As3MT、N6AMT1基因-环境交互作用对砷暴露所致皮肤损伤影响
|
摘要
目的探讨砷甲基转移酶(As3MT)和N-6-腺嘌呤特异性DNA甲基转移酶1(N6AMT1)基因多态性及基因-环境交互作用与砷暴露所致皮肤损伤(AISL)的关联性。方法于2010年9月到2011年12月在内蒙古五原县入选饮水型砷暴露人群335人,65例被确诊患有AISL。应用MassARRAY~(?)分子量阵列平台检测基因型,高效液相色谱-电感耦合等离子体质谱联用法测定尿砷代谢物,砷暴露时间由其高砷水饮用时间确定,多因子降维法与岭回归模型分析基因型、环境因素的单独效应及基因-环境的交互作用。结果 As3MT基因rs3740400位点CA/AA基因型、N6AMT1基因rs 1006903位点GC/CC基因型和尿二甲基胂酸(DMA)升高为AISL的独立危险因素(P<0.05)。rs3740400位点基因型-尿无机砷(iAs)-单甲基胂酸(MMA)的交互作用与AISL发生风险间存在显著的统计学关联(OR=0.62, 95%CI=0.41～0.94,P=0.024),模型的验证样本准确率为0.577 6,交叉验证一致性为9/10。结论 As3MT、N6AMT1基因多态性及尿砷化合物水平均与AISL独立相关,rs3740400位点基因型、尿iAs和MMA的交互作用在慢性砷中毒的发生发展中具有重要作用。
Objective To study the association of the gene polymorphism of arsenic(+3 oxidation state) methyltransferase(As3 MT) and N-6-adenine-specific DNA methyltransferase 1(N6 AMT1) with arsenic-induced skin lesions(AISL), and explore the interaction between gene polymorphism of As3 MT/N6 AMT1 and environment factors. Methods From September 2010 to December 2011,we conducted a survey among 335 adult residents(mean age: 50.59 ± 11.24) in 3 arsenic exposed villages stratified and randomly selected, based on the results of average arsenic concentration tests in previous years in Wuyuan county of Inner Mongolia Autonomous Region; then 65 residents diagnosed with AISL were assigned into a case group and the others into a control group. Blood samples were collected among all the participants for genotype detections of As3 MT and N6 AMT1 genes with MassARRAY~(?) molecular weight array platform. Urinary arsenic profiles of the participants were determined with high-performance liquid chromatography/inductively coupled plasma-mass spectrometry.The durations of arsenic exposure of the participants were determined according to their use time of high-arsenic drinking water. Multifactoral dimensionality reduction and multivariate ridge regression model were adoopted to assess geneenvironment interactive effects on AISL. Results The CA/AA genotype of As3 MT rs3740400, the GC/CC genotype of N6 AMT1 rs 1006903 and the elevated urinary dimethylarsinic acid(DMA) level were significant independent risk factors of AISL(P < 0.05 for all). Significant association of the interaction between As3 MT rs3740400 genotype and urinary inorganic arsenic(iAs)-monomethylarsonic acid(MMA) with the risk of AISL(odds ratio = 0.62, 95% confidence interval: 0.41,0.94;P = 0.024) was observed, with the accuracy rate of 0.5776 and a cross-validation consistency of 9/10 for the established 3 factors analysis model. Conclusion Genetic variants in As3 MT and N6 AMT1 genes and urine DMA level are independently associated with AISL. The interaction among As3 MT rs3740400 gene, urinary iAs, and MMA level plays an important role in the development of arsenical ism in the population with chronic arsenic exposure through drinking water.
