title: Clinical and genetic association of serum ceruloplasmin with cardiovascular risk.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, 9500 Euclid Ave, Desk J3-4, Cleveland, OH 44195, USA. tangw@ccf.org
authors.forename: W H Wilson
authors.initials: WH
authors.lastname: Tang
authors.forename: Yuping
authors.initials: Y
authors.lastname: Wu
authors.forename: Jaana
authors.initials: J
authors.lastname: Hartiala
authors.forename: Yiying
authors.initials: Y
authors.lastname: Fan
authors.forename: Alexandre F R
authors.initials: AF
authors.lastname: Stewart
authors.forename: Robert
authors.initials: R
authors.lastname: Roberts
authors.forename: Ruth
authors.initials: R
authors.lastname: McPherson
authors.forename: Paul L
authors.initials: PL
authors.lastname: Fox
authors.forename: Hooman
authors.initials: H
authors.lastname: Allayee
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood / Q000453:epidemiology* / Q000235:genetics; D002570:Ceruloplasmin / Q000235:genetics* / Q000378:metabolism*; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D015994:Incidence; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood / Q000453:epidemiology* / Q000235:genetics; D011237:Predictive Value of Tests; D015995:Prevalence; D011446:Prospective Studies; D012189:Retrospective Studies; D012307:Risk Factors; D020521:Stroke / Q000097:blood / Q000453:epidemiology* / Q000235:genetics
chemical_list: D015415:Biomarkers; D002570:Ceruloplasmin
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