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
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.
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."
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).