Section of Occupational and Environmental Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden.
PLoS One. 2013;8(1):e53732. doi: 10.1371/journal.pone.0053732. Epub 2013 Jan 14.
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.
砷是一种非常有效的有毒物质。砷相关性毒性的一个主要易感性因素是砷代谢的效率。而效率又与 10 号染色体 q24 上的砷甲基转移酶 AS3MT 的非编码单核苷酸多态性 (SNP) 有关。然而，这些 SNP 的作用机制尚不清楚。在这里，我们评估了 AS3MT 中的遗传变异对饮用水中砷暴露人群 10q24 内 DNA 甲基化和基因表达的影响。从阿根廷安第斯山脉的女性（N=103）外周血和孟加拉国新生儿的脐血中提取 DNA。使用 Sequenom 或 Taqman 测定法分析 AS3MT SNPs。用 Infinium HumanMethylation450 BeadChip 对亚硫酸氢盐处理过的 DNA 进行全基因组表观遗传分析。用 Illumina DirectHyb HumanHT-12 v4.0 对来自外周血的 RNA 进行全基因组基因表达分析。用 HPLC-ICPMS 评估砷暴露。在阿根廷妇女中，与更有效的砷代谢相关的主要 AS3MT 单倍型显示 AS3MT 的甲基化增加（p=10(-6)），并且在大约 800 千碱基对范围内的其他几个基因也存在差异甲基化：CNNM2（p<10(-16)），NT5C2（p<10(-16)），C10orf26（p=10(-8)），USMG5（p=10(-5)），TRIM8（p=10(-4)）和 CALHM2（p=0.038）（经多次比较调整）。在孟加拉国的脐带血中也观察到 AS3MT 单倍型与 10q24 中 DNA 甲基化之间存在类似但较弱的关联。与 AS3MT 单倍型相关的改变的 CpG 甲基化与 AS3MT 和 CNNM2 的表达减少（r(s)=-0.22 至-0.54）以及 NT5C2 和 USMG5 的表达增加（r(s)=0.25 至 0.58）相关。在多变量线性模型中考虑其他可能有影响的变量仅在一定程度上改变了关联的强度。总之，AS3MT 单倍型状态强烈预测了 10q24 中 AS3MT 以及几个基因的 DNA 甲基化和基因表达。这增加了该区域的几个基因对砷代谢很重要的可能性。
