title: Ceruloplasmin and atrial fibrillation: evidence of causality from a population-based Mendelian randomization study.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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).
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Adamsson Eryd
authors.forename: M
authors.initials: M
authors.lastname: Sjögren
authors.forename: J G
authors.initials: JG
authors.lastname: Smith
authors.forename: P M
authors.initials: PM
authors.lastname: Nilsson
authors.forename: O
authors.initials: O
authors.lastname: Melander
authors.forename: B
authors.initials: B
authors.lastname: Hedblad
authors.forename: G
authors.initials: G
authors.lastname: Engström
mesh_terms: D000328:Adult; D001281:Atrial Fibrillation / Q000097:blood* / Q000453:epidemiology / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D002570:Ceruloplasmin / Q000235:genetics* / Q000378:metabolism*; D015331:Cohort Studies; D005500:Follow-Up Studies; D005787:Gene Frequency; D006801:Humans; D015994:Incidence; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D013548:Sweden / Q000453:epidemiology
chemical_list: D015415:Biomarkers; D002570:Ceruloplasmin
keywords: atrial fibrillation; biomarker; cohort study; epidemiology; gene polymorphism; protein