ACC 2009: 9p21 Variant Predicts Long-Term Risk of Revascularization

April 09, 2009

April 8, 2009 (Orlando, Florida) — People who suffered an early-onset MI were more likely to undergo future revascularization during 20 years of follow-up if they carried a particular genetic variant on chromosome 9p21, according to a new Italian study reported at the American College of Cardiology 2009 Scientific Sessions last week.

"None of us could believe that one single genetic variant could have such a big biological influence," said Dr Diego Ardissino (University of Parma, Italy), who presented the findings during a late-breaking clinical-trials session. "Surprisingly, we showed that there was a strong influence of this genetic variation on the progression of coronary atherosclerosis, which translated into the probability of these patients undergoing new percutaneous coronary intervention or bypass surgery."

Identification of the genetic variant could help doctors in decisions about treatment following an MI, Ardissino said. "My sincere hope is that this could be the first study that brings genetics into the clinical arena of ischemic heart disease."

Experts not connected with the work said it added to previous research in this field. "These findings extend the broad replication of 9p21 sequence variants for susceptibility for coronary artery disease by nicely demonstrating a 'dose-response'-like effect for the need for subsequent coronary revascularization and progression of atherosclerotic disease," said Dr Eric Topol (Scripps Translational Research Institute, La Jolla, CA).

And Dr Nilesh Samani (University of Leicester, UK), told heartwire : "This is an interesting study--there are not many studies that have followed people like this. It tells us a little more about the biology of what this locus does--it appears to affect the development or progression of atherosclerosis rather than the risk of MI directly."

However, Samani is not convinced that these results will necessarily help to predict future events. "The clinical utility of these findings still remains to be determined," he noted.

rs 1333040 Variant of 9p21 Had Strongest Association With Early-Onset MI

At the meeting, Ardissino said that genomewide association studies have shown variants in chromosomal region 9p21.3 to be convincingly associated with ischemic heart disease, but that it was not known whether these variants might influence prognosis after an acute event.

The influence of genetic factors is greater when the coronary event occurs at a young age, so early MI is an ideal condition for assessing the role of newly discovered genetic variants associated with the disease, he explained.

In their trial--which was prospective but observational and nonrandomized--Ardissino and colleagues examined 2000 patients who had an MI before the age of 45 who had undergone coronary angiography at the index event and 2000 age- and sex-matched controls, the cross-sectional part of the study.

They then followed 1508 of the 2000 patients who had experienced early MI--these 1508 were the ones who did not undergo primary PCI at the time of the index event--for 20 years in the longitudinal part of the study.

Five allelic variants of 9p21.3 were tested in the cross-sectional part of the study--all were associated with early-onset MI, with the highest odds ratio (OR) found for the rs 1333040 variant.

Similar Magnitude of Association to Obesity and Hyperlipidemia

During longitudinal follow-up, there were 683 major cardiovascular events among the 1508 patients, including 77 cardiovascular deaths (5.1%), 223 new MIs (14.8%), and 383 coronary artery revascularizations (25.4%).

The rs 1333040 variant significantly affected (p=0.01) the occurrence of cardiovascular events during follow-up, with a relative risk of 1.19 for those who were heterozygous for this risk allele and 1.41 for homozygous carriers.

This effect was mainly explained by the significant influence of the genotype on the risk of coronary revascularization (p=0.00015).

Ardissino said the magnitude of risk is of the same order as that for obesity and hypercholesterolemia.