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Wednesday, April 16, 2003, 12:00 a.m. EDT
'Environome' Studies Gain on Leukemia, Cardiovascular Disease
In a milestone for the Environmental Genome Project, NIEHS Director Ken Olden told reporters April 16 that cooperating scientists have re-sequenced some 200 environmentally responsive genes in representative groups of people, showing the variations that can occur in these genes and identifying their links to conditions such as leukemia and cardiovascular disease that affect the quality and length of life of many Americans.
Olden said the announcement was appropriately timed to the 50th anniversary of the Watson-Crick description of DNA. "It is clear that even with the human genome known, we haven't solved the problem of human disease... and that it will take studies such as the Environmental Genome Project to show the gene-environment interactions at the base of most complex diseases - the major causes of morbidity and mortality today."
In the first phase, NIEHS Deputy Director Sam Wilson told the news conference, "we decided to do (look at the variations of) 200 of just over 500 known environmentally sensitive genes. And we're right on the money - completing this first phase of the project on time and at a cost of about 25 percent of the $60 million anticipated when we planned the project in the late 90's."
The findings are on NIEHS and other websites available as what Wilson called "200 research tools" for scientists probing the interactions of genes and the environment in causing disease.
In phase two, variations of the rest of 500-some susceptibility genes will we studied, Olden and Wilson said. In further studies, just in their early stages, these variations will be associated with exposures and diseases in groups of people and then, in phase three, in the general population. In the third and final phase, screening will identify high-risk persons.
Two speakers at the symposium suggested with some amusement that science has entered the world of the "environome" - a contraction of the Environmental Genome Project.
In other reports at the meeting, which Wilson organized:
- Mary-Claire King, Professor at the University of Washington said that although variations of the BRCA1 and 2 genes explain some clusters of breast cancer in families, many such clusters can't be explained by these genes. So other gene variations or gene-gene or gene-environment interactions are being sought. But she said she believes recent increases in breast cancer are due to environmental causes: well-fed girls have menarche at 12 instead of 15 and working women having their first children later in life. Deborah Nickerson, also of the University of Washington: In the BRCA1 gene, there have been 300 SNPs (variations) shown, many within a significant block-like structure, whose significance is currently not known.
- Clement Furlong, Medical Genetics Research Professor at the University of Washington, said a plasma enzyme PON1 that metabolizes pesticides and drugs also appears to be associated with a risk of carotid artery clogging.
- Martyn Smith, Professor at U.C. Berkeley, said that his research shows that a small minority of individuals with two mutated copies of the MTHFR gene were up to five times less likely to develop acute lymphocytic leukemia than people without the mutation. In short, the mutated MTHFR gene changes the way that folic acid is used in the body. Instead of being utilized in other cellular processes, the mutation directs more folic acid towards DNA synthesis. This reduces the chance that dividing cells will suffer the genetic damage that causes them to become cancerous. By consuming more folic acid-rich foods or taking supplements, Dr. Smith said, people may significantly reduce the risk for leukemia and other types of cancer. (Folic acid is the B vitamin advised for women of child-bearing age to reduce the risk of spina bifida in their children.)
- Charles Rotimi, the Nigerian-born Director of Genetic Epidemiology at Howard University, said there is a bigger difference between the high blood pressure rates of Nigerians and blacks in the United States than the well-known difference between the rates of African Americans and U.S. whites. He said this suggests that what may appear to be racial health disparities reflect changes in the environment. Similarly, a "thrifty genotype" that helps people survive in a feast-famine African environment may result in the high rates of diabetes among well-fed African Americans.
- Lynn Jorde, Professor of Human Genetics at the University of Utah, reported on the use of genetic variations to track the history of humankind. He said that genetic diversity is greatest in the African population. This appears to confirm, he said, that this is the parent population from which a subset (with fewer genetic variations) populated Europe and Asia.
- Jeffrey Trent of the Translational Genomics Research Institute in Phoenix: Proposed the use of gene array technology to identify those patients with advanced metastatic melanoma who can benefit from IL-2, a useful therapy for some but an ineffective ordeal for others.
The Meeting Summary can be found at Genetic Variation and Gene Environment Interaction in Human Health and Disease (231KB).
For meeting questions, contact Dr. Leslie Reinlib, NIEHS - firstname.lastname@example.org 919-541-4998.
