Celera and Leiden University Medical Center Discover Genetic Markers Associated with Deep Vein Thrombosis

ALAMEDA, Calif. & LEIDEN, The Netherlands--(BUSINESS WIRE)--Celera (NYSE:CRA), an Applera Corporation business, and researchers at the Leiden University Medical Center in the Netherlands, today announced the publication of a paper describing the identification of several novel gene variants that each are associated with approximately 50 percent increased risk of deep vein thrombosis (DVT). The paper is scheduled to appear in the March 19, 2008 edition of the Journal of the American Medical Association, and is currently available on the journal’s website at http://jama.ama-assn.org/.

Researchers from the two organizations investigated whether any of 19,682 gene variants (primarily missense single nucleotide polymorphisms, or SNPs) were associated with DVT in three case-control research studies including over 8,000 individuals. A key finding of the paper was the identification of seven gene variants that were associated with DVT. Of these seven gene variants, the strongest evidence for association with DVT was found for three common variants of CYP4V2, a novel cytochrome p450 gene, SERPINC1, and GP6. These gene variants are either in, or near, genes that have a clear role in blood coagulation.

Since it has been suggested that thrombosis is a multicausal disease due to multiple risk factors, the current findings complement the two common genetic variants, Factor V Leiden and prothrombin G20210A, that have been consistently found to be associated with DVT. In the current study, the CYP4V2 gene variant, which is present in over 50 percent of the population, was found to increase risk of DVT 1.5 fold. In contrast, Factor V Leiden and Factor II (prothrombin) are present in only 1 to 8 percent of the population, although carriers of these variants have been found to have higher levels of risk for DVT. The proportion of all thrombotic events attributable to the risk factor in the population for CYP4V2 carriers was therefore approximately the same as for Factor V Leiden and Factor II, suggesting clinical utility in identifying high-risk individuals.

The SERPINC1 gene encodes antithrombin, a serine protease inhibitor located on chromosome 1 that plays a central role in natural anticoagulation. The GP6 gene encodes glycoprotein VI, a 58-kDa platelet membrane glycoprotein that plays a crucial role in the collagen-induced activation and aggregation of platelets and may play a role in DVT.

“It’s been ten years since our center discovered Factor V Leiden and the prothrombin 20210A mutation, and now we have identified several new common risk factors for thrombosis,” said Professor Frits Rosendaal, M.D., Ph.D. at the Leiden University Medical Center, the lead author of the study. “It is striking that most of these genetic variants are connected to the clotting system, indicating that this is well-characterized. Although these new risk factors are not as strong as the ones known so far, their importance lies in the high prevalence.”

“The determinants of the severity of deep vein thrombosis are complex, but rigorous studies such as this one provide sound evidence of a major genetic component,” said Tom White, Ph.D., Chief Scientific Officer at Celera. “Building on these studies and in line with our vision for personalized disease management, physicians and patients should eventually have access to blood tests that provide a measure of each individual’s respective genetic risk of developing this disease, which in turn will enable earlier therapeutic intervention.”

About Deep Vein Thrombosis

One in one thousand individuals develop deep vein thrombosis (DVT) or pulmonary embolism (PE) annually. DVT is clotting of the blood that blocks the blood flow in the veins, i.e. the blood vessels that transport the blood from the extremities and organs back to the heart. Parts of a clot that break off are transported through the heart to the lungs and cause pulmonary embolism. Six percent of patients die shortly after developing thrombosis, and 20 percent of patients die after a year. Of those who survive, more than a third will again develop thrombosis within 10 years. Venous thrombosis is caused by acquired and genetic risk factors. Acquired risk factors include age, hospitalization, cancer, surgery, pregnancy, hormone therapy, and air travel. Family and twin studies indicate that genetics accounts for about 60 percent of the risk of DVT and PE.

About the studies at the Leiden University Medical Center

The Leiden University Medical Center, with its Departments of Clinical Epidemiology and Thrombosis and Hemostasis, working together in the Einthoven Laboratory for Experimental Vascular Medicine has a long and highly successful track record in research on the causes of venous thrombosis. A series of risk factors for thrombosis, including factor V Leiden and prothrombin 20210A, were first identified by the Leiden group. In addition, the Leiden studies into thrombosis have focused on environmental determinants, such as oral contraceptive use and air travel, and particularly on the combined effect of genetic and environmental risk factors.