Objective To study the association of the gene polymorphism of arsenic(+3 oxidation state) methyltransferase(As3 MT) and N-6-adenine-specific DNA methyltransferase 1(N6 AMT1) with arsenic-induced skin lesions(AISL), and explore the interaction between gene polymorphism of As3 MT/N6 AMT1 and environment factors. Methods From September 2010 to December 2011,we conducted a survey among 335 adult residents(mean age: 50.59 ± 11.24) in 3 arsenic exposed villages stratified and randomly selected, based on the results of average arsenic concentration tests in previous years in Wuyuan county of Inner Mongolia Autonomous Region; then 65 residents diagnosed with AISL were assigned into a case group and the others into a control group. Blood samples were collected among all the participants for genotype detections of As3 MT and N6 AMT1 genes with MassARRAY~(?) molecular weight array platform. Urinary arsenic profiles of the participants were determined with high-performance liquid chromatography/inductively coupled plasma-mass spectrometry.The durations of arsenic exposure of the participants were determined according to their use time of high-arsenic drinking water. Multifactoral dimensionality reduction and multivariate ridge regression model were adoopted to assess geneenvironment interactive effects on AISL. Results The CA/AA genotype of As3 MT rs3740400, the GC/CC genotype of N6 AMT1 rs 1006903 and the elevated urinary dimethylarsinic acid(DMA) level were significant independent risk factors of AISL(P < 0.05 for all). Significant association of the interaction between As3 MT rs3740400 genotype and urinary inorganic arsenic(iAs)-monomethylarsonic acid(MMA) with the risk of AISL(odds ratio = 0.62, 95% confidence interval: 0.41,0.94;P = 0.024) was observed, with the accuracy rate of 0.5776 and a cross-validation consistency of 9/10 for the established 3 factors analysis model. Conclusion Genetic variants in As3 MT and N6 AMT1 genes and urine DMA level are independently associated with AISL. The interaction among As3 MT rs3740400 gene, urinary iAs, and MMA level plays an important role in the development of arsenical ism in the population with chronic arsenic exposure through drinking water.
引文
[1] Smith AH, Lopipero PA, Bates MN, et al. Public health. Arsenic epidemiology and drinking water standards[J]. Science, 2002,296(5576):2145-2146.
[2] Sun GF. Arsenic contamination and arsenicosis in China[J].Toxicology and Applied Pharmacology, 2004,198(3):268-271.
[3] Jomova K, Jenisova Z, Feszterova M, et al. Arsenic:toxicity,oxidative stress and human disease[J]. Journal of Applied Toxicology, 2011,31(2):95-107.
[4] Hsu LI, Chen GS, Lee CH, et al. Use of arsenic-induced palmoplantar hyperkeratosis and skin cancers to predict risk of subsequent internal malignancy[J]. American Journal of Epidemiology, 2013,177(3):202-212.
[5] Paul S, Majumdar S, Giri AK. Genetic susceptibility to arsenicinduced skin lesions and health effects:a review[J]. Genes and Environment:the Official Journal of the Japanese Environmental Mutagen Society, 2015, 37:23.
[6] Pierce BL, Tong L, Argos M, et al. Arsenic metabolism efficiency has a causal role in arsenic toxicity:mendelian randomization and gene-environment interaction[J]. Int J Epidemiol., 2013, 42(6):1862-1872.
[7] Guo XJ, Cui H, Zhang HY, et al. Protective effect of folic acid on oxidative DNA damage:a randomized, double-blind, and placebo controlled clinical trial[J]. Medicine, 2015, 94(45):e1872.
[8]卫生部.WS/T 211-2001地方性砷中毒诊断标准[S].北京:中国标准出版社,2004.
[9] Haque R, Samanta S, Ghosh N, et al. Arsenic in drinking water and skin lesions:dose-response data from West Bengal, India[J].Epidemiology, 2003,14(2):174-182.
[10] Su L, Cheng Y, Lin S, et al. Study of relationship between arsenic methylation and skin lesion in a population with long-term high arsenic exposure[J]. Journal of Hygiene Research, 2007, 36(3):336-340.
[11] Engstr(o|¨)m K, Vahter M, Mlakar SJ, et al. Polymorphisms in arsenic(+III oxidation state)methyltransferase(AS3MT)predict gene expression of AS3MT as well as arsenic metabolism[J].Environmental Health Perspectives, 2011, 119(2):182-188.
[12]张强,郑全美,席淑华,等.高砷暴露致皮肤损伤人群尿砷代谢产物分析[J].环境与健康杂志,2009,26(12):1048-1050.
[13] Wei B, Yu J, Li H, et al. Effects of arsenic methylation and metabolism on the changes of arsenic-related skin lesions[J].Environmental Science and Pollution Research International, 2018,25(7):1-9.
[14] Ren XF, Aleshin M, Jo WJ, et al. Involvement of N-6 adeninespecific DNA methyltransferase 1(N6AMT1)in arsenic biomethylation and its role in arsenic-induced toxicity[J]. Environ.Health Perspect,2011, 119(6):771-777.
[15] Harari F, Engstrom K, Concha G, et al. N-6-adenine-specific DNA methyltransferase 1(N6AMT1)polymorphisms and arsenic methylation in Andean women[J]. Environmental Health Perspectives, 2013, 121(7):797-803.
[16] Zhang H, Ge YC, He P, et al. Interactive effects of N6AMT1 and As3MT in arsenic biomethylation[J]. Toxicol Sci, 2015, 146(2):354-362.