Very Low Lead Levels Linked with IQ Deficits, according to NEJM Study
A new study suggests that lead may be harmful even at very low blood concentrations. The study, funded by the National Institute of Environmental Health Sciences of the National Institutes of Health, will appear in the April 17 edition of The New England Journal of Medicine (http://content.nejm.org/).
The five-year study found that children who have blood lead concentration lower than 10 micrograms per deciliter suffer intellectual impairment from the exposure. The researchers also discovered that the amount of impairment attributed to lead was most pronounced at lower levels. The study was carried out by researchers from Cornell University, Cincinnati Children's Hospital Medical Center, and the University of Rochester School of Medicine.
An important feature of this new study is its focus on children with blood lead levels below 10 micrograms per deciliter, a threshold currently used by the Centers for Disease Control and Prevention to define an elevated lead level. Previous research has been concerned primarily with lead's effects in the 10 to 30 micrograms per deciliter range, yet the new study finds lead-related impairments at lower levels.
"In this sample of children we find that most of the damage to intellectual functioning occurs at blood lead concentrations that are below 10 micrograms per deciliter," said Richard Canfield, Division of Nutritional Sciences at Cornell University (http://www.human.cornell.edu/che/bio.cfm?netid=rlc5) and primary author on the study. The amount of impairment attributed to lead exposure was much greater than the researchers had expected. "We were surprised to find that in our study the IQ scores of children who had blood lead levels of 10 micrograms per deciliter were about 7 points lower than for children with levels of 1 microgram per deciliter," Canfield said.
At the same time, the study found that an increase in blood lead from 10 to 30 micrograms per deciliter is associated with only a small additional decline in IQ. "Because most prior research focused on children with higher exposures than in our sample, we suspected that those investigators could estimate only the amount of additional damage that occurs after blood lead has reached 10 micrograms per deciliter - unaware that more damage may occur at lower levels," said Charles Henderson, Department of Human Development at Cornell (http://www.human.cornell.edu/HD/index.cfm) .
Deborah Cory-Slechta, director of the NIEHS Environmental Health Sciences Center at University of Rochester School of Medicine (http://www2.envmed.rochester.edu/envmed/EHSC/index.html) , said, "Our study also emphasizes the need to understand the behavioral deficits indicated by lower IQ scores."
Before 1970, childhood lead poisoning was defined by a blood lead concentration greater than 60 micrograms per deciliter. Since then, the threshold used to define an elevated blood lead level declined several times, before reaching the current value of 10 micrograms per deciliter. Under this definition, more than one in every 50 children in the United States between the ages of 1 and 5 years is adversely affected by lead, which has been linked to lowered intelligence, behavioral problems, and diminished school performance. Nearly 1 in 10 young children have a lead level above 5 micrograms per deciliter, according to CDC figures.
"Our study suggests that there is no discernable threshold for the adverse effects of lead exposure and that many more children than previously estimated are affected by this toxin," said Bruce Lanphear, Cincinnati Children's Hospital and director of the hospital's Children's Environmental Health Center (http://www.cincinnatichildrens.org/svc/find-professional/l/bruce-lanphear.htm) . "Despite a dramatic decline over the last two decades in the prevalence of children who have blood lead concentrations above 10 micrograms per deciliter, these data underscore the increasing importance of prevention."
The study followed 172 children in the Rochester, N.Y., area whose blood lead was assessed at 6, 12, 18, 24, 36, 48, and 60 months, and who were tested for IQ at both 3 and 5 years of age. The researchers controlled for many other factors that contribute to a child's intellectual functioning, such as birth weight, mother's intelligence, income, education, and amount of stimulation in the home.
"Any detectable effect occurring from such a widespread exposure is cause for concern," Walter J. Rogan, M.D., said. Rogan is a NIEHS researcher who has studied lead exposure in children but was not an author on the study. "Relatively small changes in the mean IQ of a large number of children will dramatically increase the proportion of children below any fixed level of concern, such as an IQ of 80, and decrease the proportion above any 'gifted' level such as 120," Rogan said.
The authors of the study are Richard L. Canfield and Charles R. Henderson, Jr., Cornell University, Ithaca, N.Y.; Deborah A. Cory-Slechta, University of Rochester School of Medicine, Rochester, N.Y.; Christopher Cox, National Institute of Child Health and Human Development, NIH, DHHS, Bethesda, Md.; Todd A. Jusko, University of Washington, Seattle, Wash.; and Bruce P. Lanphear, Cincinnati Children's Hospital Medical Center. NIEHS funds centers for environmental and children's health at University of Rochester, University of Cincinnati, and University of Washington.
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