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


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.


CONCLUSIONS
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.
CNR Istituto di Fisiologia Clinica, Pisa, Italy. andreas@ifc.cnr.it
Maria Grazia
MG
Andreassi
Daniel
D
Adlerstein
Clara
C
Carpeggiani
Erlet
E
Shehi
Sonia
S
Fantinato
Elisa
E
Ghezzi
Nicoletta
N
Botto
Michele
M
Coceani
Antonio
A
L'abbate
D000368:Aged; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D018572:Disease-Free Survival; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D007558:Italy / Q000453:epidemiology; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics / Q000401:mortality / Q000628:therapy; D017202:Myocardial Ischemia / Q000150:complications / Q000235:genetics* / Q000401:mortality; D009204:Myocardial Revascularization; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D012008:Recurrence; D018570:Risk Assessment; D012307:Risk Factors; D055502:Secondary Prevention; D013997:Time Factors