BioWorld International Correspondent
LONDON - A genetic variant has been identified that can increase the risk of myocardial infarction (MI) by more than 60 percent among people who have two copies of it.
The variant, a single nucleotide polymorphism (SNP) that has been tracked down by scientists at DeCode Genetics in Iceland, with collaborators in the U.S., will form the basis for a test that soon will be available to assess someone's inherited risk of MI.
Drug development also could benefit. Knowledge of where the SNP lies in the genome may help in pinpointing targets for drugs to prevent MI, the researchers predict.
Kari Stefansson, chief executive officer of DeCode Genetics of Reykjavik, told BioWorld International, "This is a pretty exciting discovery. This variant has a very large effect, on a disease that causes many deaths in our society."
A paper reporting the finding was published online by Sciencexpress May 3. Its title is "A Common Variant on Chromosome 9p21 Affects the Risk of Myocardial Infarction".
DeCode Genetics is planning to make a test available "later this year," Stefansson said. That would make it possible to send off a blood sample to a reference laboratory to find out information about someone's genetic predisposition to coronary artery disease.
The company also is working with Illumina Inc., of San Diego, to develop a diagnostic kit that clinicians could use on site. Such a kit would use "the simplest of SNP genotyping technology," Stefansson said.
DeCode estimates that the variant accounts for approximately one-fifth of the incidence of myocardial infarction in populations of European origin, and nearly one-third of early-onset cases, making it one of the most significant genetic risk factors found to date for heart attack.
Stefansson and his colleagues began by identifying SNPs in Icelandic patients with MI, and looked at the disease compared with controls who did not have a history of coronary heart disease. They also used data from the international HapMap Project to identify additional SNPs.
They then focused on a single SNP, which had the highest association with myocardial infarction. The SNP, called rs10757278, lies on chromosome 9p21, close to two tumor suppressor genes called CDKN2A and CDKN2B.
The study showed that the association of this SNP with MI held true for three cohorts of European descent from Philadelphia, Atlanta and Durham, N.C. Of more than 17,000 patients and control subjects in the study, more than 20 percent carried two copies of the variant, corresponding to a more than 60 percent increased risk of heart attack compared to those without the variant.
In early onset cases - men and women who suffered a heart attack before the ages of 50 and 60, respectively - carrying two copies of the variant meant they had double the risk compared to those who had no copies. Stefansson said: "For men over the age of 40 years, the lifetime risk of a heart attack is already 49 percent. But when you find a variant that increases that risk by over 50 percent, it means that the absolute risk of disease if you have that variant is very large. The variant is also strongly associated with early-onset myocardial infarction. This is important in terms of the clinical utility of this finding, as the clinical significance of a risk is much greater when it is conferred to the person at an early age."
As well as developing new tests, DeCode scientists will be trying to find out by what mechanism the genetic variant confers an increased risk. "We want to better understand the biochemical pathways that are affected by this variant," Stefansson said. Interestingly, the proteins encoded by the two tumor suppressor genes that lie close to SNP rs10757278 are involved in cell proliferation, cell aging and apoptosis. The processes are important in atherogenesis, the build-up of fatty plaques within arteries that eventually leads to coronary artery disease and myocardial infarction.
Stefansson said: "Our current hypothesis is that this variant mediates the risk by attacking the expression of these oncogenes. We are investigating whether this is correct. We are not interested only in new diagnostics - this kind of work could also lead to the identification of new drug targets for the development of compounds that could counteract the biological effects of these variants and so prevent heart attack."