GSTO and AS3MT genetic polymorphisms and differences in urinary arsenic concentrations among residents in Bangladesh

Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115, USA.
Biomarkers (Impact Factor: 2.26). 02/2012; 17(3):240-7. DOI: 10.3109/1354750X.2012.658863
Source: PubMed


We determined whether single nucleotide polymorphisms (SNPs) in the glutathione S-transferase omega (GSTO) and arsenic(III)methyltransferase (AS3MT) genes were associated with concentrations of urinary arsenic metabolites among 900 individuals without skin lesions in Bangladesh. Four SNPs were assessed in these genes. A pathway analysis evaluated the association between urinary arsenic metabolites and SNPs. GSTO1 rs4925 homozygous wild type was significantly associated with higher monomethylarsonic acid (MMA) and dimethylarsinic acid urinary concentrations, whereas wild-type AS3MT rs11191439 had significantly lower levels of As(III) and MMA. Genetic polymorphisms GSTO and As3MT modify arsenic metabolism as evidenced by altered urinary arsenic excretion.

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Available from: Elaine Borland Hoffman, PhD, Oct 04, 2015
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    • "In addition to AS3MT, dozens of candidate genes have been examined for association with arsenic methylation capacity in prior candidate gene studies, based on various hypotheses related to methyltransferases, one-carbon metabolism, and reduction reactions (Schlawicke Engstrom et al. 2009). GSTO1, GSTO2 (Paiva et al. 2010; Rodrigues et al. 2012), MTHFR (Steinmaus et al. 2007), PNP (De Chaudhuri et al. 2008), GSTM1 (Breton et al. 2007; Chiou et al. 1997; Steinmaus et al. 2007) and several other genes have even been reported to be associated with the arsenic methylation capacity (Agusa et al. 2012; Engstrom et al. 2011; Engstrom et al. 2010; Ghosh et al. 2008; Hernandez and Marcos 2008; Porter et al. 2010; Schlawicke Engstrom et al. 2009). However, many of these studies were limited by small sample sizes, and the genetic variants under investigation have not shown a great deal of consistency across studies (e.g., (Ahsan et al. 2007; Hernandez and Marcos 2008; Xu et al. 2009). "
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    ABSTRACT: Consumption of arsenic-contaminated drinking water adversely affects health. There is inter-individual variation in arsenic metabolism efficiency, partially due to genetic variation in the arsenic methyltransferase (AS3MT) gene region. To assess the overall contribution of genetic factors to variation in arsenic metabolism efficiency, as measured by relative concentration of dimethylarsinic acid (DMA%) in urine. Using data on genome-wide single nucleotide polymorphisms (SNPs) and urinary DMA% for 2,053 arsenic-exposed Bangladeshi individuals, we employed various SNP-based approaches for heritability estimation and polygenic modelling. Using data on all participants, the percent variance explained (PVE) for DMA% by all measured and imputed SNPs was 16% (p=0.08) and was reduced to 5% (p=0.34) after adjusting for AS3MT SNPs. Using information on close relatives only, the PVE was 63% (P=0.0002), but decreased to 41% (P=0.01) after adjusting for AS3MT SNPs. Regional heritability analysis confirmed 10q24.32 (AS3MT) as a major arsenic metabolism locus (PVE= 7%, p = 4.4x10(-10)), but revealed no additional regions. We observed a moderate association between a polygenic score reflecting elevated DMA% (composed of thousands of non-AS3MT SNPs) and reduced skin lesion risk in an independent sample (p < 0.05). We observed no associations for SNPs reported in prior candidate gene studies of arsenic metabolism. Our results suggest that there are common variants outside of the AS3MT region that influence arsenic metabolism in Bangladeshi individuals, but the effects of these variants are very weak compared to variants near AS3MT. The high heritability estimates observed using family-based heritability approaches suggest substantial effects for rare variants and/or unmeasured environmental factors.
    Environmental Health Perspectives 03/2015; DOI:10.1289/ehp.1408909 · 7.98 Impact Factor
