GW-As: The Toxicity Risk in the Genes

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By Rob Mitchum

Arsenic is a deadly toxin, but it’s not one dose fits all. Two people exposed to the same level of the chemical can have entirely different responses, with Patient A developing the skin lesions, cancers, and respiratory conditions that are a hallmark of arsenic toxicity, while Patient B is entirely unaffected. Currently, no test exists to tell in advance who might be more vulnerable to the effects of arsenic, but scientists suspect that some clues may lie in a person’s genes. In the latest paper from Habibul Ahsan‘s massive study of arsenic exposure in Bangladesh, researchers uncovered a promising genetic story that could help identify people at higher risk — and potentially help protect them from toxicity.

As discussed before on ScienceLife, Ahsan’s two studies in Bangladesh follow the victims of an almost unfathomable mass poisoning event. In the 1970’s, an international effort was put together to switch millions of Bangladeshis from disease-ridden water sources to well-water. Unfortunately, the groundwater tapped by those wells turned out to contain very high levels of arsenic…a dark fact that wasn’t discovered until some 20 years after their installation. Over those decades, some 77 million people in the country were drinking water containing arsenic concentrations as high as 27 times safe limits.

For more than a decade, Ahsan has studied the epidemiology of that long-term exposure in some 20,000 volunteers, as well as low-priced interventions to try to reduce toxicity. In his latest paper, published last week in PLoS Genetics, Ahsan’s team zoomed in on the DNA of those subjects, looking for genetic variants that predict higher arsenic toxicity in a pool of 3,000 Bangladeshi citizens from the larger studies. Using the methods of genome-wide association studies (GWAS) — one of the first such studies conducted in the developing world — the researchers found a genetic region that offers a promising and refreshingly logical story about what creates individual differences in vulnerability to arsenic.

“These results add clarity to the genetic architecture that is playing a role in arsenic toxicity and its underlying biology,” said Ahsan, Louis Block Professor of health studies, medicine and human genetics at the University of Chicago Medicine. “It’s a rare type of study for a major problem affecting millions of people around the world, and it opens up opportunities for genetic studies of other major public health problems in developing countries.”

Led by Ahsan and Brandon Pierce, assistant professor of epidemiology at the University of Chicago Medicine, the team looked for potential genetic influences on phenotypes such as arsenic metabolism and the risk of acquiring arsenic-induced skin lesions. After ingestion, the body metabolizes inorganic arsenic into first monomethylarsonic acid (MMA) and then dimethylarsinic acid (DMA). MMA is considered to be more toxic, while DMA is water-soluble and more easily excreted. Higher levels of DMA or lower levels of MMA measured from an individual’s urine are associated with lower toxicity.

A GWAS search for variants associated with high or low DMA/MMA ratios turned up several candidates in the region of a likely suspect gene: arsenite methyltransferase (As3MT), an enzyme known to be involved in arsenic metabolism. A second GWAS that compared subjects who suffered skin lesions after arsenic versus subjects who did not pointed to variants in the same region, offering more evidence for the gene’s involvement and a rare straightforward result for a genomic study.

“This makes perfect sense,” Ahsan said. “It gives us a very coherent story that we can now investigate in relation to other arsenic pathologies and in relation to a wide range of arsenic doses in this population. Many genomic signals that we see are not robust enough or do not pertain to a large population. But in this study, that is not the case. The finding is robust, and the impact is massive.”

Interestingly, the most significant variants were not located in the As3MT gene itself, but in a neighboring gene called C10orf32 that is co-expressed with the arsenic metabolizing enzyme. The result opens up new avenues to explore how this lesser-known gene controls As3MT function, and how the gene variants affect this relationship and lead to increase arsenic toxicity. Understanding this pathway could point to new protective interventions against the harmful effects of arsenic exposure, while people in areas with arsenic contamination can be easily screened for the risk variants discovered in this paper.

The ramifications of that advance go beyond Bangladesh to areas around the world (including parts of the United States) that struggle with arsenic contamination of groundwater. Recent reports that low levels of arsenic can be found in rice and organic foods that use rice syrup have also highlighted the need to understand who is at higher risk for the toxin’s damaging effects. In some cases, the poison has even become a healing tool, as arsenic compounds are used as a chemotherapy drug to treat certain types of leukemia. Knowing whether a person possesses one of the riskier variants for arsenic toxicity can help oncologists modify the dose of these therapies to keep them within safer ranges.

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

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Pierce, B., Kibriya, M., Tong, L., Jasmine, F., Argos, M., Roy, S., Paul-Brutus, R., Rahaman, R., Rakibuz-Zaman, M., Parvez, F., Ahmed, A., Quasem, I., Hore, S., Alam, S., Islam, T., Slavkovich, V., Gamble, M., Yunus, M., Rahman, M., Baron, J., Graziano, J., & Ahsan, H. (2012). Genome-Wide Association Study Identifies Chromosome 10q24.32 Variants Associated with Arsenic Metabolism and Toxicity Phenotypes in Bangladesh PLoS Genetics, 8 (2) DOI: 10.1371/journal.pgen.1002522

About Rob Mitchum (526 Articles)
Rob Mitchum is communications manager at the Computation Institute, a joint initiative between The University of Chicago and Argonne National Laboratory.
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