N-6-腺嘌呤特异性 DNA 甲基转移酶 1 (N6AMT1) 多态性与安第斯妇女的砷甲基化。
N-6-adenine-specific DNA methyltransferase 1 (N6AMT1) polymorphisms and arsenic methylation in Andean women.
机构信息
Institute of Environmental Medicine, Unit of Metals and Health, Karolinska Institutet, Stockholm, Sweden.
出版信息
Environ Health Perspect. 2013 Jul;121(7):797-803. doi: 10.1289/ehp.1206003. Epub 2013 May 10.
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.
背景
在人类中，无机砷主要由砷（+3 氧化态）甲基转移酶（AS3MT）代谢为甲基化代谢物。AS3MT 多态性与砷代谢效率有关。最近，发现一种假定的 N-6-腺嘌呤特异性 DNA 甲基转移酶 1（N6AMT1）能够在体外将砷甲基化。
目的
我们评估 N6AMT1 多态性在人类砷甲基化效率中的作用。
方法
我们通过高效液相色谱-氢化物发生-电感耦合等离子体质谱法测量尿中砷代谢物的相对浓度[无机砷、甲基胂酸（MMA）和二甲基砷酸]，评估了 188 名暴露于阿根廷安第斯山脉饮用水（~200μg/L）中的砷的妇女的砷甲基化效率。我们通过 Taqman 测定法对 N6AMT1 和 AS3MT 多态性进行基因分型，并使用 Illumina HumanHT-12 v4.0 进行基因表达（血液；n=63）。
结果
五个 N6AMT1 单核苷酸多态性（SNP；rs1997605、rs2205449、rs2705671、rs16983411 和 rs1048546）和两个 N6AMT1 单倍型与尿中 MMA（%MMA）的百分比显著相关，即使在调整 AS3MT 单倍型后也是如此。%MMA 随每个 SNP 的等位基因数单调增加（例如，对于 rs1048546，GG 携带者的平均%MMA 为 7.5%，GT 携带者为 8.8%，TT 携带者为 9.7%）。三个 SNP 处于连锁不平衡（R2>0.8）。N6AMT1（单倍型 1）和 AS3MT（单倍型 2）联合效应的估计关联通常与每个单倍型对%MMA 的加性效应一致。与低 %MMA 相关的 N6AMT1 基因型携带者的 N6AMT1 表达最低，但仅有一种基因型和一种单倍型的拷贝数呈单调相关。
结论
N6AMT1 多态性与安第斯妇女的砷甲基化有关，独立于 AS3MT。N6AMT1 多态性可能是砷相关毒性作用的易感标志物。
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