Abstract 17262: Evaluation of the Effect of Interleukin 18 Associated Genetic Polymorphisms on Risk of Cardiovascular Events in Patients With Acute Coronary Syndrome
Background: Interleukin 18 (IL-18) concentrations are increased in patients with acute coronary syndromes (ACS). Even though IL-18 has been associated with poor disease outcome, a clear causal effect of IL-18 on cardiovascular events has not been demonstrated. We have recently performed a genome-wide association study (GWAS) of IL-18 levels and identified seven independent SNPs, of which some are located in genes known to regulate IL-18 production (IL18, NLRC4 and CARD18).
Methods: Baseline plasma IL-18 levels were measured (using MBL human IL-18 ELISA) in 16,633 ACS patients in the PLATelet inhibition and patient Outcomes (PLATO) trial of which 9,340 were successfully genotyped (using Illumina HumanOmni2.5 or HumanOmniExpressExome BeadChip). Hazard ratio (HR) was estimated using multiple Cox regression, adjusting for relevant clinical variables (e.g. medical treatment, previous cardiovascular events, gender, age and smoking status). Weighted genetic risk scores (GRS) were calculated using seven genotyped or imputed SNPs (rs385076, rs149451729, rs34649619, rs360718, rs17229943, rs2290414, rs11226633) with regression coefficients retrieved from a multivariable regression model.
Results: Patients within the fourth quartile of the IL-18 distribution (>310 ng/L) had higher incidence (HR = 1.95, 95% CI 1.40 to 2.71, p = 7.79=10-5) of cardiovascular death (CVD) compared to patients within the first quartile (<180 ng/L). An IL-18 increase by one standard deviation (SD) resulted in higher risk of CVD (HR= 1.31, 95% CI 1.17-1.47, p=2.55e-06). However, a GRS increasing IL-18 by one SD was not associated with risk of CVD (HR 1.18, 95% CI 0.82-1.71, p=0.37). No difference in risk for recurrent myocardial infarction was seen either between the fourth and first IL-18 quartile (HR=0.99, 95% CI 0.77-1.27, p=0.94) or with one SD increase in IL-18 levels due to GRS (HR= 1.12, 95% CI 0.85-1.47, p=0.42).
Conclusion: We show a strong association between IL-18 levels and CVD in patients with ACS. However, patients with genetically higher IL-18 levels did not have a higher risk for CVD, suggesting that IL-18 might not have a strong causal effect on risk of CVD but rather being an indicator of disease progress.
- Acute coronary syndromes
- Gene mutations
- Genome-wide association studies (GWAS)
- Myocardial infarction
- © 2013 by American Heart Association, Inc.