Aims: A pooled analysis of 14 genome-wide association studies revealed 23 susceptibility loci for coronary artery disease (CAD), thereby providing the most comprehensive genetic blueprint of CAD susceptibility. Here, we evaluated whether these 23 loci also predispose to recurrent myocardial infarction (MI) or cardiac death following an acute coronary syndrome (ACS). Methods and results: A total of 2099 ACS patients enrolled in the Global Registry of Acute Coronary Events (GRACE) UK-Belgian study were prospectively followed for a median of 5 years (1668 days). C-allele carriers of the rs579459 variant, which is located upstream of the ABO gene and correlates with blood group A, were independently associated with recurrent MI [multivariable-adjusted hazard ratio (HR) 2.25, CI = 1.37-3.71; P = 0.001] and with recurrent MI or cardiac death [multivariable-adjusted (HR) 1.80, CI = 1.09-2.95; P = 0.021] within 5 years after an index ACS. The association of rs579459 was replicated in 1250 Polish patients with 6 months follow-up after an index ACS [multivariable-adjusted (HR) 2.70, CI = 1.26-5.82; P = 0.011 for recurrent MI]. Addition of rs579459 to a prediction model of 17 clinical risk factors improved risk classification for recurrent MI or cardiac death at 6 months as calculated by the integrated discrimination improvement method (P = 0.037), but not by C-statistics (P = 0.096). Conclusion: In this observational study, rs579459 was independently associated with adverse cardiac outcome after ACS. A weak improvement in clinical risk prediction was also observed, suggesting that rs579459 should be further tested as a potentially relevant contributor to risk prediction models for adverse outcome following ACS.

AIMS: Recent genetic studies identified the rs1333049 variant on chromosome 9p21 as a major susceptibility locus for coronary artery disease and myocardial infarction (MI). Here, we evaluated whether this variant also contributes to recurrent MI or cardiac death following an acute coronary syndrome (ACS). METHODS AND RESULTS: A total of 3247 patients with ACS enrolled in the Global Registry of Acute Coronary Events (GRACE) in three distinct populations (UK, Belgium and Poland) were prospectively followed for 6 months and genotyped for rs1333049, in addition to 3004 and 2467 healthy controls from the UK and Belgium. After having confirmed that the at-risk C allele of rs1333049 was associated with index ACS in the UK and Belgian populations, we found that the rs1333049 at-risk C allele was significantly and independently associated with recurrent MI [age- and gender-adjusted hazard ratio (HR) 1.48, CI = 1.00-2.19, P = 0.048; and multivariable-adjusted HR 1.47, CI = 0.99-2.18; P = 0.053] and with recurrent MI or cardiac death (age- and gender-adjusted HR 1.58, CI = 1.00-2.48; P = 0.045; and multivariable adjusted HR 1.49, CI = 1.03-1.98; P = 0.028) within 6 months after an index ACS. Inclusion of rs1333049 into the GRACE risk score significantly improved classification for recurrent MI or cardiac death (P = 0.040), as calculated by the integrated discrimination improvement method. CONCLUSION: In this large observational study, the 9p21 variant was independently associated with adverse cardiac outcome after ACS.