Associations between arsenic (+3 oxidation state) methyltransferase (<i>AS3MT</i>) and N‐6 adenine‐specific DNA methyltransferase 1 (<i>N6AMT1</i>) polymorphisms, arsenic metabolism, and cancer risk in a chilean population

Rosa, Rosemarie de la; Steinmaus, Craig; Akers, Nicholas K.; Conde, Lucía; Ferreccio, Catterina; Kalman, David A.; Zhang, Kevin R; Skibola, Christine F.; Smith, Allan H.; Zhang, Luoping; Smith, Martyn T.

doi:10.1002/em.22104

Cited by 43 publications

(27 citation statements)

References 64 publications

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“…More research is needed to understand the underlying mechanisms and pathways. It also remains to be elucidated whether the variations in selenium metabolism may influence the selenium status in terms of plasma selenium, expression and function of selenoproteins, and health effects of selenium intake (both low and high) as previously shown for arsenic through, for example, higher susceptibility to toxicity in individuals with higher percentages of MMA ( de la Rosa et al 2017 ).…”

Section: Discussionmentioning

confidence: 97%

Associations between Methylated Metabolites of Arsenic and Selenium in Urine of Pregnant Bangladeshi Women and Interactions between the Main Genes Involved

Skröder

Engström

Kuehnelt

et al. 2018

Environ Health Perspect

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Background:It has been proposed that interactions between selenium and arsenic in the body may affect their kinetics and toxicity. However, it is unknown how the elements influence each other in humans.Objectives:We aimed to investigate potential interactions in the methylation of selenium and arsenic.Methods:Urinary selenium (U-Se) and arsenic (U-As) were measured using inductively coupled plasma mass spectrometry (ICPMS) in samples collected from pregnant women (n=226) in rural Bangladesh at gestational weeks (GW) 8, 14, 19, and 30. Urinary concentrations of trimethyl selenonium ion (TMSe) were measured by HPLC–vapor generation–ICPMS, as were inorganic arsenic (iAs), methylarsonic acid (MMA), and dimethylarsinic acid (DMA). Methylation efficiency was assessed based on relative amounts (%) of arsenic and selenium metabolites in urine. Genotyping for the main arsenite and selenium methyltransferases, AS3MT and INMT, was performed using TaqMan probes or Sequenom.Results:Multivariable-adjusted linear regression analyses indicated that %TMSe (at GW8) was positively associated with %MMA (β=1.3, 95% CI: 0.56, 2.0) and U-As, and inversely associated with %DMA and U-Se in producers of TMSe (INMT rs6970396 AG+AA, n=74), who had a wide range of urinary TMSe (12–42%). Also, %TMSe decreased in parallel to %MMA during pregnancy, especially in the first trimester (−0.58 %TMSe per gestational week). We found a gene–gene interaction for %MMA (p-interaction=0.076 for haplotype 1). In analysis stratified by INMT genotype, the association between %MMA and both AS3MT haplotypes 1 and 3 was stronger in women with the INMT GG (TMSe nonproducers, 5th–95th percentile: 0.2–2%TMSe) vs. AG+AA genotype.Conclusions:Our findings for Bangladeshi women suggest a positive association between urinary %MMA and %TMSe. Genes involved in the methylation of selenium and arsenic may interact on associations with urinary %MMA. https://doi.org/10.1289/EHP1912

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Section: Discussionmentioning

confidence: 97%

Associations between Methylated Metabolites of Arsenic and Selenium in Urine of Pregnant Bangladeshi Women and Interactions between the Main Genes Involved

Skröder

Engström

Kuehnelt

et al. 2018

Environ Health Perspect

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“…An association has been reported between polymorphisms in the arsenic methyltransferase gene (AS3MT) and arsenic-related cancer risk. 42 Multiple studies have demonstrated that incomplete arsenic metabolism, with higher fractions of inorganic arsenic and methyl-arsenic acid and lower fractions of dimethyl-arsenic acid, is a marker for increased susceptibility to arsenic-related cancers. 5,43,44 The methylation of arsenic is thought to be one of the primary aspects of arsenic carcinogenicity.…”

