Study identifies gene variants associated with early heart attack

WASHINGTON, Feb. 8 (Chinese media) -- A study available here

on Sunday of genetic factors associated with heart attacks has identified nine

genetic regions that appear to increase the risk for early-onset myocardial

infarction.

The largest study ever completed in this field from

the Myocardial Infarction Genetics Consortium, based on information from a total

of 26,000 individuals in 10 countries, will appear in Nature Genetics.

"For several decades, it has been known that the risk

for heart attack -- the leading cause of death and disability in the U.S.

--clusters in families and that some of this familial clustering is due to

differences in DNA sequence," says Sekar Kathiresan, director of Preventive

Cardiology at Massachusetts General Hospital (MGH) and corresponding author of

the Nature Genetics report. "We set out to find specific, single-letter

differences in the genome, what are called single-nucleotide polomorphisms

(SNPs),that may be responsible for an increased familial risk for heart attack."

Groundwork for the current study was laid more than

10 years ago when co-author Christopher O'Donnell, now based at the Framingham

Heart Study, began to gather data on patients treated at the MGH for early-onset

heart attack -- men under 50 and women under 60. Kathiresan soon joined the

project, and in 2006 they formed the Myocardial Infarction Genetics Consortium

along with David Altshuler, of the MGH Center for Human Genetic Research and the

Broad Institute of MIT and Harvard, eventually involving six groups around the

world that had collected samples on a total of about 3,000 early-onset heart

attack patients and 3,000 healthy controls.

The current study took advantage of several

scientific tools developed over the past decade. These include the International

Haplotype Map, a comprehensive map of SNPs across the genome; genotyping arrays

that allow screening of hundreds of thousands of SNPs at once; and a gene chip

developed by Altshuler's team that can simultaneously screen for SNPs and for

copy-number variants --deletions or duplications of gene segments, a type of

change associated with several disease categories. After analysis of the

consortium's samples identified SNPs that could be associated with heart attack

risk, the researchers ran replication screens in three independent groups of

samples, resulting in a total of 13,000 heart attack patients and 13,000

controls.

Significant associations with the risk of early-onset

heart attacks were found for common SNPs in nine genetic regions. Three of those

associations with heart attack risk were identified for the first time; and one

of the novel regions also had been found, in a separate study by O'Donnell, to

promote the buildup of atherosclerotic plaque in the coronary arteries. To

analyze the effect of inheriting several risk-associated SNPs, participants were

assigned a genotype score, which revealed that those with the highest number of

risk-associated variants had more than twice the risk of an early-onset heart

attack as those with the fewest. No risk associations were identified with

copy-number variants.

Although the increased risk associated with

individual SNPs is small, knowledge gained from the association could prove

extremely valuable.

"One of the known variants we identified is at a gene

called PCSK9, which was originally identified in 2003," explains Kathiresan, an

assistant professor of Medicine at Harvard Medical School. "Extensive study of

that gene region has led to significant insight into the biology of

atherosclerosis and heart attack and to efforts to develop targeted drugs. We

are optimistic that investigating the mechanics of the newly mapped variants

could yield similar insights. And since we already have effective ways to reduce

heart-attack risk, individuals at higher genetic risk may benefit from earlier

intervention, something that needs to be tested in future studies."