Separate genetic variants discovered for CAD and MI

January 14, 2011

Philadelphia, PA - Researchers have discovered two new genetic variants, one predisposing to the development of coronary atherosclerosis and the other predisposing to subsequent plaque rupture and acute MI[1].

In a paper published online in the Lancet on January 15, 2010, a team led by Dr Muredach Reilly (University of Pennsylvania, Philadelphia) concludes that "the relation to specific CAD phenotypes might modify how novel loci are applied in personalized risk assessment and used in the development of novel therapies for CAD."

Commenting for heartwire, Dr Eric Topol (Scripps Health, La Jolla, CA) described the latest findings as "interesting." He said: "A nice contribution here, by virtue of having angiographic data, was the dissection of the two phenotypes for CAD and MI (which have all too often been lumped together). Both of the new variants are common and carry a modest 20% to 30% increased risk [per risk allele] for either CAD or MI, respectively."

Topol noted that this work adds to the extensive genomewide association studies of CAD/MI, "but most of the heritability (>90%) for these conditions is left unexplained. . . . There is much more work to be done to get that sorted out." He added: "Also, unlike the previous SORT -1 story, the report does not provide any insights on the 'culprit' functional genomic variant implicated in either case, so that requires some extensive 'drill down,' as well."

Unique factors

In the paper, the authors note that since all patients with plaque rupture or MI have coronary atherosclerosis, but only a few with coronary atherosclerosis develop MI, unique factors—some genetic—are likely to predispose to plaque rupture or MI in coronary atherosclerosis.

They report two genomewide association studies designed to address the hypothesis that genetic factors predisposing to MI in patients with coronary atherosclerosis are distinct from those that associate with the presence of coronary atherosclerosis. They used coronary angiography to ascertain whether an individual had coronary artery disease, which allows discrimination of risk alleles for plaque rupture and MI from those for coronary atherosclerosis.

For the first study, Reilly and colleagues compared 12 393 individuals with coronary artery disease with 7383 without any stenosis on angiography (controls) and identified a new locus, ADAMTS7, to be a common genetic risk factor for coronary atherosclerosis, with a 19% increased risk for carriers.

Blood group O protective

In the other study, the researchers compared 5783 patients with coronary artery disease and MI (cases) with 3644 individuals with coronary artery disease but free from MI (controls) to identify variants associated with coronary thrombosis but not atherosclerosis. They found that blood group ABO single nucleotide polymorphisms (SNPs) were associated with MI in the context of coronary artery disease. The ABO association was attributable to the glycotransferase-deficient enzyme that encodes the ABO blood group O phenotype previously proposed to protect against MI. They say: "Discovery of ABO as the top locus for myocardial infarction in patients with angiographic CAD is notable, in view of decades of work suggesting a relation between ABO blood groups and both thrombosis and coronary heart disease."

Reilly told heart wire that "our study supports prior research showing that having ABO blood group O may reduce the risk of heart attack by up to 20%. This is a fairly modest effect, so this effect needs to be considered in combination with other traditional risk factors. Our study specifically suggests that it will be most useful when used in patients who have established coronary plaques."

Addressing the issue of how ABO blood groups are related to MI, Reilly explained that the ABO protein is an enzyme (glycotransferase) that coats cells with certain types of sugar molecules, and the ABO blood group O results in loss of function of the ABO enzyme, which reduces the clotting activity of Von Willebrand factor. "Although much work needs to be done, our work raises the question of whether drugs that block ABO enzyme activity or certain sugar modifications of proteins or Von Willebrand factor might be developed to reduce heart attack."

Adding to current genetic knowledge

In an accompanying editorial[2], Drs Luca Lotta and Flora Peyvandi (University of Milan, Italy) explain that in coronary disease, nine genomewide studies have found 14 chromosomal loci at which one or more common SNPs are associated with coronary artery disease or MI, with almost all these studies implicating the 9p21.3 locus, which is therefore considered the most widely and consistently replicated genetic risk factor for coronary artery disease and MI. But still much of the genetic risk that underlies the development of coronary artery disease and MI is unexplained by common risk SNPs.

They point out that most of the risk SNPs for coronary artery disease and MI identified by previous genomewide association studies were associated with coronary atherosclerosis rather than with thrombosis.

Reilly explained to heart wire that ADAMTS7 is similar to 9p21, in that they both appear to be involved in the development of atherosclerosis. "But all of the new genetic risk factors, including 9p21 and ADAMTS7, have quite modest effects; individually they may increase risk by 5% to 20%. Most likely, therefore, we will have to measure combinations of these genetic factors to produce a genetic risk score to provide real value in clinical practice," he said.

Steering new drug development

In terms of developing new drugs for heart disease, Reilly said that the evidence so far suggests that blocking ADAMTS7 should be protective, so this should be a focus for drug development. In contrast, it is not yet clear what the actual gene or mechanism for the 9p21 locus is; this represents an ongoing barrier to designing drugs for heart disease related to this locus.

He notes that ADAMTS7 belongs to a specific class of enzymes, so it should be possible to screen for small molecules that block its action and start a drug development program. He adds that "blocking the ABO enzyme may be more challenging as it may alter immune responses, but the concept of modifying specific targets of ABO or sugar coating proteins may lead to completely new treatments for heart attacks."

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