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    • "Key enzymes involved in the onecarbon methylation of As with S-adenosyl methionine (SAM) as the methyl donor include arsenic-3-methyltransferase (AS3MT), methylenetetrahydrofolate reductase (MTHFR), cystathionine beta-synthase (CBS), and purine nucleoside phosphorylase (PNP). Genetic polymorphisms in genes encoding the above-mentioned enzymes have been related to differences in the distribution of As metabolites in urine (Agusa et al., 2010; Engstrom et al., 2011; Lindberg et al., 2007; Marnell et al., 2003; Pierce et al., 2012; Porter et al., 2010; Rodrigues et al., 2012; Schlawicke Engstrom et al., 2007; Steinmaus et al., 2007; Yu et al., 2003). Some of these polymorphisms have also been related to CVD risk (Agusa et al., 2010; de Waart et al., 2001; Klerk et al., 2002; Kolsch et al., 2004, 2007; Li et al., 2001; Olshan et al., 2003; Pezzini et al., 2002; Roest et al., 2001; Wang et al., 2002). "
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    ABSTRACT: Epidemiologic studies that evaluated genetic susceptibility to the effects of arsenic exposure from drinking water on subclinical atherosclerosis are limited. We conducted a cross-sectional study of 1,078 participants randomly selected from the Health Effects of Arsenic Longitudinal Study in Bangladesh to evaluate whether the association between arsenic exposure and carotid artery intima-medial thickness (cIMT) differs by 207 single-nucleotide polymorphisms (SNPs) in 18 genes related to arsenic metabolism, oxidative stress, inflammation, and endothelial dysfunction. Although not statistically significant after correcting for multiple testing, nine SNPs in APOE, AS3MT, PNP, and TNF genes had a nominally statistically significant interaction with well-water arsenic in cIMT. For instance, the joint presence of a higher level of well-water arsenic (≥ 40.4 μg/L) and the GG genotype of AS3MT rs3740392 was associated with a difference of 40.9 μm (95% CI=14.4, 67.5) in cIMT, much greater than the difference of cIMT associated with the genotype alone (β=-5.1 μm, 95% CI=-31.6, 21.3) or arsenic exposure alone (β=7.2 μm, 95% CI=-3.1, 17.5). The pattern and magnitude of the interactions were similar when urinary arsenic was used as the exposure variable. Additionally, the at-risk genotypes of the AS3MT SNPs were positively related to proportion of monomethylarsonic acid (MMA) in urine, which is indicative of arsenic methylation capacity. The findings provide novel evidence that genetic variants related to arsenic metabolism may play an important role in arsenic-induced subclinical atherosclerosis. Future replication studies in diverse populations are needed to confirm the findings.
    Toxicology and Applied Pharmacology 03/2014; 276(3). DOI:10.1016/j.taap.2014.02.014 · 3.71 Impact Factor
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    ABSTRACT: Potential occupational arsenic exposure is a significant problem in smelting plants. The metabolites containing arsenic with an oxidation of +3 have been considered more cytotoxic and genotoxic than their parent inorganic species. The current study examined the capacity of arsenic methylation and its risk on skin lesions. The primary aim of this study is to determine if methylation capacity, as measured by urinary arsenic metabolites, differed in workers with skin lesions compared to workers without skin lesions. Hydride generation-atomic absorption spectrometry was used to determine three arsenic species in urine of workers who had been working in arsenic plants, and primary and secondary methylation indexes were calculated. Skin lesions were examined at the same time. Many workers had obvious skin lesions (36/91). The mean concentrations of inorganic arsenic (iAs), monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) in urine of workers are obviously higher than those of the control group. There are more iAs, MMA, and DMA in urine, higher MMA%, lower iAs% for workers with skin lesions compared with those without skin lesions. Workers with skin lesions have the lowest SMI (3.50±1.21), and they may be in danger. Our results support the viewpoint that individuals who metabolize inorganic arsenic to MMA easily, but metabolize MMA to DMA difficulty have more risk of skin lesions.
    07/2012; 34(2):624-630. DOI:10.1016/j.etap.2012.07.003
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