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Arsenic is a very potent toxicant. One major susceptibility factor for arsenic-related toxicity is the efficiency of arsenic metabolism. The efficiency, in turn, is associated with non-coding single nucleotide polymorphisms (SNPs) in the arsenic methyltransferase  AS3MT  on chromosome 10q24. However, the mechanism of action for these SNPs is not yet clarified. Here, we assessed the influence of genetic variation in  AS3MT  on DNA methylation and gene expression within 10q24, in people exposed to arsenic in drinking water. DNA was extracted from peripheral blood from women in the Argentinean Andes (N = 103) and from cord blood from new-borns in Bangladesh (N = 127).  AS3MT  SNPs were analyzed with Sequenom or Taqman assays. Whole genome epigenetic analysis with Infinium HumanMethylation450 BeadChip was performed on bisulphite-treated DNA. Whole genome gene expression analysis was performed with Illumina DirectHyb HumanHT-12 v4.0 on RNA from peripheral blood. Arsenic exposure was assessed by HPLC-ICPMS. In the Argentinean women, the major  AS3MT  haplotype, associated with more efficient arsenic metabolism, showed increased methylation of  AS3MT  (p = 10 −6 ) and also differential methylation of several other genes within about 800 kilobasepairs:  CNNM2  (p<10 −16 ),  NT5C2  (p<10 −16 ),  C10orf26  (p = 10 −8 ),  USMG5  (p = 10 −5 ),  TRIM8  (p = 10 −4 ), and  CALHM2  (p = 0.038) (adjusted for multiple comparisons). Similar, but weaker, associations between  AS3MT  haplotype and DNA methylation in 10q24 were observed in cord blood (Bangladesh). The haplotype-associated altered CpG methylation was correlated with reduced expression of  AS3MT  and  CNNM2  (r s  = −0.22 to −0.54), and with increased expression of  NT5C2  and  USMG5  (r s  = 0.25 to 0.58). Taking other possibly influential variables into account in multivariable linear models did only to a minor extent alter the strength of the associations. In conclusion, the  AS3MT  haplotype status strongly predicted DNA methylation and gene expression of  AS3MT  as well as several genes in 10q24. This raises the possibility that several genes in this region are important for arsenic metabolism.

Efficient Arsenic Metabolism — The AS3MT Haplotype Is Associated with DNA Methylation and Expression of Multiple Genes Around AS3MT