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Thomas M. Morgan, MD; Harlan M. Krumholz, MD, MS; Richard P. Lifton, MD, PhD; John A. Spertus, MD, MPH

JAMA. 2007;297:1551-1561.

Context  Given the numerous, yet inconsistent, reports of genetic variants being associated with acute coronary syndromes (ACS), there is a need for comprehensive validation of ACS susceptibility genotypes.

Objective  To perform an extensive validation of putative genetic risk factors for ACS.

Design, Setting, and Participants  Through a systematic literature search of articles published before March 10, 2005, we identified genetic variants previously reported as significant susceptibility factors for atherosclerosis or ACS. Restricting our analysis to white patients to reduce confounding from racial admixture, we identifed 811 patients who presented from March 2001 through June 2003 with ACS at 2 Kansas City, Mo, university-affiliated hospitals. During 2005-2006, we genotyped the 811 patients along with 650 age- and sex-matched controls for 85 variants in 70 genes and attempted to replicate previously reported associations. We further explored possible associations without prior assumption of specific risk models and used the Sign test to search for weak associations.

Main Outcome Measures  Compare each prespecified gene variant associated with ACS risk among cases and controls. A surplus of associations would imply that some are associated with ACS.

Results  Of 85 variants tested, only 1 putative risk genotype (–455 promoter variant in -fibrinogen) was nominally statistically significant (P = .03). Only 4 additional genes were positive in model-free analysis. Neither number of associations was more frequent than expected by chance, given the number of comparisons. Finally, only 41 of 84 predefined risk variants were even marginally more frequent in cases than in controls (with 1 tie), representing a 48.8% "win rate" (95% confidence interval, 38.1%-59.5%) for the collective risk genotypes (P = .91, Sign test).

Conclusions  Our null results provide no support for the hypothesis that any of the 85 genetic variants tested is a susceptibility factor for ACS. These results emphasize the need for robust replication of putative genetic risk factors before their introduction into clinical care.

Author Affiliations: Department of Genetics, Howard Hughes Medical Institute (Drs Morgan and Lifton), Robert Wood Johnson Clinical Scholars Program and Department of Internal Medicine (Dr Krumholz), Yale University School of Medicine, New Haven, Conn, and Mid-America Heart Institute and University of Missouri-Kansas City, Mo (Dr Spertus). Dr Morgan is now with the Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St Louis, Mo.

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