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Good genes—Bad genes
By Marina Chicurel

The same gene that predisposes people to developing Alzheimer's disease may help protect them from kidney damage. At least that is what researchers at the Duke University Medical Center in Durham, North Carolina, suspect, based on a preliminary study in which APOE-4, a variant of the apolipoprotein gene associated with Alzheimer's disease, appeared to be slightly correlated with a decreased risk of kidney malfunction after cardiac bypass surgery. Using a small number of patients and revealing a moderate effect, the study, published in the August issue of Anesthesiology, is only a first hint of a correlation.

But it illustrates a recurring theme that is emerging as researchers probe the genetics of disease: genes are probably only rarely unidimensionally good or bad. "Genes can act differently in different environments," says James Hixson, of the University of Texas in Houston. Several studies are showing that genes can be beneficial or harmful depending on the tissue and time in which they are active, the presence or absence of other genes, as well as the gender and life history of the individual in whom they reside.

‘In one organ, a gene can be the villain and in another, the hero’

Two of the genes that have been most clearly associated with longevity in humans, for example, can also predispose their carriers to disease. Jonathan Smith, at the Rockefeller University in New York, notes that people who live longer are more likely to carry the APOE-2 gene, another variant of the apolipoprotein E gene. Yet individuals who carry two copies of this variant seem to be more prone to getting retinitis pigmentosa, a disease of the eyes. The other gene robustly associated with long-lived humans—a variant of the ACE (angiotensin-converting enzyme) gene—also has its dark side. People who carry this gene are more likely to suffer from coronary heart disease.

One reason why genes may have such paradoxical effects is because their activities depend on context. Based on his study linking APOE-4 to decreased kidney damage, Mark Stafford-Smith, of Duke University Medical Center, for example, thinks that expression of APOE-4 may be beneficial in the kidneys, but harmful in the brain. "In one organ, a gene can be the villain and in another, the hero," he says.

Age itself may also contribute to the multiple effects of genes on their hosts. One of the main theories of aging proposes that genes that are detrimental in older individuals are maintained in the population because of their beneficial effects on younger individuals. Studies in several organisms, including humans, have shown an inverse relationship between lifespan and family size. It is possible that the same genes that make an organism fertile when it is young, contribute to its death later on.

The simplistic view that single genes map to single functions or diseases has prevailed partly due to the lack of information on the extent of multiple, or pleiotropic, effects on genes. But new studies are filling the gap, suggesting pleiotropy is widespread. Trudy Mackay, of North Carolina State University in Raleigh, NC, recently found that the genetic variations that confer longevity in fruit flies, for example, are very often pleiotropic. Every single variation that correlated with increased lifespan in a given group of flies, she found, had neutral or adverse effects on flies of the opposite sex or with different life experiences. "I would predict that it will become quite clear that pleiotropy is the rule rather than the exception," she says.

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Chew, S.T.H. et al. Preliminary report on the association of apolipoprotein E polymorphisms, with postoperative peak serum creatinine concentrations in cardiac surgical patients. Anesthesiology 93, 325-331 (August 2000).
Smith, J.D. Apolipoprotein E4: an allele associated with many diseases. Ann Med 32, 118-127 (March 2000).
Westendorp, R.G. & Kirkwood, T.B. Human longevity at the cost of reproductive success. Nature 396, 743-746 (December 1998).
Vieira, C. et al. Genotype-environment interaction for quantitative trait loci affecting life span in Drosophila melanogaster. Genetics 154, 213-227 (January 2000).

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