Why Arsenic Makes Some People Sicker Than Others

One of the first large-scale genomic studies conducted in a developing country has discovered genetic variants that elevate the risk for skin lesions in people chronically exposed to arsenic. Genetic changes found near the enzyme for metabolizing arsenic into a less toxic form can significantly increase an individual’s risk for developing arsenic-related disease.

The discovery could point the way to new screening and intervention options for people who are exposed to groundwater with high levels of arsenic, according to the investigators at the University of Chicago School of Medicine, Columbia University's Mailman School of Public Health, and in Bangladesh. The study is published in PLoS Genetics.

The group's genome-wide association study, or GWAS, was conducted in nearly 3,000 individuals exposed to arsenic for decades in Bangladesh. Since the widespread installation of hand-pumped wells to tap groundwater sources in the 1970s, as many as 77 million people – about half the population of Bangladesh – have been accidentally exposed to dangerous levels of arsenic. The World Health Organization calls the exposure "the largest mass poisoning of a population in history."

For more than a decade, the scientists have studied the epidemiology of arsenic-related disease, such as skin lesions, diabetes, and respiratory illnesses, in this population, as well as the effectiveness of interventions to prevent toxicity. In the new study, the researchers sought genetic answers for why some individuals appear to be at higher risk for developing disease after arsenic exposure.

"These results add clarity to the genetic architecture that is playing a role in arsenic toxicity and its underlying biology," said senior author Habibul Ahsan, MD, MMedSc, Louis Block Professor of health studies, medicine and human genetics at the University of Chicago School of 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."

The researchers genotyped thousands of arsenic-exposed individuals from the group's main studies for single nucleotide polymorphisms (SNPs) throughout the genome, and looked for associations with arsenic metabolite levels and risk of skin lesions.

The genetic findings provided strong evidence that efficient metabolism of arsenic through methylation protects against the toxin. Compounds that boost methylation, such as folic acid, could reduce arsenic toxicity – a strategy currently being tested by co-author Mary Gamble, PhD, associate professor of Environmental Health Sciences at Columbia University’s Mailman School of Public Health.

"If we could somehow find a way to do that in Bangladesh, it would make individuals much better methylators of arsenic, and as this current study shows if you're a better methylator you're at a lower risk for disease," said co-author Joseph Graziano, PhD, professor of Environmental Health Sciences and Director of Superfund Research Program at the Mailman School of Public Health of Columbia University.

Risk variants may also help assess the potential toxicity of cancer chemotherapies which use arsenic or related compounds. SNPs associated with elevated sensitivity to arsenic toxicity could steer oncologists toward lower doses or alternative treatments in certain cancer patients, the investigators noted.

Beyond the clinical applications, the current study demonstrates that large-scale genomic studies are possible in a largely rural population of a developing country. The study offers a rare example of a GWAS result with clear, immediate potential for translational impact.

The research was supported by the National Institute of Environmental Health Sciences and the National Cancer Institute.