Medical Device Daily Contributing Writer

The identification of genetic variants associated with a higher risk of coronary artery disease will provide new insights into its causes, together with the possibility of developing novel ways of preventing it, predicting it and treating it.

Five studies published in the Feb. 8 issue of Nature Genetics detail genetic loci that are associated with a higher risk of heart attack. The findings will put the spotlight on proteins that researchers will want to investigate for their biological role, to find out how mutations or single nucleotide polymorphisms (SNPs) affect their functions.

Three of the studies included information from more than 20,000 patients with heart disease and involved a total of more than 33,000 samples. These studies, conducted by numerous international collaborators, including the Myocardial Infarction Genetics Consortium, the Wellcome Trust Case Consortium and the Cardiogenics Consortium, examined early-onset heart disease, on the grounds that early-onset myocardial infarction is more likely to have a genetic cause.

These three studies together found five new genetic loci associated with increased risk. In some cases, the risk of heart disease in individuals who had inherited the most unfavorable variants was twice that of those who had inherited the most favorable variants.

Jeanette Erdmann, head of the Molecular Genetics Laboratory at Lubeck University in Germany, and first author of one of the papers, told Medical Device Daily's sister publication, BioWorld International:"Our most important finding was the identification of a gene that has never before been linked to myocardial infarction. This discovery is likely to give us totally new insights into the pathogenesis of this disease."

Little is known about the function of the gene, which is called MRAS. It clearly has a role in vascular biology: it is highly expressed in vascular tissues such as the heart.

Erdmann and her collaborators are currently trying to find out more about its function, by studying mice that lack a functional copy of MRAS.

"Ultimately," Erdmann added,"if we can find out what is the underlying mechanism by which this gene causes disease, this information may lead us to new therapeutics for heart disease in years to come."

The paper by Erdmann and collaborating groups is titled:"New susceptibility locus for coronary artery disease on chromosome 3q22.3".

Similarly, little is known about the genes highlighted in the second study, conducted by the Myocardial Infarction Genetics Consortium (titled"Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants").

SNPs in one of these genes, called PHACTR1, have already been associated with an increased risk of coronary artery calcification, suggesting that mutant variants may directly lead to atherosclerosis.

A statement released by the Wellcome Trust Sanger Institute (Hinxton, UK), said the results suggest that nine of the variants now identified by these and earlier studies are, together, as good a predictor of myocardial infarction as other established factors, such as plasma low-density lipoprotein (LDL) cholesterol. One possibility in the future will be to examine the usefulness of a test across the best-validated SNPs for increased risk of myocardial infarction, the statement said.

The third study in this group reports that there is an increased risk of myocardial infarction associated with a cluster of variants spanning three genes on chromosome 6. One of these genes encodes apolipoprotein(a), the main protein component of lipoprotein(a), which is a known risk factor for coronary artery disease.

The fourth paper in the same issue of Nature Genetics shows that a variant in a gene called BRAP is associated with risk of myocardial infarction. BRAP binds to two other proteins that have been previously identified as risk factors for heart disease when mutated, and which may be involved in inflammation.

Finally, researchers from deCODE Genetics (Reykjavik, Iceland), report finding SNPs that increase levels of eosinophils in the bloodstream, after a genome-wide search in about 10,000 Icelanders. Eosinophils are white blood cells that fight infection by parasites and play a role in inflammation.

The deCODE team, collaborating with several international teams, then went on to show that one of these SNPs, located on chromosome 12q24, was associated with increased risk of myocardial infarction in more than 46,000 patients and controls from Iceland, New Zealand, Italy and the U.S. This SNP is in the SH2B3 gene, which encodes a protein known to be involved in inflammation and hematopoiesis.

Because eosinophils are known to play a role in asthma, the researchers then investigated if the SNPs that increase the numbers of eosinophils correlated with increased risk of asthma. After analyzing the genomes of more than 50,000 people with asthma and healthy controls, from the same countries listed above and from Germany, Sweden, Australia and South Korea, the team was able to establish that an SNP on chromosome 2q12 was associated with an increased risk of asthma, and that three other SNPs were associated with an increased risk of atopic asthma.

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