Variation in the human genome is a source of genomic markers for drug efficacy, adverse reactions and disease predisposition, providing an important step towards personalized medicine. The current common practice in this field is to genotype single nucleotide polymorphisms (SNPs). However the importance of non-SNP variation has become apparent with more and more polymorphic sites being discovered.
Through a concentrated effort made since 2006, Compugen has developed the GeneVaTM genomic markers discovery platform based on genotyping of genomic non-SNP variations. These structural variations may now be studied in relation to phenotypic phenomena. Compugen also believes that these variations will facilitate drug response and disease predisposition studies with a higher degree of success than current SNP-only approaches.
The GeneVaTM platform incorporates a database of approximately 350,000 insertions and deletions of size ranging from two to 500 nucleotides, a system linking genomic variations, genes, diseases and drugs, and a novel PCR-based genotyping method for insertions and deletions. The database was created from the analysis of more than 200 million genome sequencing fragments, expressed sequences, and entries from public databases of variations. A specialized bioinformatics analysis platform was developed to handle and integrate many disparate data sources, to identify possible genomic structural variations and, in many cases, to predict their association with specific disease pathways, such as those associated with breast and colon cancer, congestive heart failure, type II diabetes, hypertension, lipid disorders, rheumatoid arthritis and stroke. The genotyping method analyzes complicated cases including alleles appearing only in the heterozygote state and identification of new alleles that were not predicted, especially in multi-allelic sites.
From the approximately 350,000 multiple nucleotide genetic variations predicted by the GeneVa® platform, a very small set of variations was selected as being potentially related to type 2 diabetes in Caucasians. This very small set, consisting of only 135 variations, was then tested in a genotyping experiment. In this study, CGEN-40001, a novel 15bp insertion in PFKP (a key regulatory enzyme in glycolysis), demonstrated the predicted correlation with type 2 diabetes in Caucasians. This correlation was then validated in a second study based on an independent set of samples. According to the two studies performed by Compugen, approximately 15% of the Caucasian population has at least one copy of this insertion. Furthermore, the studies showed that the presence of this insertion increases the risk of type 2 diabetes by 50-80%.