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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.To perform an extensive validation of putative genetic risk factors for ACS.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.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.Of 85 variants tested, only 1 putative risk genotype (−455 promoter variant in β-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).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.