Ceruloplasmin and Heart Failure in the Atherosclerosis Risk in Communities Study

Background Ceruloplasmin (Cp) decreases nitric oxide bioavailability in blood and has been associated with cardiovascular disease (CVD) in clinical studies. We assessed the associations between Cp and incident heart failure (HF), death, and CVD in the Atherosclerosis Risk in Communities (ARIC) study. Methods and Results Cp was measured at ARIC visit 4 (1996-1998). We studied 9240 individuals without HF or CVD at ARIC visit 4 and followed them for a mean of 10.5 years. Genome-wide association study was performed to identify genetic determinants of Cp levels and evaluate their association with incident HF in ARIC participants. Cp levels (meanSD) were higher in women versus men (335 +/- 79 versus 258 +/- 44 mg/L; P<0.0001), women on versus not on hormone-replacement therapy (398 +/- 89 versus 291 +/- 60 mg/L; P<0.0001), and African Americans versus whites (299 +/- 63 versus 293 +/- 74 mg/L; P=0.0005). After adjusting for traditional risk factors, high-sensitivity C-reactive protein, N-terminal pro-B-type natriuretic peptide, and high-sensitivity cardiac troponin T, higher levels of Cp were associated with HF (hazard ratio, 1.44; 95% confidence interval, 1.13-1.83) and mortality (hazard ratio, 1.38; 95% confidence interval, 1.11-1.63). A locus on the ceruloplasmin gene on chromosome 3 was significantly associated with Cp levels (normal 295.56 +/- 77.60 mg/L; heterozygote 316.72 +/- 88.02 mg/L; homozygote 331.04 +/- 85.40 mg/L; P=8.3x10(-13)) but not with incident HF. After adjustment for traditional risk factors, Cp levels were also weekly associated with CVD. Conclusions Cp was associated with incident HF, mortality, and CVD in the ARIC population. A single locus on chromosome 3 was associated with Cp levels but not with HF.