Study fails to verify gene variations as risk factors for certain cardiovascular problems

April 10, 2007

New research has failed to confirm findings from smaller studies that 85 gene variations are associated with an increased risk for acute coronary syndromes (ACS), which includes heart attack and a type of angina, according to a study in the April 11 issue of JAMA.

Previous studies have identified a number of genetic variations as potential cardiovascular risk factors, but few, if any, have been established definitively. "Before use in clinical care, potential genetic risk factors would ideally be replicated en masse in large, well-characterized patient populations. To date, no such comprehensive validation of genetic variants potentially associated with ACS or atherosclerosis has been reported," the authors write.

Thomas M. Morgan M.D., formerly of the Yale University School of Medicine, New Haven, Conn., and colleagues conducted a study to validate genetic risk factors for ACS. The researchers identified genetic variants previously reported as significant susceptibility factors for atherosclerosis or ACS through a literature search of published articles. This study included 811 patients with ACS and 650 age- and sex-matched controls who were genotyped for 85 variants in 70 genes and attempted to replicate previously reported associations.

Of 85 variants tested, only one of the gene variants was nominally statistically significant. Only four additional genes were positive in model-free analysis. Neither number of associations was more frequent than expected by chance, given the number of comparisons. Only 41 of 84 predefined risk variants were even marginally more frequent in cases than in controls (with 1 tie).

"We were unable to confirm as risk factors for ACS 85 genetic variants because none were unequivocally validated in this large case-control study of 1,461 participants," the authors write. "We therefore conclude that our findings, in this large sample of well-characterized ACS patients and controls, cannot support that this panel of gene variants contains bona fide ACS risk factors."

"Our findings come at a critical juncture in complex disease genetics. Some cardiovascular gene variants included in our study can already be ordered clinically, for indications that explicitly include possible ACS risk. However, our findings suggest that such clinical genetic testing is premature and underscore the importance of robust replication studies of reported associations prior to their application to clinical care."
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(JAMA. 2007;297:1551-1561. Available pre-embargo to the media at www.jamamedia.org)

Editor's Note: Dr. Morgan is now with the Washington University School of Medicine, St. Louis. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

For More Information: Contact the JAMA/Archives Media Relations Department at 312-464-JAMA or email: mediarelations@jama-archives.org.

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