Human genetics of arsenic biotransformation

Relevance to SWEHSC: 

Individual variation in the efficiency of metabolic arsenic methylation is one of the most consistently reported predictors of disease risk in arsenic-exposed human populations. Defining the genetic and environmental determinants of arsenic methylation efficiency should establish easily measured biomarkers of increased susceptibility in an exposed population.

Cluster of Efforts: 

Investigators/Funding: Klimecki (RFG1), Gandolfi (RFG1), Billheimer (IHSFC-Biostats) NIEHS/ES004940 (Superfund Component Project)


  • This epidemiology project is studying about 800 arsenic-exposed subjects from our geographical region, residing in Northern Sonora, Mexico. Demographic and questionnaire data, urine (for arsenic metabolite determination) and buccal swabs (for genetic variant testing) are being collected.
  • A detailed characterization of chromosome 10 surrounding AS3MT,the key arsenic metabolic gene, revealed an extraordinarily large region of linkage disequilibrium (LD) that spans nearly 400,000 bases at very high LD, potentially confounding genetic association studies of arsenic metabolism.
  • Replicating the first published genetic association of AS3MT with arsenic metabolism (our report), intronic variants in AS3MT were shown to be associated with more efficient arsenic methylation, however this is complicated by the occurrence of these variants within the extremely large cluster of linked polymorphisms that spans 5 genes.
  • Quantitative ascertainment of ancestry using a set of 90 ancestry informative marker SNPs suggests that arsenic methylation efficiency is positively correlated with the fraction of indigenous ancestry in mestizo populations. NIEHS/ES004940 (Superfund Component Project)