New Genomic Markers Associated with Risk of Heart Disease and Early Heart Attack

Five short reports published simultaneously by the journal Nature Genetics have for the first time identified clusters of genetic markers associated with heart attack and coronary heart disease. In one of the reports, from the largest ever study of its kind, the Myocardial Infarction Genetics Consortium identified nine precise genes associated with an increased risk of infarction (MI), three of them newly discovered; the investigators said that these nine gene variants "identify 20% of the population at 2.25-fold increased risk for MI".

This study set out to find "single letter" differences in gene sequences (known as single nucleotide polymorphisms, SNPs) in 26,000 individuals in ten countries in order to explain why the pattern of early onset heart attack is often clustered in families. Using recently developed techniques for comparing an individual's gene sequences with reference sequences, the researchers found significant associations with risk of early heart attack for common SNPs in nine genetic regions.

One of the investigators, Dr Sekar Kathiresan from the Consortium, said, "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."

Other studies reported in the journal included one from the Universite Pierre et Marie Curie in Paris which newly identified a new gene cluster (of three genes) as a possible susceptibility site for coronary artery disease. This study, unlike the first, compared individual and reference groups of SNPs (known as haplotypes).

Adding the studies together, the results suggest the identification of several new gene sites (loci) which appear to affect the risk of coronary heart disease and early heart attack. So far, the added risk from any abnormality in these gene sequences seems small, but the genomic association seems clear. Furthermore, there seems no specific theme to the SNPs involved, suggesting that, while the expression (phenotype) of heart disease and infarction may be consistent, the pathways of risk may be multiple at the genetic level.

Speaking on behalf of the European Society of Cardiology, Professor Thomas Lüscher from the University of Zurich in Switzerland agreed that risk stratification via genetic pathways in coronary heart disease is an important future approach, but warned that these latest results reported in Nature Genetics were from case-control and not prospective studies. He said: "The next stage is to confirm the results in a prospective cohort to find out if they really do provide the same sort of prognostic information we already have from the classical risk factors."

Professor Lüscher added that there is also a need to discover what the SNPs and gene clusters are doing biologically. "We have to find out what's going on at the cellular level as well," he said. "Several of the SNPs have been linked to cholesterol metabolism in the liver, but there are some new ones here associated with coronary artery disease and atherosclerosis.

"This is important work but we need further evidence with statistical power and biological plausibility."

Reference
1. See Myocardial Infarction Genetics Consortium. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat Genet 2009; DOI: 10.1038/ng.327.

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