Efficient arsenic metabolism--the AS3MT haplotype is associated with DNA methylation and expression of multiple genes around AS3MT.
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.
Section of Occupational and Environmental Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden.
Karin S
KS
Engström
Mohammad Bakhtiar
MB
Hossain
Martin
M
Lauss
Sultan
S
Ahmed
Rubhana
R
Raqib
Marie
M
Vahter
Karin
K
Broberg
D000328:Adult; D001151:Arsenic / Q000378:metabolism* / Q000633:toxicity; D002648:Child; D002879:Chromosomes, Human, Pair 10 / Q000187:drug effects / Q000235:genetics; D015331:Cohort Studies; D018899:CpG Islands / Q000187:drug effects / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects; D004785:Environmental Pollutants / Q000378:metabolism* / Q000633:toxicity; D057890:Epigenomics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006239:Haplotypes / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008297:Male; D008780:Methyltransferases / Q000235:genetics*; D009035:Mothers; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011247:Pregnancy
D004785:Environmental Pollutants; D008780:Methyltransferases; C505756:AS3MT protein, human; D001151:Arsenic