The SNPs described in this paper were associated with DVT in a total of 3,155 cases and 5,087 controls in 3 studies drawn from two large population-based studies: the Leiden Thrombophilia Study (LETS) and the Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis (MEGA study).

In the LETS study, 474 patients who were 70 years or younger and without a known malignancy were recruited, from three anticoagulation clinics in The Netherlands. For each patient, an age- and sex-matched control participant without a history of DVT was enrolled.

The MEGA study enrolled patients aged 18 to 70 years who presented with their first diagnosis of DVT or PE. Control subjects included partners of patients and random population control subjects frequency-matched on age and sex to the patient group. For the present analyses, the MEGA study was split to form 2 case-control samples: the first subset, MEGA-1, included 1,398 cases and 1,757 controls, and the remaining second subset MEGA-2 comprised of 1,314 cases and 2,877 controls.

This design was chosen to enable the replication of positive findings and avoid false positive findings, which is a major issue in studies in which very large numbers of variants are tested. The design with three large sample sets, including a quantification of this effect by the ‘false discovery rate,’ makes it highly likely that the findings are correct.

About Applera Corporation and Celera

Applera Corporation consists of two operating groups. Celera is a diagnostics business delivering personalized disease management through a combination of products and services incorporating proprietary discoveries. Berkeley HeartLab, a subsidiary of Celera, offers services to predict cardiovascular disease risk and optimize patient management. Celera also commercializes a wide range of molecular diagnostic products through its strategic alliance with Abbott and has licensed other relevant diagnostic technologies developed to provide personalized disease management in cancer and liver diseases. Applied Biosystems serves the life science industry and research community by developing and marketing instrument-based systems, consumables, software, and services. Customers use these tools to analyze nucleic acids (DNA and RNA), small molecules, and proteins to make scientific discoveries and develop new pharmaceuticals. Applied Biosystems’ products also serve the needs of some markets outside of life science research, which we refer to as “applied markets,” such as the fields of: human identity testing (forensic and paternity testing); biosecurity, which refers to products needed in response to the threat of biological terrorism and other malicious, accidental, and natural biological dangers; and quality and safety testing, such as testing required for food and pharmaceutical manufacturing. Applied Biosystems is headquartered in Foster City, CA, and reported sales of approximately $2.1 billion during fiscal 2007. Information about Applera Corporation, including reports and other information filed by the company with the Securities and Exchange Commission, is available at http://www.applera.com, or by telephoning 800.762.6923. Information about Celera is available at http://www.celera.com.

Forward-Looking Statements

Certain statements in this press release are forward-looking. These may be identified by the use of forward-looking words or phrases such as "believe," "expect," "plan," and "should," among others. These forward-looking statements are based on Applera Corporation’s current expectations. The Private Securities Litigation Reform Act of 1995 provides a "safe harbor" for such forward-looking statements. In order to comply with the terms of the safe harbor, Applera notes that a variety of factors could cause actual results and experience to differ materially from the anticipated results or other expectations expressed in such forward-looking statements. These factors include but are not limited to: (1) uncertainty in obtaining intellectual property protection for inventions made by Celera; (2) unproven ability of Celera to discover, develop, and commercialize diagnostic products based on findings from its disease association studies; (3) unproven use of genomics information to develop diagnostic products; (4) uncertainty as to whether Celera will be able to obtain any required regulatory clearance or approval of its diagnostic products; (5) uncertainty of market acceptance of its products, including the risk that its products will not be competitive with products offered by other companies, or that users will not be entitled to receive adequate reimbursement for its products from third party payors such as private insurance companies and government insurance plans; and (6) other factors that might be described from time to time in Applera’s filings with the Securities and Exchange Commission. All information in this press release is as of the date of the release, and Applera does not undertake any duty to update this information, including any forward-looking statements, unless required by law.

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