[17] Chen XS, Guo XJ, He P, et al. Interactive influence of N6AMT1and As3MT genetic variations on arsenic metabolism in the population of Inner Mongolia, China[J]. Toxicol Sci, 2017, 155(1):124-134.
[18] Bahl C, Sharma S,Singh N,et al. Association study between genetic variations in Axin2 gene and lung cancer risk in North Indian population:a multiple interaction analysis[J]. Tumor Biol,2017,39(4):18.
[19] Su YS, Ding WH, Xing MJ, et al. The Interaction of TXNIP and AFql genes increases the susceptibility of schizophrenia[J].Molecular Neurobiology, 2017, 54(6):4806-4812.
[2] Sun GF. Arsenic contamination and arsenicosis in China[J].Toxicology and Applied Pharmacology, 2004,198(3):268-271.
[3] Jomova K, Jenisova Z, Feszterova M, et al. Arsenic:toxicity,oxidative stress and human disease[J]. Journal of Applied Toxicology, 2011,31(2):95-107.
[4] Hsu LI, Chen GS, Lee CH, et al. Use of arsenic-induced palmoplantar hyperkeratosis and skin cancers to predict risk of subsequent internal malignancy[J]. American Journal of Epidemiology, 2013,177(3):202-212.
[5] Paul S, Majumdar S, Giri AK. Genetic susceptibility to arsenicinduced skin lesions and health effects:a review[J]. Genes and Environment:the Official Journal of the Japanese Environmental Mutagen Society, 2015, 37:23.
[6] Pierce BL, Tong L, Argos M, et al. Arsenic metabolism efficiency has a causal role in arsenic toxicity:mendelian randomization and gene-environment interaction[J]. Int J Epidemiol., 2013, 42(6):1862-1872.
[7] Guo XJ, Cui H, Zhang HY, et al. Protective effect of folic acid on oxidative DNA damage:a randomized, double-blind, and placebo controlled clinical trial[J]. Medicine, 2015, 94(45):e1872.
[8]卫生部.WS/T 211-2001地方性砷中毒诊断标准[S].北京:中国标准出版社,2004.
[9] Haque R, Samanta S, Ghosh N, et al. Arsenic in drinking water and skin lesions:dose-response data from West Bengal, India[J].Epidemiology, 2003,14(2):174-182.
[10] Su L, Cheng Y, Lin S, et al. Study of relationship between arsenic methylation and skin lesion in a population with long-term high arsenic exposure[J]. Journal of Hygiene Research, 2007, 36(3):336-340.
[11] Engstr(o|¨)m K, Vahter M, Mlakar SJ, et al. Polymorphisms in arsenic(+III oxidation state)methyltransferase(AS3MT)predict gene expression of AS3MT as well as arsenic metabolism[J].Environmental Health Perspectives, 2011, 119(2):182-188.
[12]张强,郑全美,席淑华,等.高砷暴露致皮肤损伤人群尿砷代谢产物分析[J].环境与健康杂志,2009,26(12):1048-1050.
[13] Wei B, Yu J, Li H, et al. Effects of arsenic methylation and metabolism on the changes of arsenic-related skin lesions[J].Environmental Science and Pollution Research International, 2018,25(7):1-9.
[14] Ren XF, Aleshin M, Jo WJ, et al. Involvement of N-6 adeninespecific DNA methyltransferase 1(N6AMT1)in arsenic biomethylation and its role in arsenic-induced toxicity[J]. Environ.Health Perspect,2011, 119(6):771-777.
[15] Harari F, Engstrom K, Concha G, et al. N-6-adenine-specific DNA methyltransferase 1(N6AMT1)polymorphisms and arsenic methylation in Andean women[J]. Environmental Health Perspectives, 2013, 121(7):797-803.
[16] Zhang H, Ge YC, He P, et al. Interactive effects of N6AMT1 and As3MT in arsenic biomethylation[J]. Toxicol Sci, 2015, 146(2):354-362.
[17] Chen XS, Guo XJ, He P, et al. Interactive influence of N6AMT1and As3MT genetic variations on arsenic metabolism in the population of Inner Mongolia, China[J]. Toxicol Sci, 2017, 155(1):124-134.
[18] Bahl C, Sharma S,Singh N,et al. Association study between genetic variations in Axin2 gene and lung cancer risk in North Indian population:a multiple interaction analysis[J]. Tumor Biol,2017,39(4):18.
[19] Su YS, Ding WH, Xing MJ, et al. The Interaction of TXNIP and AFql genes increases the susceptibility of schizophrenia[J].Molecular Neurobiology, 2017, 54(6):4806-4812.