Sanger Researchers, Collaborators Uncover Warfarin Response Genes in Large GWAS
In a genome-wide association study of more than 1,500 Swedish individuals, researchers from the Wellcome Trust Sanger Institute and elsewhere have uncovered three SNPs associated with warfarin dose response.
Based on their GWAS study of 1,523 individuals in the Warfarin Genetics cohort, the team identified two SNPs in well-known warfarin response genes — VKORC1 and CYP2C9 — as well as a SNP that changed the coding sequence of a third gene, CYP4F2, Sanger statistical geneticist Ralph McGinnis told reporters last week at the American Society of Human Genetics meeting in Philadelphia.
Others have implicated CYP4F2 as having a role in warfarin metabolism, McGinnis said, but it has not been previously detected in large-scale dose response studies.
The researchers verified these results in a smaller study of nearly 600 Swedes.
Because there is such a wide variation in the warfarin dose required to achieve a targeted amount of blood thinning, researchers are using GWAS in an effort to find genetic variants influencing dose response. This is not the first such study, but, McGinnis said it is the largest to date.
McGinnis and his team concluded that variations in VKORC1, CYP2C9, and CYP4F2 can predict 29 percent, 11 percent, and 1.5 percent of the warfarin response, respectively. Together with factors such as age and gender, which account for roughly 15 percent of the variation in warfarin response, the team noted that it is now possible to predict about half of the warfarin response variation observed in treated individuals.
The researchers also made predictions about the sorts of genetic variations that may have evaded their detection. For instance, McGinnis noted that SNPs commonly found in the general population may influence two to three percent of the variation in warfarin response. On the other hand, he added, there may be low-frequency SNPs — carried by fewer than ten percent of individuals — that influence around five percent of the variation.
In addition, McGinnis said, the researchers may have missed other genetic variants such as copy number variations and inversions.
Down the road, the researchers hope to gain even more insight into the genetics of warfarin response. For example, McGinnis noted that they are interested in finding genetic variants that can help predict adverse warfarin response events, such as a sometimes-fatal severe bleeding condition that affects a small percentage of those taking the drug. These variants may not necessarily be the same as those influencing dose response, he added.
While McGinnis stressed that he is a research scientist and not a clinician, he expressed optimism that such genetic approaches will improve warfarin treatment, decreasing over- and under-dosing and adverse events. “This is potentially an important advance,” he said. “Our GWAS lays out what the genetic landscape looks like.”
— Andrea Anderson, GenomeWeb Daily News Reporter
Epigenomics, Abbott Expand MDx Pact
Epigenomics and the Abbott Molecular business of Abbott have expanded their collaboration and amended an earlier licensing deal aimed at developing molecular diagnostic products.
The firms began collaborating in September 2007 on development of a colorectal cancer diagnostic based on Epigenomics' intellectual property.
Under the amended deal announced this week, Abbott has obtained additional non-exclusive licenses to Epigenomics’ proprietary DNA methylation technology to develop and commercialize a blood test for colorectal cancer detection based on Epigenomics’ Septin 9 biomarker.
In addition, Abbott gains access to blood samples collected in the ongoing Presept clinical study sponsored by Epigenomics. Abbott will use the samples for clinical validation of a Septin 9 in vitro diagnostic test, which the firms intend to file for US regulatory clearance in 2010. They also plan to release a CE-marked test, which will run on Abbott’s m2000 molecular diagnostics instrument, next year.
In return for the license, Abbott will pay Epigenomics a technology license fee, certain milestone payments, and reimbursements associated with the Presept study, as well as royalties based on sales of the Septin 9 test.
C-Path Gets $9M Award from Arizona Science Foundation
Science Foundation Arizona has awarded $9 million to the Critical Path Institute to support the institute’s mission to develop new tests that could help accelerate the process of getting new drugs and therapies to the public, C-Path said last week.
A Tucson-based non-profit, C-Path aims to lower the high failure rate of new drugs by “improving the current slow and unreliable process, thereby saving lives and billions of dollars each year,” according to a statement.
Specifically, the institute has a goal of improving the success rate at which new medicines that make it to human trials reach the market. C-Path said this success rate is currently 5 percent and that it hopes to move that to 95 percent. The institute also wants to speed that process up so that it takes less than three years.
The institute was formed in 2005 as one prong of the US Food and Drug Administration’s Critical Path Initiative.
The Science Foundation Arizona is a public-private partnership created in 2006 to support a range of technology development programs in Arizona.
“In the United States alone, the annual cost of caring for patients with just one disease, Alzheimer’s, is $150 billion, a staggering figure that is projected to reach $1 trillion, or 8 percent of today’s total US economy,” C-Path CEO and President Raymond Woosley said in a statement. “Without breakthroughs, we face a medical tsunami of healthcare costs posing immense economic and social threats."
C-Path said it has struck partnerships with a number of drug companies, including those with presences in Arizona, such as Roche’s Ventana Medical Systems, Sanofi-Aventis, and Merck affiliate High Throughput Genomics.
International Cancer Genome Consortium Announces Eight New Projects
The International Cancer Genome Consortium announced this week that eight countries and 11 funding agencies have signed on to participate in comprehensive analyses of the genomic changes underlying eight types of cancer.
The new projects are designed to complement the Cancer Genome Atlas pilot projects on brain, lung, and ovarian cancers. The goal is to map the genetic and genomic changes occurring in different types and stages of cancer in an effort to understand disease biology and develop new preventive strategies, diagnostics, and therapies.
Each participating organization will tackle one or more types of cancer using samples collected from about 500 individuals. Data collection and analysis will be standardized and is to follow ICGC guidelines released in April. Participating countries and agencies will also use common informed consent and ethical oversight standards. The estimated cost of each project is $20 million.
The ICGC anticipates additional countries and groups joining the effort through other projects in the next decade and eventually plans to study 50 types of cancer. Overall, the ICGC expects to generate some 25,000 times more data than the Human Genome Project.
ICGC data will be made available to the research community freely and rapidly, and participants are expected to agree that they will not file patents or make intellectual property claims on ICGC project primary data.
The new ICGC projects include:
- An Australian study funded by the National Health and Medical Research Council (the tumor type to has not yet been announced)
- A Canadian study funded by the Ontario Institute for Cancer Research on pancreatic cancer
- A Chinese study funded by the Chinese Cancer Genome Consortium on stomach cancer
- French studies on alcohol-related liver cancer and HER2-positive breast cancers funded by the Institut National du Cancer
- An Indian study on oral cavity cancer funded by the Department of Biotechnology Ministry of Science and Technology
- A study of virus-related liver cancer in Japan, funded by RIKEN, the National Cancer Center, and the National Institute of Biomedical Innovation
- A Spanish study of chronic lymphocytic leukemia funded by the Spanish Ministry of Science and Innovation
- A study of several breast-cancer subtypes in the UK, funded by the Wellcome Trust and the Wellcome Trust Sanger Institute