Individual and summed effects of high-risk genetic polymorphisms on recurrent cardiovascular events following ischemic heart disease.

AIMS: High-risk single nucleotide polymorphisms (SNPs) have been recently identified as risk factors for ischemic heart disease in large epidemiological and genome-wide association studies. However, their influence on prognosis remains uncertain. The aim of the study was to investigate the impact of previously identified SNPs and their joint effects in a genetic score (GS) on Major Adverse Cardiac Events (MACEs). METHODS AND RESULTS: High-throughput genotyping for 48 high-risk SNPs was performed in 498 patients (432 males; 57.4 ± 8.3 years) who were followed-up for 6.9 ± 3.4 years. First MACE-coronary-related death, nonfatal myocardial infarction, or myocardial revascularization- was the endpoint taken into consideration. A GS was obtained by summing the number of significant high-risk alleles associated to MACEs. One-hundred and nineteen patients (24%) had a MACE. The hazard ratio (HR) for SNPs with a significant difference in cumulative survival were: APOC3 -482C > T (HR = 1.7, 95% CI 1.01-3.0), MTHFR (HR = 1.5, 95% CI 1.02-2.2), NADHPH oxidase- p22-PHOX C242T (HR = 1.9, 95% CI 1.2-2.8), PON-2 (HR = 0.2, 95% CI 0.1-0.8), and SELP (HR = 0.6, 95% CI 0.4-0.8). The resulting GS predicted a 25% risk for MACEs per risk allele (HR = 1.25, 95% CI 1.1-1.4, p = 0.001). The highest HR for MACEs was found in patients in the top tertile (HR = 3.0, 95% CI 1.4-6.7, p = 0.0005) of the GS compared with those in the bottom tertile. CONCLUSION: Our findings show that high-risk SNPs may be used to create a useful GS that predicts MACEs in a secondary prevention setting, which in turn allows a better risk stratification