Ceruloplasmin and atrial fibrillation: evidence of causality from a population-based Mendelian randomization study
Article first published online: 23 OCT 2013
© 2013 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine
Volume 275, Issue 2, pages 164–171, February 2014
How to Cite
Department of Clinical Sciences, Lund University, Malmö; and Department of Cardiology, Lund University, Lund, Sweden). Ceruloplasmin and atrial fibrillation: evidence of causality from a population-based Mendelian randomization study. J Intern Med 2014; 275: 164–171., , , , , , (
- Issue published online: 17 JAN 2014
- Article first published online: 23 OCT 2013
- Accepted manuscript online: 1 OCT 2013 10:56AM EST
- Swedish Heart and Lung Foundation
- Swedish Research Council. Grant Number: 2011-3891
- Region Skåne, Skåne University Hospital Foundation
- Swedish Academy of Pharmaceutical Sciences
- Ernhold Lundström Foundation
- atrial fibrillation;
- cohort study;
- gene polymorphism;
Inflammatory diseases and inflammatory markers secreted by the liver, including C-reactive protein (CRP) and ceruloplasmin, have been associated with incident atrial fibrillation (AF). Genetic studies have not supported a causal relationship between CRP and AF, but the relationship between ceruloplasmin and AF has not been studied. The purpose of this Mendelian randomization study was to explore whether genetic polymorphisms in the gene encoding ceruloplasmin are associated with elevated ceruloplasmin levels, and whether such genetic polymorphisms are also associated with the incidence of AF.
Genetic polymorphisms in the ceruloplasmin gene (CP) were genotyped in a population-based cohort study of men from southern Sweden (Malmö Preventive Project; n = 3900). Genetic polymorphisms associated with plasma ceruloplasmin concentration were also investigated for association with incident AF (n = 520) during a mean follow-up of 29 years in the same cohort. Findings were replicated in an independent case–control sample (The Malmö AF cohort; n = 2247 cases, 2208 controls).
A single nucleotide polymorphism (rs11708215, minor allele frequency 0.12) located in the CP gene promoter was strongly associated with increased levels of plasma ceruloplasmin (P = 9 × 10−10) and with AF in both the discovery cohort [hazard ratio 1.24 per risk allele, 95% confidence interval (CI) 1.06–1.44, P = 0.006] and the replication cohort (odds ratio 1.13, 95% CI 1.02–1.26, P = 0.02).
Our findings indicate a causal role of ceruloplasmin in AF pathophysiology and suggest that ceruloplasmin might be a mediator in a specific inflammatory pathway that causally links inflammatory diseases and incidence of AF.