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GSK Researchers Sequence Drug Target Genes to Help ID Drug Repositioning Opportunities

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Researchers from GlaxoSmithKline have sequenced 202 drug target genes in more than 14,000 individuals in order to look for variants that would suggest novel targets or a way to repurpose existing drugs.

The team is now following up on the results, which were published earlier this month in Science.

"We were looking to identify functional variants in those [202] genes that we could associate with disease phenotype that would suggest opportunities to recommission drugs in development for alternate indications, or to strengthen or validate the indication," Stephanie Chissoe, who heads the genetics department at GSK, told Clinical Sequencing News.

The GSK team selected 14,204 people, 10,621 of whom were from 12 case-control studies of common diseases, including coronary artery disease, metabolic syndrome, multiple sclerosis, osteoarthritis, rheumatoid arthritis, irritable bowel syndrome, epilepsy, Alzheimer’s disease, unipolar depression, bipolar disorder, schizophrenia and chronic obstructive pulmonary disease. Additionally, 3,381 individuals were from two different population studies, both of which had extensive cardiovascular trait measurements and psychiatric evaluations.

Of the 202 genes, 12 encode targets of currently marketed GSK drugs, 44 encode targets of drugs that were terminated after having conducted human trials, 76 encode targets of drugs under active clinical development, and 70 are genes that are of interest for pre-clinical development.

Sequencing was outsourced to BGI, which used Roche's Nimblegen arrays to enrich for the genes and 48-plex, paired-end sequencing on the Illumina Genome Analyzer. Each sample was sequenced to around 27-fold coverage.

"We did not find any major association with any of our primary disease endpoints that we had analyzed in this study," said Matt Nelson, a principal scientific investigator in GSK's statistical genetics department and lead author of the paper. "However, there was a vast array of other intermediate measures of health, particularly cardiovascular health."

Overall, "we identified multiple potential opportunities for repurposing drugs," Nelson said. While "none of those associations were highly statistically significant, several of them are undergoing various forms of follow-up studies," including typing the variants in larger numbers of subjects in appropriate disease collections.

For example, the GSK team found novel, rare variants in the ADIPOQ gene, which is thought to be involved in type 2 diabetes. The gene encodes adiponectin, increased levels of which have been shown to be associated with a lower risk of type 2 diabetes.

Since then they have evaluated the variants in more than 11,000 individuals from the Genetics of Diabetes Audit and Research in Tayside, Scotland, cohort, the results of which were published in March in the journal Diabetes.

While a statistically significant association was not found between the ADIPOQ variants and type 2 diabetes, the authors said they were "unable to exclude the possibility of substantial effects" and concluded that "further investigation by large-scale and well-powered Mendelian randomization is warranted."

Additionally, said Nelson, the team identified rare, nonsynonymous variants in the gene PLA2G7, for which additional studies have since helped inform decisions around a drug currently in phase III development for treatment of coronary artery disease.

"We learned quite a bit about these drug target genes and the extent of functional variation that is relevant for us as we plan future studies," he added.

One somewhat surprising finding in the Science study was the abundance of rare variants present in the drug target genes.

On average, the researchers found one rare variant every 17 base pairs, and among all the variants, over 95 percent were rare, 90 percent were novel, and 74 percent were found in only one or two individuals.

Before starting the study, the distribution of rare variants was unknown, said Chissoe, and "what we found was an abundance of these rare, functional variants," which has given GSK a detailed view of the different drug target genes and the distribution of rare variants across those genes.

Additionally, said Nelson, "by identifying subjects that carry these [very rare] variants, you can investigate more carefully what's going on in those subjects and learn more about disease biology and potentially more about how drugs that target those genes may be useful," he added.

Moving forward, the GSK team plans to use an array of technologies, including targeted next-gen sequencing, microarrays, and exome sequencing. The company has internal sequencing capabilities, although it declined to disclose the platforms it currently employs, and it also outsources sequencing to BGI and other partners.

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