Discovery of two gene variants associated with increased risk for early heart attack

May 12 2006

Scientists at University of California - San Francisco (UCSF), Celera Genomics and The Cleveland Clinic have discovered two gene variants associated with a significantly increased risk for early heart attack, or myocardial infarction (MI).

One of the genes, known as VAMP8, normally expresses a protein essential for early stages of clotting. When clotting occurs in a coronary blood vessel, it can lead to heart attack. Knowing gene mutations that increase heart attack risk can help identify people at risk and clarify molecular changes involved in heart disease. This knowledge can lead to new potential drug targets to treat the disease.

The research will be reported in the July 2006 edition of Arteriosclerosis, Thrombosis, and Vascular Biology and is being made available online May 11, 2006.

A person with either of the two gene variants has about twice the risk of early heart attack as someone with neither, the research showed. The retrospective study analyzed clinical records and gene variations in more than 2,000 patients and controls in three independent investigations. All study participants were Caucasian, and the average age of heart attack among the cardiac patients was under 60.

Neither of the two genetic variants, known as single nucleotide polymorphisms or (SNPs), has previously been associated with heart attack. VAMP8 is involved in platelet aggregation. The other gene, HNRPUL1, encodes a protein involved in RNA activity.

Celera Genomics is an Applera Corporation business.

"This research and other large, carefully controlled studies can provide valuable insights into genetic contributions to early-onset heart attack," said John P. Kane, MD, PhD, professor of medicine at UCSF and associate director of UCSF's Cardiovascular Research Institute. "A number of studies have identified genes linked to increased heart attack risk, but many of the studies have been made with a single cohort of patients and have not been replicated. The new study involved three sequential cohorts, and applied a statistical analysis that increases the likelihood that these are indeed true associations."

Kane, a collaborator and a co-author on this study, was senior author on a paper published last fall with many of the Celera colleagues, identifying four gene variants associated with heart attacks. Kane and his UCSF colleagues have identified nine genes linked to increased heart attack risk thus far.

He suspects that the newly discovered variant of VAMP8 either speeds the clotting process, triggers it too early or allows clotting to continue too long.

"We are now eager to screen the population for people with two copies of this gene and study its action at the molecular level," Kane said. "VAMP 8 could be a target for a new drug."

Large scale studies like this one, with well-characterized samples from carefully selected patients, hold significant promise to enable the development of new diagnostics and targeted therapeutics, the scientists say.

"In order for genetic marker studies to translate into diagnostic tests with significant medical impact, discovery study results must be reproducible and applicable to a wide group of people," said Tom White, PhD, chief scientific officer at Celera Genomics. "Too often, when new markers are reported, the disease association cannot be confirmed because the study used a small sample set. In addition, a spurious disease association could be found due to chance alone if a large number of SNPs are not tested."

The size of this study and the identification of VAMP8, coupled with other prospective studies of the general population underway at Celera, are providing valuable insight toward the development of a "Genetic Risk Score" that is expected to identify individuals at elevated risk for heart disease, White said.

Celera evaluated DNA samples from more than 2,000 individuals in three studies to compare patterns of genetic variation in people with a history of early-onset MI to those with no history of heart disease. The results were significant in all three studies.

The key finding of the study was that variants of the VAMP 8 and HNRPUL1 genes were associated with early-onset MI, and the same variants were associated with risk in all three studies. Each of these gene variants individually confers an increased risk for MI that is comparable to conventional risk factors such as smoking, high blood pressure and elevated cholesterol levels.

These genetic markers were identified through a genome-wide study of 11,647 single SNPs in 7,136 genes. The study focused on SNPs that could influence gene function in order to increase the likelihood of identifying disease-causing gene variants. These were tested for association with early-onset MI in three case-control studies with a total of 821 cases and 1,200 controls.

Two of the samples drew on the very large and complete collection of clinical records, blood samples, DNA analysis and other records of more than 27,000 heart disease patients stored and studied as part of the Genomics Resource in Arteriosclerosis at UCSF's Cardiovascular Research Institute (CVRI). The third sample comes from a collection at The Cleveland Clinic

The study is a collaboration of UCSF, Celera, The Cleveland Clinic Foundation, Case Western Reserve University and Brigham Young University.

First author on the paper is Dov Shiffman, PhD, senior staff scientist at Celera. Co-authors at Celera are James J. Devlin, PhD, director of cardiovascular research, and Charles Rowland, Judy Louie, May Luke, Lance Bare , Joel Bolnick, Bradford Young and Joseph Catanese.

Colleagues and co-authors with Kane at UCSF's CVRI are Mary Malloy, MD, UCSF professor of medicine and pediatrics, and Clive Pullinger, PhD, adjunct associate professor of genetics. Other co-authors on the paper are Stephen Ellis, MD, director of the Sones Cardiac Department of Cardiovascular Medicine and professor of medicine at The Cleveland Clinic, Charles Stiggins at Brigham Young University, and Eric Topol at Case Western Reserve University.