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Team in Canada, US Identifies Large-Scale Gene Variants. Will They Play Role in PGx?


Researchers at three US and Canadian hospitals and university medical centers have identified “significant differences” in the genomes of a group of healthy individuals that may enable drug makers to develop new kinds of pharmacogenomics-based therapeutics.

The team, comprising scientists from the Hospital for Sick Children, Brigham and Women’s Hospital, and Harvard Medical School, claim to have used a pair of genome-scanning technologies to find large-scale copy variations in 25 healthy individuals that may “overlap” with other genes or mutations to foster differences in drug efficacy or adverse drug reactions.

“At first we were astonished and didn’t believe our results because for years we had been taught that most variation in DNA was limited to very small changes,” Stephen Scherer, co-principal investigator of the study and a Sick Kids senior scientist, said in a statement this week. Scherer, who is also an associate professor in the Department of Molecular and Medical Genetics at the University of Toronto, said he happened to learn that a team at Harvard was making similar observations, and “ultimately we combined our data and came to the same conclusion.”

To arrive at their results, the researchers used comparative genomic-hybridization arrays made by Spectral Genomics, and later quantitative PCR and in situ hybridization, to study the genomes of 50 individuals pulled from various publicly available databases.

The new data from the Sick Kids and Harvard groups revealed 255 regions — or more than 0.1 percent of the genome — where massive sections of DNA exist in a variety of copy numbers between individuals.

More than half of these variations “lead to changes in gene numbers and at least 14 regions overlapped with known sites associated with human disease,” Scherer said.

“Because these newly discovered variants exist in the genomes of healthy individuals, their presence could lead to subtle differences affecting physical or behavioral traits by influencing the expression of specific genes, but they could also predispose to future disease,” Charles Lee, co-principal investigator and assistant professor at Harvard Medical School, added in the statement.

For example, he said, the most common large-scale copy variation, or LCV, involves amylase genes. In their study, the authors discovered that “some people” may have 10 copies of this gene while others may have as much as 24 copies. “It would be really exciting if we found that an increased copy number of these genes was associated with increased susceptibility to pancreatic diseases or cancer,” Lee said. “This would allow us to use these LCVs as disease markers.”

The information on identified LCVs has been collated into a publicly accessible database called the Genome Variation Database clinical [find the database here]. According to the researchers, the goal of the database is to “provide a comprehensive summary of human large-scale genomic variants with information about frequency and their relation to genes, segmental duplications and genome assembly gaps, the group said on its web site. The database also aims at providing a catalog of control data for studies seeking to link LCVs with phenotypic data.

The study appears in the September issue of the scientific journal Nature Genetics, and has been available online since Aug. 1.

“Fifty percent of the LCVs we identified have genes that are entirely encompassed within the LCV, and in some cases you have multiple copies of these,” Scherer told Pharmacogenomics Reporter this week. “It could be very reminiscent of things like multi-drug-resistance genes and the cytochrome oxidase genes. Depending on the copy number that you have, you’d have increased resistance or sensitivity … to a particular drug.

“I think this type of genomic variation will contribute to many different features, and certainly I think the most obvious one is the potential applications for pharmacogenomics,” he said.

In fact, portions of these data will appear in the second edition of a pharmacogenomics book written by Werner Kalow. The book, called Pharmacogenomics, is due out in December, Scherer said.

Scherer said he believes LCVs “in most cases won’t have a direct role … but in some cases they will.” He supports this belief by saying that it has been well established that if an individual carries a certain chromosomal imbalance, “often it can lead to more complex chromosome rearrangement in the next generation.

“The fact that we found a few of these LCVs overlapping with known disease, it was quite significant to suggest that these may actually be involved as predisposition factors in these diseases,” he added.

However, he stressed that “a lot” of the genes his group identified to be within the LCVs have unknown function. “So we can’t really do any correlation at this time.

“Different dosages of these genes or proteins could certainly be involved in drug response or drug metabolism and things like this,” said Scherer. “We’re really just scratching the surface.”


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