Schläwicke Engström Karin, Nermell Barbro, Concha Gabriela, Strömberg Ulf, Vahter Marie, Broberg Karin
Department of Laboratory Medicine, Section of Occupational and Environmental Medicine, Lund University, Lund, Sweden.
Mutat Res. 2009 Jul 10;667(1-2):4-14. doi: 10.1016/j.mrfmmm.2008.07.003. Epub 2008 Jul 17.
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.
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 microg/L of arsenic in drinking water, with a unique metabolism with low percent monomethylated arsenic (%MMA) and high percent dimethylated As (%DMA).
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, 27kilobasepairs (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.
Polymorphisms in AS3MT and in genes involved in one-carbon metabolism and reduction reactions affects arsenic metabolism.
个体对砷（As）诱导疾病的易感性差异很大，这可能在很大程度上归因于砷代谢的遗传差异。本研究的目的是鉴定影响砷代谢的基因变异。
我们评估了尿代谢物模式与砷代谢相关的三个基因组中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，以及（3）参与还原反应的基因。在阿根廷北部的本土女性（N = 104）中成功对49个多态性进行了基因分型，这些女性饮用水中砷含量约为200微克/升，具有独特的代谢模式，单甲基化砷（%MMA）百分比低，二甲基化砷（%DMA）百分比高。
影响砷代谢物模式的遗传因素包括砷（+III）甲基转移酶（AS3MT）中的两个多态性（rs3740400，rs7085104），携带者的%MMA较低，%DMA较高。这些单核苷酸多态性（SNP）与三个内含子AS3MT SNP处于强连锁不平衡（LD）状态，先前报道这些SNP与砷代谢相关，表明存在一种强甲基化的、特定人群的单倍型。CYP17A1 rs743572位于AS3MT上游27千碱基对（kb）处，与AS3MT SNP处于强LD状态，因此对代谢物谱有类似影响。对于参与一碳代谢的基因胆碱脱氢酶（CHDH）（rs9001，rs7626693）和5-甲基四氢叶酸-同型半胱氨酸甲基转移酶还原酶（MTRR）（rs1801394）以及参与还原反应的基因谷氧还蛋白（GLRX）（rs3822751）和过氧化物酶2（PRDX2）（rs10427027，rs12151144）也观察到较小的影响。与更有益的砷代谢物谱（尿中%MMA低和/或%DMA高）相关的基因型在该人群中更常见，该人群已饮用含砷水数千年。
AS3MT以及参与一碳代谢和还原反应的基因中的多态性会影响砷代谢。
