Antonio P Arenas de Larriva1, Faye L Norby2, Lin Y Chen3, Elsayed Z Soliman4, Ron C Hoogeveen5, Dan E Arking6, Laura R Loehr7, Alvaro Alonso8. 1. Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, United States; Lipid and Atherosclerosis Unit, IMIBIC/Hospital Universitario Reina Sofía/Universidad de Córdoba, Córdoba, Spain; CIBER Fisiopatología Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain. 2. Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, United States. 3. Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, United States. 4. Wake Forest University, Winston-Salem, NC, United States. 5. Department of Medicine, Baylor College of Medicine, Houston, TX, United States. 6. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States. 7. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, United States. 8. Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, United States. Electronic address: alvaro.alonso@emory.edu.
Abstract
BACKGROUND: Ceruloplasmin (CP) may promote structural changes in the atrium making it more arrhythmogenic. We assessed the associations between CP, CP-associated genetic variants, and incident atrial fibrillation (AF) in the Atherosclerosis Risk in Communities (ARIC) study. METHODS AND RESULTS: We studied 10,059 men and women without prevalent AF aged 53 to 75years in 1996-1998 and followed through 2012. Circulating CP was measured in stored blood samples obtained in 1996-1998. Polymorphisms rs11708215 and rs13072552, previously associated with CP concentrations, were measured in 10,059 and 8829 participants respectively. AF was ascertained from study electrocardiograms, hospital discharge codes, and death certificates. Multivariable Cox models were run to study the association between circulating CP, CP-associated polymorphisms, and the incidence of AF. Over 10.5years of mean follow-up, 1357 cases of AF were identified. After adjusting for traditional risk factors and biomarkers, higher levels of circulating CP were associated with incident AF (hazard ratio [HR] 1.33, 95% confidence interval [CI] 1.11, 1.61 comparing top to bottom quartiles). Both rs11708215 and rs13072552 were significantly associated with CP levels. Presence of the CP-increasing alleles in rs11708215 and rs13072552, however, were significantly associated with lower risk of AF in whites (HR 0.84, 95%CI 0.76, 0.94, p=0.002 and HR 0.83; 95%CI 0.69, 0.99, p=0.043 respectively per CP-increasing allele in the final adjusted model) but not in African Americans. CONCLUSIONS: Even though higher CP concentrations were associated with increased AF risk, genetic variants associated with higher CP decreased the risk of AF in whites. Our results suggest that circulating CP levels may not be causally related to risk of incident AF.
BACKGROUND: Ceruloplasmin (CP) may promote structural changes in the atrium making it more arrhythmogenic. We assessed the associations between CP, CP-associated genetic variants, and incident atrial fibrillation (AF) in the Atherosclerosis Risk in Communities (ARIC) study. METHODS AND RESULTS: We studied 10,059 men and women without prevalent AF aged 53 to 75years in 1996-1998 and followed through 2012. Circulating CP was measured in stored blood samples obtained in 1996-1998. Polymorphisms rs11708215 and rs13072552, previously associated with CP concentrations, were measured in 10,059 and 8829 participants respectively. AF was ascertained from study electrocardiograms, hospital discharge codes, and death certificates. Multivariable Cox models were run to study the association between circulating CP, CP-associated polymorphisms, and the incidence of AF. Over 10.5years of mean follow-up, 1357 cases of AF were identified. After adjusting for traditional risk factors and biomarkers, higher levels of circulating CP were associated with incident AF (hazard ratio [HR] 1.33, 95% confidence interval [CI] 1.11, 1.61 comparing top to bottom quartiles). Both rs11708215 and rs13072552 were significantly associated with CP levels. Presence of the CP-increasing alleles in rs11708215 and rs13072552, however, were significantly associated with lower risk of AF in whites (HR 0.84, 95%CI 0.76, 0.94, p=0.002 and HR 0.83; 95%CI 0.69, 0.99, p=0.043 respectively per CP-increasing allele in the final adjusted model) but not in African Americans. CONCLUSIONS: Even though higher CP concentrations were associated with increased AF risk, genetic variants associated with higher CP decreased the risk of AF in whites. Our results suggest that circulating CP levels may not be causally related to risk of incident AF.
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