Author:

Keywords:

genetics, acute coronary syndrome, rs1333049, chromosome 9p21, 1101 Medical Biochemistry and Metabolomics, General & Internal Medicine, 3202 Clinical sciences

Abstract:

Background: Acute coronary syndrome (ACS) patients are at highest risk for recurrent myocardial infarction or cardiac death within 6 months. Recent genetic studies identified the rs1333049 variant at chromosome 9p21 locus as the major susceptibility gene for coronary artery disease (CAD) in the general population. It is not known whether this genetic variant also contributes to recurrent myocardial infarction (MI) or cardiac death following an ACS, and whether it could improve clinical prediction of adverse outcome. Materials and Methods: 2,942 patients with ACS and enrolled in the Global Registry of Acute Coronary Events (GRACE) program in 3 distinct populations (Belgium, UK and Poland) between May 2001 and December 2007, were prospectively followed for 6 months. In addition, 3,004 and 2,467 healthy individuals drawn from population-based studies in the UK (the WTCCC study) and Belgium (the Asklepios study), respectively, were used as control populations. Rs1333049, representing the chromosome 9p21 cardiovascular risk locus, was genotyped by MALDI-TOF. Results: 699 ACS patients were included in Belgium, 999 in the United Kingdom (UK) and 1,244 in Poland, totalling 2,942 patients with a median follow-up of 195 days (interquartile range [IQR]: 185-212). 170 patients developed a recurrent MI (5.8%) with a median time to recurrence of 12 days (IQR: 4-57) and 205 patients developed the combined endpoint of recurrent MI or cardiac death (7.0%), with a median time to event of 29 days (IQR 4-121). We first confirmed that the at-risk C allele of rs1333049 was associated with an index ACS in the UK and Belgian case-control studies (pooled odds ratio of 1.21, 95% confidence interval [CI] =1.10-1.32; P=4.6x10-5). This association was not confined to any of the ACS subtypes, and no association with the number of coronary vessels with >50% stenosis was seen. Subsequently and most interestingly, 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, after adjustment for age, gender, history of angina, prior myocardial infarction, diabetes, current smoking status, systolic blood pressure, heart rate, total cholesterol, initial serum creatinine level, elevated initial cardiac enzymes, ST segment depression, Killip class, percutaneous coronary intervention, coronary artery bypass graft, thrombolytics and participating country), and with the combined endpoint of 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 clinical GRACE risk score, a validated clinical risk tool to predict cumulative risk of recurrent MI or death, significantly improved risk classification for recurrent MI or cardiac death at 6 months (P=0.040), as calculated by the Integrated Discrimination Improvement method. Conclusions: In the GRACE Genetics Study, the 9p21 variant not only conferred a risk for primary ACS, but also for recurrent MI or cardiac death within 6 months, independently from known cardiovascular risk factors. In addition, the 9p21 variant improved the prediction of recurrent MI or cardiac death when added to the GRACE risk score. These data might be of importance for clinical risk prediction in ACS patients.