September 28, 2001

Genetics symposium offers insights, theories

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Dr. Art Beaudet of Baylor College of Medicine was the keynote speaker at last week's Genetics Symposium. (photo by Dana Johnson)

Genetics symposium offers insights, theories

The second annual Meharry/Vanderbilt sponsored Genetics Symposium, held last week on the campus of Meharry Medical College, offered the audience of researchers, students, physicians, and administrators a collection of presentations in the areas of genetic modifiers, minority health, and pharmacogenomics.

Opening remarks by Lee E. Limbird, Ph.D., associate vice chancellor for Research at Vanderbilt, acknowledged this time of national difficulty.

“In light of these national events, one wonders whether science, and understanding who we are and how we became, has any value,” she said. “Maybe the discoveries themselves in a week like this may not seem so important, but the process does. I hope we can move forward to a mindset where we are ready to learn from each other, in every capacity, and have a day that is also fun and joyful.”

The first speaker, Marylyn D. Ritchie, a graduate student in Molecular Physiology and Biophysics at Vanderbilt, presented a powerful statistical approach to genetic analysis developed by her and her co-workers that is designed to identify the interaction of multiple risk factors in causing disease. Ritchie explained how the analytical method, called Multifactor Dimensionality Reduction, implicated four sequence variations in three genes in increased risk for non-familial breast cancer.

This idea that multiple factors— from genetic changes to the influence of diet, stress, and toxic environmental exposures—are most likely at the root of many of the common diseases that affect our society was the theme that recurred throughout the day.

The examination of modifier genes in multiple sclerosis and Alzheimer disease was discussed by Jonathan L. Haines, Ph.D., professor of Molecular Physiology and Biophysics and director of the Program in Human Genetics at Vanderbilt. Haines emphasized that, though the number of genes identified by the Human Genome Project is relatively small, the number of variations in gene expression is tremendous.

“Rather than simply ask the binary question if disease is present, ‘yes or no,’” he said, “the researcher must take into account the complexity and subtlety of phenotypic variation in disease expression.”

Several mid-morning speakers presented current research in genetic diseases occurring in higher frequency in minority populations.

The susceptibility factors for early-onset periodontal disease were outlined by Harvey Schenkein, D.D.S., Ph.D., assistant dean for Research, and director of the Clinical Research Center for Periodontal Disease at Virginia Commonwealth University School of Dentistry.

Aggressive periodontitis is a clinically heterogeneous disease causing bone resorption and subsequent tooth loss during puberty and early adulthood. Risk factors for this disease that aggregates in families and affects blacks disproportionately include smoking and the presence of specific bacteria.

Alzheimer disease in African Americans was discussed by Robert F. Clark, Ph.D., assistant professor of Psychiatry, Neurology, and Behavioral Sciences at Meharry. The cumulative incidence of Alzheimer’s in African-Americans and Caribbean Hispanics by age 90 is twice that of Caucasians.

Scott M. Williams, Ph.D., associate professor of Microbiology at Meharry, presented a genetic association study of keloids—a type of overhealing that occurs more frequently in blacks—in an extended family of African Americans. Suggested risk factors associated with keloid formation include hypertension and allergies.

The keynote speech, given by Dr. Arthur L. Beaudet, chairman of Molecular and Human Genetics at Baylor College of Medicine, explained his “rheostat theory” of how genetic imprinting —the unequal inheritance of a paternal or maternal allele at a particular gene locus—provides a mechanism for differential gene expression, and perhaps accelerated gene evolution.

In much the same way a rheostat can brighten or dim a light, Beaudet suggests that regulatory elements allow the imprinted genes to “crank up or crank down expression,” depending on parental origin.

Using as examples Angelman and Prader-Willi syndromes, which are caused by loss of maternal or paternal inheritance, respectively, of the identical region on chromosome 15, Beaudet outlined a hypothesis of how differential DNA methylation might control variable expression of a disease-causing gene.

The afternoon session focused on the development of genetically targeted pharmaceuticals. Dr. Nancy J. Brown, associate professor of Medicine and Pharmacology at Vanderbilt, explained that much of the variability in drug therapy is now understood to be genetically determined, “often by common mutations that were not anticipated.”

“In the past,” she said, “we looked at rare mutations, but now we can start to look at common mutations. This will have a great impact on drug development.”

Dr. C. Michael Stein, associate professor of Medicine and Pharmacology at Vanderbilt, presented evidence for ethnic differences in response to anti-hypertensive drugs. Stein saw differences between African Americans and whites people in alpha-adrenergic vasodilative and beta-adrenergic vasoconstrictive responses to these drugs when testing forearm blood flow.

Drug transport was the topic of the presentation by Dr. Richard B. Kim, associate professor of Medicine and Pharmacology at Vanderbilt. His studies have identified a number of genetic variants, or polymorphisms, in the MDR1 gene encoding p-glycoprotein, the “pump” that controls the efflux of drug from certain tissues. Kim found that these polymorphisms must be considered together—as a haplotype—for drug targeting; the variants did not affect response of the p-glycoprotein pump individually. Drug response differed between African Americans and white people with the same haplotype.

The symposium ended with a discussion led by Carole L. Freund, Ph.D., assistant professor of Pediatrics and recent addition to the Center for Genetics and Health Policy at Vanderbilt, of the ethical issues raised by the emerging science of pharmacogenomics.