Superfund Research Program
The Human Genetics of Arsenic Biotransformation
Project Leader: H. Vasken Aposhian
Grant Number: P42ES004940
Funding Period: 2000-2010
Final Progress Reports
Year: 2009 2004
The objective of the project is to understand the factors that determine person-to-person variability in arsenic metabolism, since it is likely that one of the reasons for individual susceptibility to arsenic-induced disease in humans is the variation in rates of metabolic conversion of inorganic arsenic to highly toxic species like monomethylarsenous acid. The researchers' first major Superfund milestone this year was the publication of a detailed genetic study of variations in the main arsenic-metabolizing gene, called AS3MT. In 2005, they reported that individuals carrying variant DNA sequences in AS3MT had more efficient arsenic methylation, a characteristic that epidemiological studies have shown to be protective against a variety of arsenic-associated diseases. This year, the researchers published a more detailed follow-up study validating that arsenic-exposed people carrying the AS3MT DNA sequence variation methylated arsenic more efficiently than the people carrying the typical AS3MT DNA sequence. Genetic-association studies in humans have been criticized frequently for failure to replicate, so this was an important confirmation; in fact, the researchers' study now has been replicated in at least four published studies from at least three different research groups. Included in the researchers' recent publication is a description of a very unusual finding regarding genetic variations in the segment of human chromosome 10 that includes the AS3MT gene. They found a set of 46 polymorphisms that span nearly 400,000 bases of DNA that "travel together" nearly perfectly. In other words, if an individual has any one of these polymorphisms, he/she almost always has all 46 of them. It is very unusual in humans for this to occur over such a long distance along a chromosome, and it creates special problems for investigators conducting genetic studies, as well as for investigators who seek to understand the molecular mechanism for the researchers' highly replicated genetic association between AS3MT DNA variation and human arsenic metabolism. The researchers' work in 2009 has established the reliability of a genetic marker of susceptibility to arsenic-associated disease, as well as defining important caveats created by the unusual genetic structure of human AS3MT.