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Ceruloplasmin and atrial fibrillation: evidence of causality from a population-based Mendelian randomization study
S Adamsson Eryd1, M Sjögren, J G Smith
1Department of Clinical Sciences, Lund University, Malmö, Sweden.
Insights
This study suggests ceruloplasmin plays a causal role in atrial fibrillation (AF) development. Genetic variations linked to higher ceruloplasmin levels also increased AF incidence, indicating a potential inflammatory pathway.
Area of Science:
- Cardiovascular Medicine
- Genetics
- Inflammation Biology
Background:
- Inflammatory markers like C-reactive protein (CRP) and ceruloplasmin are linked to atrial fibrillation (AF).
- Previous genetic studies have not established a causal link between CRP and AF.
- The relationship between ceruloplasmin and AF incidence remains uninvestigated.
Purpose of the Study:
- To investigate if genetic polymorphisms in the ceruloplasmin gene (CP) are associated with elevated ceruloplasmin levels.
- To determine if these genetic polymorphisms are also associated with the incidence of AF.
Main Methods:
- A Mendelian randomization study was conducted using the Malmö Preventive Project cohort (n=3900).
- Genetic polymorphisms in the CP gene were genotyped and analyzed for association with plasma ceruloplasmin levels and incident AF.
- Findings were validated in an independent case-control study (Malmö AF cohort; n=4455).
Main Results:
- A specific single nucleotide polymorphism (rs11708215) in the CP gene promoter strongly correlated with increased plasma ceruloplasmin levels (P = 9 × 10(-10)).
- This polymorphism was also significantly associated with a higher incidence of AF in both the discovery cohort (HR 1.24, P=0.006) and the replication cohort (OR 1.13, P=0.02).
Conclusions:
- The study provides evidence for a causal role of ceruloplasmin in the pathophysiology of AF.
- Ceruloplasmin may act as a mediator in an inflammatory pathway connecting inflammatory diseases to AF incidence.
Objectives:
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.
Design:
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.
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