Arteriosclerosis, Thrombosis, and Vascular Biology
Objective—Ceruloplasmin (Cp) is an acute-phase reactant that is increased in inflammatory diseases and in acute coronary syndromes. Cp has recently been shown to possess nitric oxide (NO) oxidase catalytic activity, but its impact on long-term cardiovascular outcomes in stable cardiac patients has not been explored. Methods and Results—We examined serum Cp levels and their relationship with incident major adverse cardiovascular events (MACE; death, myocardial infarction [MI], stroke) over 3-year follow-up in 4177 patients undergoing elective coronary angiography. We also carried out a genome-wide association study to identify the genetic determinants of serum Cp levels and evaluate their relationship to prevalent and incident cardiovascular risk. In our cohort (age 63±11 years, 66% male, 32% history of MI, 31% diabetes mellitus), mean Cp level was 24±6 mg/dL. Serum Cp level was associated with greater risk of MI at 3 years (hazard ratio [quartile 4 versus 1] 2.35, 95% confidence interval [CI] 1.79–3.09, P<0.001). After adjustment for traditional risk factors, high-sensitivity C-reactive protein, and creatinine clearance, Cp remained independently predictive of MACE (hazard ratio 1.55, 95% CI 1.10–2.17, P=0.012). A 2-stage genome-wide association study identified a locus on chromosome 3 over the CP gene that was significantly associated with Cp levels (lead single-nucleotide polymorphism rs13072552; P=1.90×10−11). However, this variant, which leads to modestly increased serum Cp levels (≈1.5–2 mg/dL per minor allele copy), was not associated with coronary artery disease or future risk of MACE. Conclusion—In stable cardiac patients, serum Cp provides independent risk prediction of long-term adverse cardiac events. Genetic variants at the CP locus that modestly affect serum Cp levels are not associated with prevalent or incident risk of coronary artery disease in this study population.
Tang, W.H. Wilson; Wu, Yuping; Hartiala, Jaana; Fan, Yiying; Stewart, Alexandre F.R.; Roberts, Robert; McPherson, Ruth; Fox, Paul L.; Allayee, Hooman; and Hazen, Stanley L., "Clinical and Genetic Association of Serum Ceruloplasmin with Cardiovascular Risk" (2012). Mathematics Faculty Publications. 172.
This study was supported by National Institutes of Health Grant P01-HL076491. The study GeneBank was supported in part by National Institutes of Health Grants 1P01-HL098055 (to S.L.H.), 1R01-HL103866 (to S.L.H.), 1R01-DK080732 (to S.L.H.), 1R01-DK083359 (to P.L.F.), and 1R01-HL103931 (to W.H.T.). The John and Jennifer Ruddy Canadian Cardiovascular Genetics Centre investigators are supported by Canadian Institute of Health Research (CIHR) #MOP-82810 (to R.R.), Canadian Foundation for Innovation (CFI) #11966 (to R.R.), Heart and Stroke Foundation of Ontario (HSFO) #NA6001 (to R.M.), CIHR #MOP172605 (to R.M.), and CIHR #MOP77682 (to A.F.R.S.). Supplies for Cp testing were provided for by Abbott Laboratories, Inc.