recently, a putative N-6-adenine-specific DNA methyltransferase 1 (N6AMT1) was found to methylate arsenic in vitro.
  
  
  OBJECTIVE
  We evaluated the role of N6AMT1 polymorphisms in arsenic methylation efficiency in humans.
  
  
  METHODS
  We assessed arsenic methylation efficiency in 188 women exposed to arsenic via drinking water (~ 200 µg/L) in the Argentinean Andes by measuring the relative concentrations of arsenic metabolites in urine [inorganic arsenic, methylarsonic acid (MMA), and dimethylarsinic acid] by high-performance liquid chromatography coupled with hydride generation and inductively coupled plasma mass spectrometry. We performed genotyping for N6AMT1 and AS3MT polymorphisms by Taqman assays, and gene expression (in blood; n = 63) with Illumina HumanHT-12 v4.0.
  
  
  RESULTS
  Five N6AMT1 single nucleotide polymorphisms (SNPs; rs1997605, rs2205449, rs2705671, rs16983411, and rs1048546) and two N6AMT1 haplotypes were significantly associated with the percentage of MMA (%MMA) in urine, even after adjusting for AS3MT haplotype. %MMA increased monotonically according to the number of alleles for each SNP (e.g., for rs1048546, mean %MMA was 7.5% for GG, 8.8% for GT, and 9.7% for TT carriers). Three SNPs were in linkage disequilibrium (R2 > 0.8). Estimated associations for joint effects of N6AMT1 (haplotype 1) and AS3MT (haplotype 2) were generally consistent with expectations for additive effects of each haplotype on %MMA. Carriers of N6AMT1 genotypes associated with lower %MMA showed the lowest N6AMT1 expression, but associations were monotonic according to copy number for only one genotype and one haplotype.
  
  
  CONCLUSIONS
  N6AMT1 polymorphisms were associated with arsenic methylation in Andean women, independent of AS3MT. N6AMT1 polymorphisms may be susceptibility markers for arsenic-related toxic effects.
authors.affiliation: Institute of Environmental Medicine, Unit of Metals and Health, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Florencia
authors.initials: F
authors.lastname: Harari
authors.forename: Karin
authors.initials: K
authors.lastname: Engström
authors.forename: Gabriela
authors.initials: G
authors.lastname: Concha
authors.forename: Graciela
authors.initials: G
authors.lastname: Colque
authors.forename: Marie
authors.initials: M
authors.lastname: Vahter
authors.forename: Karin
authors.initials: K
authors.lastname: Broberg
mesh_terms: D000328:Adult; D001118:Argentina; D001151:Arsenic / Q000652:urine*; D001152:Arsenicals / Q000652:urine; D002101:Cacodylic Acid / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006239:Haplotypes; D006801:Humans; D013058:Mass Spectrometry; D008745:Methylation; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D060888:Real-Time Polymerase Chain Reaction; D015265:Site-Specific DNA-Methyltransferase (Adenine-Specific) / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D001152:Arsenicals; D002101:Cacodylic Acid; D008780:Methyltransferases; C505756:AS3MT protein, human; D015265:Site-Specific DNA-Methyltransferase (Adenine-Specific); C020300:monomethylarsonic acid; D001151:Arsenic