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Genome Holds Key to Preventive Medicine

Cheryl A. Thompson

It is the year 2010, and a 21-year-old healthy man whose father died of a myocardial infarction at age 48 visits his physician to discuss his recently discovered high cholesterol level. From follow-up tests on the blood sample, the physician knows not only which steps in the cholesterol pathway are not functioning optimally but also which genetic disorders the patient should be concerned about even though his family history does not suggest a higher-than-normal risk.

This is what researcher Francis S. Collins envisions as preventive medicine 10 years after the much-heralded completion of a working draft of the human genome’s sequence of nucleotides. Collins, who directs the government’s National Human Genome Research Institute (NHGRI), said recently that scientists will identify in the next five to seven years which genes contribute to hereditary diseases, opening the opportunity for "individual preventive medicine."

To fellow researcher Alex Titomirov, however, genome-based preventive medicine is a reality today. Titomirov heads Informax, a private-sector company that develops computerized databases of biological information and interfaces to help researchers access the data. Since 1995, the company has supplied bioinformatics software to the National Center for Biotechnology Information at the National Library of Medicine. Titomirov said 19 of the 20 top research-based pharmaceutical companies use his company’s products.

Journal submissionCollins and Titomirov spoke December 5 at the Fifth Annual Health Information Infrastructure Conference, sponsored by Friends of the National Library of Medicine and held in Bethesda, Maryland, home to NHGRI and Informax.

Gene-based diagnoses. Collins called his futurist patient–physician encounter "a big challenge for health information transfer." Primary care providers, he said, must learn how to explain relative and lifetime risks in language meaningful to patients. "These are not going to be yes–no answers," he said.

In the 2010 scenario described by Collins, the physician will review with the patient the results of gene-based tests for about 14 conditions, focusing the discussion on those for which the risks are at least twofold greater than in the general population.

Page 1 of the two-page report on genetic testing reveals the good news: The patient, John Bridge Jr., has lower-than-normal risks for prostate cancer and Alzheimer’s disease. Bridge’s lifetime risk for prostate cancer is 7%, and his lifetime risk for Alzheimer’s disease is 10%. The risks are low but not zero.

Page 2 shows the conditions for which Bridge’s relative risks exceed 2, the genes responsible for these increased risks, and his lifetime risks of developing the conditions.

The relative risk for heart disease is 2.5, an expected finding, given Bridge’s family history and elevated cholesterol, said Collins. But what is the basis for this risk? The report indicates that Bridge’s nucleotide sequences for the genes encoding apolipoprotein B and plasma cholesteryl ester transfer protein are variants, giving him a lifetime risk of 70% for the development of symptomatic coronary artery disease. With this information, the physician designs a treatment plan: a low-cholesterol diet and a drug that corrects the underlying problems in the cholesterol pathway. By adhering to the treatment plan, Bridge could reduce his relative risk to 1 or even lower, Collins said.

Surprising to both patient and physician, said Collins, is Bridge’s "dramatic" risk for colon cancer. The report indicates a relative risk of 4.0 and a lifetime risk of 23%. Nothing in Bridge’s family history accounts for this finding, but his variant sequences for the adenomatosis polyposis coli and familial colon cancer type 4 genes do. Whereas the 2010 physician would suggest that Bridge undergo a colonoscopy to check for the presence of cancer, Collins said a present-day physician would not even consider screening this type of patient because of the procedure’s high cost.

Bridge, a one-pack-a-day cigarette smoker, has a relative risk of 6 for developing lung cancer if he continues this habit for the next 50 or 60 years. His lifetime risk for lung cancer is 40%. A variation in the sequence of his gene encoding N-acetyltransferase 2 causes the smoke-detoxifying enzyme not to function properly, a problem only when Bridge exposes himself to cigarette smoke.

Collins said he is "not so naive as to think that this kind of information will convince smokers who are otherwise ignoring the health risks that, now, they need to pay attention. But I suspect that it will be a useful adjunct to that conversation."

The foregoing patient–physician encounter is "a halfway strategy," Collins said. By 2020 or 2030, medical interventions may be available for dealing with genetic knowledge, he predicted.

The future is now. Titomirov said that Bridge, if 21 years old today, could submit a blood sample for determination of his "expression profile," the concentrations of disease-related proteins. Then, in 2010, a repeat profile might indicate that Bridge’s expression of a certain protein is nearing the level that will trigger the development of type 2 diabetes, giving the patient and his physician the opportunity to take preventive measures. That scenario, said Titomirov, is Informax’s view of preventive medicine.

Rather than compare Bridge’s genetic makeup to the consensus genome derived by the Human Genome Project, as in Collins’s scenario, Titomirov would have the patient serve as his own control. If follow-up testing in 2010 reveals that one of Bridge’s genes expresses a protein at a concentration nearing the threshold for the onset of a disease, Informax’s system will notify the patient by e-mail or voice-mail, said Titomirov.

"Bioinformatics is the key enabler of preventive medicine," Titomirov said.

Want to Learn from the Human Genome Project?

The National Coalition for Health Professional Education in Genetics (NCHPEG), of which ASHP is a member, seeks to ensure that health professionals have "genetic literacy." The goal of the coalition, said Collins, is to ensure that encounters between patients and their health care professionals go well, not badly. NCHPEG's desired competencies for health care professionals are available online.

Available soon from the National Human Genome Research Institute will be a free educational kit—containing a multimedia interactive CD-ROM, 15-minute video documentary, informational brochure, and wall poster—designed for use by high school biology teachers but obtainable by college instructors, scientists, and the public. Sign up at