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University of Cincinnati Academic Health Center
Publish Date: 09/12/00
Media Contact: AHC Public Relations, (513) 558-4553
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Gene Variation Correlated to Drug Response

Cincinnati, Ohio--The University of Cincinnati (UC) and Genaissance Pharmaceuticals, Inc., announced a landmark paper published in today's Proceedings of the National Academy of Sciences (PNAS). UC researcher Stephen Liggett, MD, is the principal investigator of the paper entitled "Complex Promoter and Coding Region of beta 2-adrenergic Receptor Haplotypes Alter Receptor Expression and Predict In Vivo Responsiveness," which demonstrates for the first time that a response to a drug can be predicted from an individual's own DNA using genomic markers called haplotypes. The PNAS paper details the findings of a collaborative project between UC and Genaissance, a leader in applying population genomics and informatics technologies to the development of personalized medicines.

The Genaissance and UC research team used a unique approach to organize multiple points of gene variation (single nucleotide polymorphisms, SNPs) into haplotypes, or HAP® Markers, and correlate the information with clinical outcomes. HAP® Markers, analogous to genomic "bar codes," represent the distinct patterns of genomic variability that have accumulated over time in the human population. In many cases, this variation can explain why some people experience a better response to medication than others do. Conversely, it can also help explain why certain people develop side effects where others do not.

"The power of this technology was strongly demonstrated in this study," said Liggett, professor of medicine and molecular genetics at the UC College of Medicine, and executive medical advisor to Genaissance. "We found clear correlations between specific HAP® Markers and clinical response to albuterol. The drug response predictions could not have been made by using only the individual SNPs. In addition, this technology allowed us to obtain very strong results from a modest number of patients."

The study involved 121 patient volunteers in a "real world" trial that included anyone with asthma. Lung function was measured before and after treatment with albuterol, a popular drug known to act through the action of the beta 2-adrenergic receptor. The individual responses to albuterol were correlated to the variation of the genetic code for the receptor. The receptor gene was found to have 13 different points of variation, or SNPs. Theoretically, these can be arranged into 213, or 8,192 possible haplotype (HAP® Marker) combinations. However, it was discovered that only 12 unique HAP® Markers occur in nature and only four accounted for the vast majority of the patients.

"Using only SNPs as compared to haplotypes is analogous to someone being asked to predict the speed of a car by only being told that it has 16 inch wheels," says Liggett. "That, of course, would be very difficult. However, if you were told the horsepower of the engine, the weight of the car, the gear ratios, etc., then a much more accurate prediction could be made. The same scenario appears to be applicable to the human genome. Knowing all the points of variation within a gene, and how they are arranged, gives you much more predictive power than single bits of data. We have thus been able to assign to each person a haplotype, which consists of a series of 0s or 1s (a binary code), which is highly predictive of the response to the most common drug used to treat asthma."

"This study stands as a crucial proof of concept for the Genaissance HAP® Technology," said Gualberto Ruaño, MD, PhD, and Chief Executive Officer of Genaissance. "The promise of using each patient's DNA to guide the delivery of better, more personalized healthcare is quickly becoming a reality. We have planned another clinical trial in asthma, and are applying the same set of technologies to a variety of other therapeutic areas including cardiovascular disease, diabetes and schizophrenia."

Seventeen million Americans are estimated to suffer with asthma of which 4.8 million are children under the age of18. Approximately 5,000 people with asthma die each year. The healthcare costs associated with the disease are estimated to be 6 billion dollars per year.

 

"The University of Cincinnati Medical Center is committed to building our biotechnology capabilities," said Donald C. Harrison, MD, senior vice president and provost for health affairs at UC. "Genomics is the frontier of where the entire field of life sciences is going, and we want the University of Cincinnati to be on the front edge of the wave."

The research team from UC also included Dennis McGraw, MD, assistant professor of medicine. The entire paper can be found in the September12 Proceedings of the National Academy of Sciences 97:10483-10488 by the following authors: Drysdale, C., McGraw, D., Stack, C., Stephens, C., Judson, R., Nandabalan, K., Arnold, K., Ruaño, G., Liggett, S. (2000).



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