Compugen (Tel Aviv, Israel) reported the discovery and experimental confirmation of a genetic biomarker, CGEN-40001 for predisposition to Type 2 diabetes, using its GeneVa platform, which consists of an in silico database of roughly 350,000 predicted genetic variations in the human genome, with each predicted variation consisting of multiple consecutive nucleotides.

Predisposition markers are of particular value in diseases like Type 2 diabetes, where specific lifestyle and health factors are known to play an important role, Compugen said. Following diagnosis, high-risk patients may benefit from more aggressive management either through lifestyle modification or drug treatment. There are an estimated 24 million people in the U.S. with diabetes, 90% of whom are affected by Type 2 diabetes.

Compugen said that during the past few years, extensive efforts by others searching for genetic markers for Type 2 diabetes have utilized numerous genome-wide association studies, involving thousands of patients globally. Several validated genetic markers have been found; however, combining all the discovered biomarkers still explains only a small fraction of the heritability of the disease, so the need for additional markers continues to exist, the company said.

"This biomarker explains an additional fraction of the heritability of the disease," Compugen told Medical Device Daily in an email responding to MDD's questions. "If found, additional markers covering different high-risk populations would be of value."

From the roughly 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, Compugen said. 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, about 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% to 80%, Compugen told MDD.

Diabetes mellitus Type 2 is a chronic, life-long disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency, according to Compugen. When glucose builds up in the blood rather than being absorbed into cells, it can lead to diabetic complications. Over time, diabetes can lead to blindness, kidney failure and nerve damage. Diabetes is also an important factor in accelerating the hardening and narrowing of arteries (atherosclerosis), which generally leads to strokes, coronary heart disease and other large blood vessel diseases, the company noted. If left uncontrolled, the consequences can be life-threatening. However, Type 2 diabetes is manageable and can be prevented, the company said, noting diet, weight control and physical activity as "first-line" treatment.

At present, an estimated 8% of the U.S. population suffers from diabetes, 90% of whom are affected by Type 2 diabetes, Compugen said. Prevalence rates in the U.S. have more than doubled since 1990, the company added, leading the Center for Disease Control (Atlanta) to characterize this continuing increase as an epidemic. Worldwide, more than 150 million people are estimated to have the disorder and that number is expected to double by 2025, Compugen reported.

According to the company, GeneVa uses special purpose algorithms and other computational biology tools to select from the large database of genetic variations those variations that are predicted to be associated with the specific clinical phenotypes of interest, such as response or non-response to a specified drug of interest, or predisposition to a specified disease. Another key feature of the platform is a genotyping capability that allows the testing of multiple genetic variations on hundreds of DNA samples in a precise and cost-effective manner, Compugen noted.

Compugen told MDD that "the uniqueness of the platform lies within its pool of novel genetic variations, its predictive performance and the cost effectiveness of the discovery process."

Earlier this year Compugen reported the discovery and experimental verification of CGEN-327, a novel molecular biomarker candidate for the diagnosis of ovarian cancer. CGEN-327 is a previously unknown splice variant of the HE4 (Human Epididymis Protein 4) gene, which is a known biomarker for ovarian cancer (Medical Device Daily, Feb. 10, 2009).

Last year, the company reported the discovery and experimental confirmation of a combination of four biomarkers for early detection of drug-induced nephrotoxicity. Data demonstrate that the biomarker signature may enable a much earlier prediction of drug-induced kidney toxicity during pre-clinical trials in rats in comparison to traditional diagnostic methods such as histopathology or clinical chemistry. Those biomarkers were discovered through the use of Compugen's Nucleic Acid Testing discovery platform, which relies on the company's LEADS and MED infrastructure platforms and additional public and proprietary data sources (MDD, June 27, 2008).

That discovery was disclosed soon after the company reported the discovery and verification of CGEN-438, a potential blood-based biomarker for lung cancer. Compugen described CGEN-438 as "a novel splice variant peptide of delta-like protein 3 precursor (DLL3)." The peptide is secreted from the cell into the bloodstream, whereas the previously known DLL3 is a protein located on the cell membrane. Compugen said initial clinical evidence indicates that the molecule "could potentially serve as both a serum biomarker for the diagnosis of small-cell lung cancer and as a component in a biomarker combination for the diagnosis of non-small cell lung cancer patients," (MDD, May 1, 2008).