New statistical method links multiple genes to common complex diseases

used to study multiple-gene risk factors. When such an analysis is expanded to take non-genetic risk factors into account, it should significantly improve a doctors ability to determine the risk that certain treatments, like hormone replacement therapy, represent for individual patients, he says.

Most genes harbor common DNA sequence variations called polymorphisms and rare DNA sequence variations called mutations. Some mutations single-handedly increase an individuals susceptibility to specific diseases. Such "genetic" diseases are recognizable because they are heritable and so cluster in certain families. An example is hereditary breast cancer, which accounts for less than 10 percent of all breast cancer cases. It is highly associated with the action of mutations in one of two genes.

On the other hand, most common diseases do not exhibit a clear pattern of heritability. So geneticists argue that the observed variations in susceptibility must be caused by the interactions among multiple polymorphisms. In such cases, individual polymorphisms are harmless, but when they occur in a specific combination they significantly enhance a persons risk. In some cases, the increased susceptibility may be due to the collective action of a few polymorphisms, but in others they may arise from the subtle interactions among hundreds of gene-variants.

Take the case of the polymorphisms that the Vanderbilt group has linked with the sporadic breast cancers that occur in women with no family history of the disease and account for more than 90 percent of all breast cancer cases.

The researchers began by looking at five genes involved in estrogen metabolism. They chose this particular set of genes because there is considerable evidence that estrogens influence breast cancer risk and recent studies have shown that the enzymes that break down estrogen in the body produce metabolites that can cause cancer.

Moore, graduate student Marylynn Ritchie and programmer

Contact: David F. Salisbury
Vanderbilt University

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