Circulating ceruloplasmin, ceruloplasmin-associated genes and the incidence of venous thromboembolism in the Atherosclerosis Risk in Communities study

Abstract

Essentials Ceruloplasmin (CP) is an acute-phase reactant and a potential biomarker of atherothrombotic risk. We assessed associations between CP and venous thromboembolism (VTE) risk in 9933 individuals. Higher circulating CP but not CP-related genes were associated with greater incident VTE rates. Circulating CP could be considered a non-causal biomarker of VTE risk in the community. SUMMARY: Background Ceruloplasmin (CP) is an acute-phase reactant and a potential biomarker of atherothrombotic risk. We assessed the associations between CP, CP-associated genetic variants and incident venous thomboembolism (VTE) in the Atherosclerosis Risk in Communities study. Methods and results In an observational study, 9933 men and women aged 53-75 years without prevalent VTE were included in 1996-1998 and followed through 2011. Circulating CP was measured in stored blood samples obtained in 1996-1998. Polymorphisms rs11708215 and rs13072552, which have been previously associated with CP concentrations, were measured in 8439 participants. VTEs were identified from hospital discharge codes and validated by physician review of medical records and imaging reports. Over a mean of 10.5 years of follow-up, 376 cases of VTE were identified. The association between circulating CP, CP-associated polymorphisms and the incidence of VTE was estimated. After adjustment for traditional risk factors and biomarkers, higher concentrations of circulating CP were associated with greater incident VTE rates (hazard ratio 1.82, 95% confidence interval 1.12-2.95, comparing the 87.5-100th percentile with the bottom quartile). Both rs11708215 and rs13072552 were associated with CP concentrations but not with VTE risk. Conclusions Even though high CP concentrations were associated with an increased VTE risk, CP-associated genetic variants were not associated with a higher risk of VTE. Our results suggest that circulating CP concentrations may not be causally related to the risk of incident VTE.

Keywords: ceruloplasmin; oxidative stress; single-nucleotide polymorphism; venous thromboembolism.