Section: Discussionmentioning

confidence: 99%

Blood arsenic levels and the risk of familial breast cancer in Poland

Marciniak

Derkacz

Muszyńska

et al. 2019

Intl Journal of Cancer

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Arsenic is recognized as a potent carcinogen at high concentrations, but the relationship between environmental arsenic and breast cancer risk has not well been studied. Most research has focused on the effect of arsenic in populations with high endemic exposure, and not in populations with arsenic levels within normal limits. We sought to determine if blood arsenic levels predict the risk of breast and other cancers risk among women in northern Poland. The cohort consisted of 1,702 healthy women, aged 40 and above, identified between 2010 and 2017. Blood arsenic level was determined by inductively coupled plasma mass spectrometry. After an average of 4.5 years of follow‐up (range 0.7–7.3 years), there were 110 incident cases of cancer diagnosed in the cohort, including 68 cases of breast cancer. Women in the highest quartile of arsenic had a highly significant 13‐fold increased risk of developing breast cancer, compared to women in the lowest quartile (hazard ratio [HR] = 13.2; 95% confidence interval [CI] 4.02–43.0). Results were similar for arsenic and all incident cancers (HR quartile 4 vs. quartile 1 = 13.3; 95% CI 4.78–37.0). If confirmed, our study suggests that the blood arsenic level may be a useful predictive marker of cancer risk in women.

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“…Besides, it is involved in converting the arsenic metabolite monomethylarsonous acid to the lesstoix dimethylarsonic acid (Ren et al, 2011 ; Zhang et al, 2015a ). N6AMT1 polymorphisms are reported to be associated with arsenic methylation (Harari et al, 2013 ; Chen et al, 2017 ; de la Rosa et al, 2017 ). N6AMT1 rs2254638 is a T to C substitution in intron, and the exact function of the SNP remains unknown.…”

Section: Discussionmentioning

confidence: 99%

Association of N6AMT1 rs2254638 Polymorphism With Clopidogrel Response in Chinese Patients With Coronary Artery Disease

Zhang

et al. 2018

Front. Pharmacol.

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Dual antiplatelet treatment with aspirin and clopidogrel is the standard therapy for patients undergoing percutaneous coronary intervention (PCI). However, a portion of patients suffer from clopidogrel resistance (CR) and consequently with recurrence of cardiovascular events. Genetic factors such as loss-of-function variants of CYP2C19 contribute a lot to CR. Recently, the N-6-adenine-specific DNA methyltransferase 1 (N6AMT1) rs2254638 polymorphism is reported to be associated with clopidogrel response. To validate the association between N6AMT1 rs2254638 polymorphism and clopidogrel response, 435 Chinese CAD patients receiving aspirin and clopidogrel were recruited. N6AMT1 rs2254638 and CYP2C19*2/*3 polymorphisms were genotyped. Platelet reaction index (PRI) was measured by VASP-phosphorylation assay after treated with a 300 mg loading dose (LD) clopidogrel or 75 mg daily maintenance dose (MD) clopidogrel for at least 5 days. There was a significant difference in PRI between LD cohort and MD cohort. Carriers of CYP2C19*2 allele showed significantly increased PRI in the entire cohort and in respective of the MD and LD cohorts (p < 0.001, p = 0.003, p < 0.001, respectively). However, carriers of CYP2C19*3 allele exhibited significantly higher PRI only in the entire cohort and LD cohort (p = 0.023, p = 0.023 respectively). PRI value was significantly higher in CYP2C19 PM genotyped patients as compared with those carrying the IM genotypes and EM genotype (p < 0.001). Besides, carriers of the rs2254638 C allele showed significantly higher PRI in entire cohort and in the LD cohort (p = 0.023, p = 0.008, respectively). When the patients were grouped into clopidogrel resistance (CR) and non-clopidogrel resistance (non-CR) groups, CYP2C19*2 was associated with increased risk of CR in the entire cohort, the LD cohort and the MD cohort (p < 0.001, p < 0.001, and p = 0.019, respectively). Carriers of the rs2254638 C allele also showed increased risk of CR in the entire cohort and the LD cohort (p = 0.024, and p = 0.028, respectively). N6AMT1 rs2254638 remained as a strong predictor for CR (TC vs. TT: OR = 1.880, 95% CI = 1.099–3.216,p = 0.021; CC vs. TT: OR = 1.930, 95% CI = 1.056-3.527, p = 0.032; TC + CC vs. TT: OR = 1.846, 95%CI = 1.126–3.026, p = 0.015) after adjustment for confounding factors. Our study confirmed the influence of CYP2C19*2 and rs2254638 polymorphisms on clopidogrel resistance in Chinese CAD patients. Both CYP2C19*2 and N6AMT1 rs2254638 polymorphism may serve as independent biomarkers to predict CR.

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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

Cited by 43 publications

References 64 publications

Associations between Methylated Metabolites of Arsenic and Selenium in Urine of Pregnant Bangladeshi Women and Interactions between the Main Genes Involved

Associations between Methylated Metabolites of Arsenic and Selenium in Urine of Pregnant Bangladeshi Women and Interactions between the Main Genes Involved

Blood arsenic levels and the risk of familial breast cancer in Poland

Association of N6AMT1 rs2254638 Polymorphism With Clopidogrel Response in Chinese Patients With Coronary Artery Disease

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