Ceruloplasmin and atrial fibrillation: evidence of causality from a population-based Mendelian randomization study

ObjectivesInflammatory 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. DesignGenetic polymorphisms in the ceruloplasmin gene (CP) were genotyped in a population-based cohort study of men from southern Sweden (Malmo 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 29years in the same cohort. Findings were replicated in an independent case-control sample (The Malmo AF cohort; n=2247 cases, 2208 controls). ResultsA 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=9x10(-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). ConclusionsOur 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.