Individuals in a given environment contaminated with arsenic have different susceptibilities to disease, which may be related to arsenic metabolism, age, gender, genetics and other factors. This study recruited 850 subjects, including 331 cases and 519 controls, from populations exposed to high levels of arsenic in drinking water in northwest China. Genotypes were determined using a custom-by-design 48-Plex SNPscanTM kit. The results indicated that subjects who carried at least one C allele for GSTO1 rs11191979 polymorphism, at least one A allele for GSTO1 rs2164624, at least one A allele for GSTO1 rs4925, the AG genotype for GSTO2 rs156697, the AG genotype or at least one G allele for GSTO2 rs2297235 or the GG genotype or at least one G allele for PNP rs3790064 had an increased risk of arsenic-related skin lesions. In addition, the haplotype CT between rs4925 and rs11191979 appeared to confer a high risk of arsenic-included skin lesions (OR = 1.377, 95% CI = 1.03–1.84), as did the haplotype GCG among rs156697, rs157077 and rs2297235 (OR = 2.197, 95% CI = 1.08–4.44). The results showed that the variants of GSTO1, GSTO2 and PNP render the susceptible toward developing arsenic-induced skin lesions in individuals exposed to high-dose inorganic arsenic in northwest China.
The exposure/biotransformation of inorganic arsenic (iAs) may perturb DNA methylation patterns and subsequently influence disease risk by altering the expression of key genes. Interindividual variation in patterns of DNA methylation can be explained by the influence of environmental, genetic, and stochastic factors. Here, we examined promoter DNA methylation levels with urinary arsenical concentrations and investigated the genetic and nongenetic determinants of DNA methylation in 105 samples collected from populations in Shanxi Province, China, with high levels of arsenic in drinking water. Arsenic concentrations in water were determined by atomic absorption spectrophotometry (AA-6800, Shimadzu Co., Kyoto, Japan). Urine samples were measured using an atomic absorption spectrophotometer with an arsenic speciation pretreatment system (ASA-2sp, Shimadzu Co. Kyoto, Japan) for detection. Gene-specific (CDH1, EREG, ERCC2, GSTP1, and MGMT) DNA methylation was quantified by targeted bisulfite sequencing. Single-nucleotide polymorphism (SNP) genotyping was performed using a custom-by-design 2 × 48-Plex SNPscan™ Kit. These results revealed CDH1 with promoter DNA methylation levels associated with iAs. After the exclusion of confounding factors, age was correlated with increased methylation of the CDH1 gene. The susceptibility of the CDH1 and GSTP1 gene promoters to methylation was increased in individuals carrying the DNMT3B (SNP rs2424932) GA genotype, and the susceptibility of the CDH1 gene promoters to methylation was increased in individuals carrying the DNMT3B (SNP rs6087990) TC genotype. Although the above results must still be replicated in larger samples, the findings improve our understanding of the pathogenesis of arsenic and may highlight certain DNA methylation markers as attractive surrogate markers for prevention research.
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