Arsenic metabolism is influenced by polymorphisms in genes involved in one-carbon metabolism and reduction reactions
Arsenic metabolism is influenced by polymorphisms in genes involved in one-carbon metabolism and reduction reactions
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DOI：
10.1016/j.mrfmmm.2008.07.003
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发表时间：
2009-07-10
影响因子：
2.3
通讯作者：
Broberg, Karin
中科院分区：
文献类型：
--
作者：
Engstrom, Karin Schlawicke;Nermell, Barbro;Broberg, Karin
目的：砷（As）引起的疾病的易感性在个体之间差异很大，可能在很大程度上是由于砷代谢的遗传差异。本研究的目的是确定影响砷代谢的遗传变异，方法：我们评估了尿代谢模式和砷代谢相关的三个基因组的多态性之间的关联：（1）甲基转移酶，（2）参与一碳代谢的其他基因和（3）参与还原反应的基因。来自阿根廷北方的土著妇女（N = 104）成功地对49种多态性进行了基因分型，这些妇女暴露于饮用水中约200 μ g/L的砷，具有独特的代谢，具有低百分比的单甲基化砷（%MMA）和高百分比的二甲基化砷（%DMA）。影响砷代谢模式的遗传因素包括砷（+III）甲基转移酶（AS 3 MT）的两个多态性。（rs3740400，rs7085104），其中载体具有较低的MMA %和较高的DMA %。这些单核苷酸多态性（SNPs）与三个内含子AS 3 MT SNPs（先前报道与砷代谢相关）处于强连锁不平衡（LD），表明存在强甲基化的人群特异性单倍型。CYP 17 A1 rs743572（AS 3 MT上游的27个脱氢酶对（kbs））与AS 3 MT SNP存在强LD，因此对代谢产物谱具有相似的影响。一碳代谢基因胆碱脱氢酶（CHDH）（rs 9001、rs7626693）和5-甲基四氢叶酸-高半胱氨酸甲基转移酶还原酶（MTRR）（rs 1801394）以及参与还原反应的基因谷氧还蛋白（GLRX）（rs3822751）和过氧化物氧还蛋白2（PRDX 2）（rs 10427027、rs 12151144）也观察到较小的影响。基因型与更有益的砷代谢产物的配置文件（低%MMA和/或高%DMA在尿中）是更常见的在这个人群中，这已经暴露于砷在饮用水中的thousands of years.Conclusions：多态性在AS 3 MT和基因参与一碳代谢和还原反应影响砷代谢。(C)2008 Elsevier B. V.保留所有权利。
Objectives: The susceptibility to arsenic (As)-induced diseases differs greatly between individuals, probably to a large extent due to genetic differences in arsenic metabolism. The aim for this study was to identify genetic variants affecting arsenic metabolism.Methods: We evaluated the association between urinary metabolite pattern and polymorphisms in three gene-groups related to arsenic metabolism: (1) methyltransferases, (2) other genes involved in one-carbon metabolism and (3) genes involved in reduction reactions. Forty-nine polymorphisms were successfully genotyped in indigenous women (N = 104) from northern Argentina, exposed to approximately 200 mu g/L of arsenic in drinking water, with a unique metabolism with low percent monomethylated arsenic (%MMA) and high percent dimethylated As (%DMA).Results: Genetic factors affecting arsenic metabolite pattern included two polymorphisms in arsenic (+III) methyltransferase (AS3MT) (rs3740400, rs7085104), where carriers had lower %MMA and higher %DMA. These single nucleotide polymorphisms (SNPs) were in strong linkage disequilibrium (LD) with three intronic AS3MT SNPs, previously reported to be associated with arsenic metabolism, indicating the existence of a strongly methylating, population-specific haplotype. The CYP17A1 rs743572, 27 kilobasepairs (kbs) upstream of AS3MT, was in strong LD with the AS3MT SNPs and thus had similar effects on the metabolite profile. Smaller effects were also seen for one-carbon metabolism genes choline dehydrogenase (CHDH) (rs9001, rs7626693) and 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) (rs1801394) and genes involved in reduction reactions, glutaredoxin (GLRX) (rs3822751) and peroxiredoxin 2 (PRDX2) (rs10427027, rs12151144). Genotypes associated with more beneficial arsenic metabolite profile (low %MMA and/or high %DMA in urine) were more common in this population, which has been exposed to arsenic in drinking water for thousands of years.Conclusions: Polymorphisms in AS3MT and in genes involved in one-carbon metabolism and reduction reactions affects arsenic metabolism. (C) 2008 Elsevier B.V. All rights reserved.