American College of Physicians: Internal Medicine — Doctors for Adults ®

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Collaboration untangles women's DNA to diagnose common killers

Academia, government and industry seek answers from genomes

From the March ACP Observer, copyright 2007 by the American College of Physicians.

By Stacey Butterfield

The Women's Health Study (WHS), which tracked 28,000 initially healthy women for more than a decade, yielded a wealth of information about what factors influence women's risk of cardiovascular disease and cancer. Now researchers are hoping that the same data will help unravel the genetic roots of these conditions and other major diseases.

The Women's Genome Health Study, a collaboration of government, academia and industry, is sorting through DNA samples collected in the WHS to uncover genetic differences and connections to women's health. Stored genetic samples will undergo a genome-wide scan evaluating more than 317,000 potential genetic differences.

Genetic scans began in January and are expected to be complete within 18 months to two years. Scientists hope the collaboration will find genetic associations with disease in three to four years and lead to patient benefits within five to seven years.

Cost leads to sharing

The WHS began in 1991 as a project to evaluate the effects of vitamin E and low-dose aspirin in prevention of cardiovascular disease and cancer in women. Of the initially healthy entrants into the study, 900 have been diagnosed with breast cancer, 1,000 have had a major cardiovascular event and 2,500 have developed osteoporosis. Researchers hope to identify differences in the genes of those women who have developed diseases from those who have remained healthy.

"The core question is, "What are the genetic determinants of heart attack, stroke, venothrombosis, breast cancer, osteoporosis, cognitive decline?'" said Paul Ridker, MD, principal investigator of the study and director of the Center for Cardiovascular Disease Prevention at Brigham and Women's Hospital in Boston.


A lab technician retrieves blood samples to record them for the Women's Genome Health Study.



Although researchers have been following the study participants' health for an average of 12 years, such an investigation of the women's genes only recently became possible. "Just three years ago, this would have been cost-prohibitive and we would not have had the technical capability to run 28,000 of these scans," said Dr. Ridker.

The project is still expensive, leading Dr. Ridker to look beyond the usual options for collaboration. In addition to the National Institutes of Health, the study is co-sponsored by pharmaceutical manufacturer Amgen, based in Thousand Oaks, Calif.

"We're in an era when the NIH doesn't have adequate resources to cover the kind of science that must be done to advance the public health, so creative collaborations like this need to be established," said Dr. Ridker. "This is an attempt on our part to see if we can figure out a new model for doing research."

Amgen is particularly interested in knowledge that the study uncovers about cancers, inflammatory diseases and bone disorders, said the company's senior vice president of research and development, Joseph Miletich, MD.

Besides looking at the women's clinical histories, researchers will compare the genes with a wide range of blood biomarkers and risk factors, from cholesterol levels to hormone replacement therapy.

"In addition to understanding what are the core genetic determinants of breast cancer or bone fracture, we can also ask what are the genetic determinants of inflammation or hyperlipidemia," said Dr. Ridker.

Study size offers diagnostic power

The comprehensiveness of the database and the large number of participants make the Women's Genome Health Study particularly suited to uncovering relevant genetic connections, Dr. Miletich said. The research should also help to reveal genetic variations that are important to the health of women.

"We have known for years that we had a unique epidemiologic resource. If we could unlock the genetic data, we believe it would provide us a method to jumpstart personalized medicine," said Dr. Ridker.

Prior work on the WHS has already advanced the goals of personalized medicine-that is, providing every patient with treatment and screening exactly tailored to his or her needs.

Using data from the study, Dr. Ridker and his colleagues revealed the link between C-reactive protein and heart attack and stroke. "There is a powerful example of how this new kind of data can lead us in directions we never would have thought about previously," he added. "So it's a very exciting time for understanding how the genetics of disease can help us at the bedside."

Translating the data from genetic samples to clinical practice is a long, complex process handled by biologists, statisticians, epidemiologists and computational biologists, but significant findings could start coming out relatively soon, the study leaders said.

Some associations between the women's genes and disease could be uncovered within three to four years, said Dr. Miletich. "Overall," he added, "we might see some benefit that could actually be transferred to patients somewhere in the five to seven year timeframe."

Results (which are completely anonymous for participating patients) will be released to researchers and the public through the NIH, said Dr. Miletich. Patients "The intention is to get all of this information into the public domain as soon as possible so that any powerful associations for any diseases that are significant can eventually be studied."

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