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GWAS Yields SNPs Linked to Arsenic Metabolism, Toxicity in Bangladesh

NEW YORK (GenomeWeb News) – Genetic variants influencing the expression of an arsenic-methylating enzyme contribute to inter-individual variation in arsenic metabolism and toxicity, according to a study appearing online last night in PLoS Genetics.

A research team from the US and Bangladesh tracked down a handful of chromosome 10 variants with ties to arsenic metabolism through a genome-wide association study involving more than 1,300 individuals from Bangladesh who had been exposed to arsenic through contaminated drinking water. When they tested thousands more individuals, the investigators found that some of the same variants linked to levels of arsenic metabolites in urine were also associated with the presence of an arsenic-related skin condition.

Moreover, they reported, at least some of the SNPs in this region appear to influence the expression of nearby chromosome 10 genes, including one called AS3MT that codes for the arsenite methyltransferase enzyme.

"We identified multiple genetic variants in the 10q24.32 region near AS3MT … that show robust associations with urinary concentrations of arsenic metabolites, risk for arsenical skin lesions, and local gene expression, including transcript levels of AS3MT," University of Chicago human genetics researcher Habibul Ahsan, the study's senior author, and colleagues wrote.

Millions of Bangladeshis have been exposed to arsenic since the 1970s, when wells were installed to tap groundwater sources that contained higher than anticipated levels of the naturally occurring chemical. Drinking water-related exposure to arsenic has occurred in other parts of the world as well, the researchers explained, including parts of the US.

Not much is known about the genetic factors mediating arsenic metabolism or toxicity during chronic arsenic exposure, though there seems to be a good deal of variability from one individual to the next.

"Whatever the source of exposure, different individuals vary with respect to their susceptibility to the toxicity of arsenic," Ahsan said in a statement. "Even if they consume or are exposed to arsenic at the same dose and duration, some individuals will manifest toxicity phenotypes and others won't."

To explore the genetic basis of these differences, the team used Illumina arrays to genotype 1,313 arsenic-exposed individuals from Bangladesh.

They then looked for genetic patterns corresponding to participant's urine concentrations of inorganic arsenic and of two arsenic metabolites: monomethylarsonic acid, a metabolite produced through methylation of inorganic arsenic, and dimethylarsinic acid, a less toxic and more easily excreted compound formed at later stages of arsenic metabolism.

The search led to several SNPs in a chromosome 10 region that showed ties to either urine MMA concentrations, urine DMA concentrations, or to the ratio of these two metabolites in urine.

At least a subset of these arsenic metabolism-associated variants also influences arsenic toxicity, researchers reported, specifically the development of a pre-malignant skin condition attributed to arsenic exposure.

When the team tested 1,085 affected individuals and 1,794 arsenic-exposed but unaffected controls, it found that the variants influenced skin lesion risk — a pattern that held in analyses involving hundreds of individuals for whom prospective arsenic exposure information was available.

In an analysis that brought together SNP and gene expression information for 950 participants, meanwhile, researchers found that some of the arsenic toxicity-associated variants on chromosome 10 appear to have regulatory effects on the nearby genes C10otf32 and AS3MT, which code for the arsenite methyltransferase enzyme.

Together, results of the study support the notion that those who are able to most efficiently metabolize arsenic via methylation are at reduced risk of toxicity.

Based on these findings, members of the research team have speculated that therapeutics that boost methylation might curb some of the toxic effects of arsenic in those who are prone to poorer arsenic metabolism.

"Now that we understand the molecular basis of some of this disease risk, it is conceivable to now think of incorporating this information into testing, evaluating, or potentially coming up with successful biomedical interventions," Ahsan said in a statement.

"By exploiting these metabolic pathways for a subgroup of individuals who will really be at higher risk for getting those diseases," he added, "we may be able to reduce fatal outcomes in this population."

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