Genes and environment: a SNPshot. (NIEHS News).
To understand why individuals react differently to the same chemicals requires analysis of differences in their genetic makeup. Single-nucleotide polymorphisms (SNPs), which are common one-letter variations in the DNA sequence occurring in at least 1% of the population (anything rarer is a mutation), are the simplest differences to examine on the wide scale, agreed participants at "Genetic Variation and Gene-Environment Interaction in Human Health and Disease," a seminar held 16 April 2003 at the NIH campus in Bethesda, Maryland. The NIEHS, the National Human Genome Research Institute, and the National Institute on Alcohol Abuse and Alcoholism sponsored the seminar, which was part of an NIH conference marking the 50th anniversary of the discovery of the chemical structure of DNA and the recently completed sequencing of the human genome.
The Search for SNPs
Studying cancer-causing agents in the environment is difficult due to challenges such as the near-impossibility of determining a person's diet or occupational exposures over many years. SNPs, on the other hand, are abundant and traceable, said seminar participant Martyn Smith, a toxicologist at the University of California, Berkeley, School of Public Health and director of the university's NIEHS-sponsored Environmental Health Sciences Center. Functional SNPs are an intriguing topic of study, Smith said, because they are common and are likely to explain the majority of people's susceptibility.
A typical gene of 30,000 base pairs has 150 SNPs in it, noted Deborah Nickerson, a geneticist at the University of Washington in Seattle. Most SNPs are "silent," and thus have little or no effect on human health. But some greatly influence disease risk. SNPs near one another in the genome can be related, forming blocks in a gene and potentially making it easier to trace susceptibilities in the general population. The BRCA1 breast cancer gene has just such blocks, Nickerson discovered only days prior to the seminar. Discovering such blocks will make it easier for researchers to understand the role of BRCA1 in breast cancer development in women who don't have rare inherited mutations in this gene, she said.
Smith and collaborators in Leeds, England, are looking for SNPs that make humans more susceptible to leukemia. Most cases of leukemia can't be explained by environmental exposures or heredity alone, and instead arise from gene-environment interactions, he told seminar participants.
In the early 1990s, scientists discovered that a SNP on the NQO1 gene reduces the activity of the enzyme it regulates and increases the risk of benzene-induced leukemia. This finding led Smith and colleagues to propose that chemicals that cause oxidative stress and that are detoxified by NQO1, such as benzene and flavonoids in high doses, may increase the risk of myeloid leukemia. They have also suggested that low folate intake increases the risk of lymphocytic leukemia in both adults and children, whereas certain SNPs in folate-metabolizing genes decrease the risk. Smith and his colleagues are also looking at SNPs in genes involved in apoptosis and DNA repair in relation to leukemia risk, and are further expanding their research to the study of lymphoma.
Clement Furlong, a geneticist at the University of Washington in Seattle, reported that some people are more sensitive to insecticides and possibly nerve agents because of genetic variability in the gene that regulates production of the enzyme paraoxonase (PON1). PON1 oxidizes lipids, metabolizes organophosphates, and activates or inactivates medications including statins, glucocorticoids, and antibiotics.
Although children have attained their life-time level of the enzyme by about 15 months of age, PON1 levels and efficiency vary considerably from person to person, Furlong said. He cited research published in the 15 June 1999 issue of Toxicology and Applied Pharmacology showing that veterans who suffered from Gulf War syndrome had low PON1 levels. However, studies have shown that injecting purified PON1 into mice without the PON1 gene protects them against chemical assault. Furlong is confident that injections of engineered recombinant PON1 will someday be similarly used to detoxify humans who have been exposed to organophosphates.
Major Advances in the Field
The hunt for genetic susceptibility to many chemicals and diseases has been made possible by major advances in molecular methods that enable researchers to rapidly sequence whole genomes and associate SNPs with specific diseases. "We spent many, many years uncovering about a dozen polymorphisms in the [PON1] gene," Furlong said at a press conference following the seminar. But thanks to revolutionary new technologies, in just the last couple of months, Nickerson and her group have identified more than 150 additional PON1 polymorphisms. In a matter of days, she sequenced the entire PON1 gene from four individuals suspected of having sequence variations and then identified those variations, Furlong said, revealing one coding-region SNP that affects the efficiency of detoxication of some chemicals and other noncoding-region SNPs that affect PON1 plasma levels.
Nickerson's group in Seattle is part of the NIEHS Environmental Genome Project (http://www.niehs.nih.gov/envgenom/ home.htm), a national effort to identify genetic variations among individuals that make them more vulnerable to environmental agents. The Seattle researchers are resequencing 554 environmentally responsive genes taken from 450 individuals and creating a database of SNPs in those genes. As of April 2003, they had resequenced 214 of the genes.
At the postseminar press conference, NIEHS director Kenneth Olden announced the completion of the first phase of the Environmental Genome Project. Research in this phase focused on finding common sequence variations in human genes involved in DNA repair and cell cycle pathways. Future goals involve studying apoptosis, homeostasis, and drug-metabolizing genes, all of which are thought to play a role in vulnerability to environmental exposure.