Genes and environment: a SNPshot.

Have you ever heard someone try to dispel concern about their smoking by describing elderly relatives who were lifelong smokers? This gambit usually fails, but there actually is something to the excuse. Increasingly, researchers are uncovering the extent to which genes control susceptibility and vulnerability to environmental health hazards including cigarette smoke, toxic chemicals, alcohol, and more.

Understanding why individuals react differently to the same chemicals requires analysis of differences in their genetic makeup. Single-nucleotide polymorphisms (SNPs) 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.

Pinpointing long-term exposure to cancer-causing agents in the environment can be extremely 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. Smith said functional SNPs are likely to explain the majority of people's susceptibility.

A typical gene of 30,000 base pairs has 150 SNPs, noted Deborah Nickerson, a geneticist at the University of Washington in Seattle. Most SNPs 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. Only days prior to the seminar, Nickerson discovered such blocks in the BRCA1 breast cancer gene, which 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.

Smith and collaborators in Leeds, England, are looking for SNPs that confer leukemia susceptibility. Most cases of leukemia arise from gene--environment interactions, he told seminar participants. In the early 1990s, scientists discovered that a SNP on the NQO1 gene increases the risk of benzene-induced leukemia. This led Smith and colleagues to propose that chemicals that cause oxidative stress and that are detoxified by NQO1, such as benzene and fiavonoids in high doses, may increase the risk of myeloid leukemia. They also suggest that low folate intake increases the risk of lymphocytic leukemia in adults and children, whereas certain SNPs in folate-metabolizing genes decrease the risk. They are 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-1 (PON1). PON1 oxidizes lipids, metabolizes organophosphates, and activates or inactivates medications including statins, glucocorticoids, and antibiotics.

Furlong cited research from the 15 June 1999 issue of toxicology and Applied Pharmacology showing that veterans who suffered from Gulf War syndrome had low PON1 levels. Other 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 molecular methods now 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.

At the postseminar press conference, NIEHS director Kenneth Olden announced the completion of the first phase of the institute's Environmental Genome Project, which seeks to identify genetic variations among individuals that make them more vulnerable to environmental agents. 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.