智利人群中砷（+3氧化态）甲基转移酶（AS3MT）和N-6腺嘌呤特异性DNA甲基转移酶1（N6AMT1）多态性、砷代谢与癌症风险之间的关联。
Associations between arsenic (+3 oxidation state) methyltransferase (AS3MT) and N-6 adenine-specific DNA methyltransferase 1 (N6AMT1) polymorphisms, arsenic metabolism, and cancer risk in a chilean population.
作者信息
de la Rosa Rosemarie, Steinmaus Craig, Akers Nicholas K, Conde Lucia, Ferreccio Catterina, Kalman David, Zhang Kevin R, Skibola Christine F, Smith Allan H, Zhang Luoping, Smith Martyn T
机构信息
Superfund Research Program, Divisions of Environmental Health Sciences and Epidemiology, School of Public Health, University of California, Berkeley, California.
Departamento de Salud Pública, Facultad de Medicina, Pontificia Universidad Católica de Chile, Advanced Center for Chronic Diseases, ACCDiS, Santiago, Chile.
出版信息
Environ Mol Mutagen. 2017 Jul;58(6):411-422. doi: 10.1002/em.22104. Epub 2017 Jun 22.
Inter-individual differences in arsenic metabolism have been linked to arsenic-related disease risks. Arsenic (+3) methyltransferase (AS3MT) is the primary enzyme involved in arsenic metabolism, and we previously demonstrated in vitro that N-6 adenine-specific DNA methyltransferase 1 (N6AMT1) also methylates the toxic inorganic arsenic (iAs) metabolite, monomethylarsonous acid (MMA), to the less toxic dimethylarsonic acid (DMA). Here, we evaluated whether AS3MT and N6AMT1 gene polymorphisms alter arsenic methylation and impact iAs-related cancer risks. We assessed AS3MT and N6AMT1 polymorphisms and urinary arsenic metabolites (%iAs, %MMA, %DMA) in 722 subjects from an arsenic-cancer case-control study in a uniquely exposed area in northern Chile. Polymorphisms were genotyped using a custom designed multiplex, ligation-dependent probe amplification (MLPA) assay for 6 AS3MT SNPs and 14 tag SNPs in the N6AMT1 gene. We found several AS3MT polymorphisms associated with both urinary arsenic metabolite profiles and cancer risk. For example, compared to wildtypes, individuals carrying minor alleles in AS3MT rs3740393 had lower %MMA (mean difference = -1.9%, 95% CI: -3.3, -0.4), higher %DMA (mean difference = 4.0%, 95% CI: 1.5, 6.5), and lower odds ratios for bladder (OR = 0.3; 95% CI: 0.1-0.6) and lung cancer (OR = 0.6; 95% CI: 0.2-1.1). Evidence of interaction was also observed for both lung and bladder cancer between these polymorphisms and elevated historical arsenic exposures. Clear associations were not seen for N6AMT1. These results are the first to demonstrate a direct association between AS3MT polymorphisms and arsenic-related internal cancer risk. This research could help identify subpopulations that are particularly vulnerable to arsenic-related disease. Environ. Mol. Mutagen. 58:411-422, 2017. © 2017 Wiley Periodicals, Inc.
砷代谢的个体差异与砷相关疾病风险有关。砷（+3）甲基转移酶（AS3MT）是参与砷代谢的主要酶，我们之前在体外证明，N-6腺嘌呤特异性DNA甲基转移酶1（N6AMT1）也会将有毒的无机砷（iAs）代谢产物一甲基亚胂酸（MMA）甲基化，生成毒性较低的二甲基胂酸（DMA）。在此，我们评估了AS3MT和N6AMT1基因多态性是否会改变砷甲基化并影响与iAs相关癌症的风险。我们在智利北部一个独特暴露区域的砷相关癌症病例对照研究中，对722名受试者的AS3MT和N6AMT1多态性以及尿砷代谢产物（%iAs、%MMA、%DMA）进行了评估。使用定制设计的多重连接依赖探针扩增（MLPA）检测法对AS3MT基因的6个单核苷酸多态性（SNP）和N6AMT1基因的14个标签SNP进行基因分型。我们发现了几种与尿砷代谢产物谱和癌症风险相关的AS3MT多态性。例如，与野生型相比，AS3MT rs3740393中携带次要等位基因的个体%MMA较低（平均差异=-1.9%，95%置信区间：-3.3，-0.4），%DMA较高（平均差异=4.0%，95%置信区间：1.5，6.5），膀胱癌（OR=0.3；95%置信区间：0.1-0.6）和肺癌（OR=0.6；95%置信区间：0.2-1.1）的比值比更低。在这些多态性与历史砷暴露增加之间，还观察到肺癌和膀胱癌存在相互作用的证据。未发现N6AMT1有明显关联。这些结果首次证明了AS3MT多态性与砷相关的体内癌症风险之间存在直接关联。这项研究有助于识别特别易患砷相关疾病的亚人群。《环境与分子突变》58:411-422，2017年。©2017威利期刊公司
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