A functional variant in the promoter region regulates the C-reactive protein gene and is a potential candidate for increased risk of atrial fibrillation.
ABSTRACT In a large population-based cohort, the level of C-reactive protein (CRP) in patients at baseline predicts an increased risk of future development of atrial fibrillation (AF). The mechanism of this increased risk is unknown. Furthermore, both the molecular effects of CRP on atrial myocytes and fibroblasts and whether genetic variants in the CRP gene predispose to AF are also unknown.
A genetic association study between CRP gene polymorphisms and AF was performed in two independent populations (I: 100 AF patients and 101 controls; II: 348 AF patients and 356 controls), with functional studies to elucidate the mechanism of association.
Three polymorphisms (T-861C, A-821G and C-390A/C-390T) were found in the 1-kb promoter of CRP. A triallelic polymorphism (C-390A/C-390T) captured all haplotype information and determined the CRP gene promoter activity and the plasma CRP level, and was in nearly complete linkage disequilibrium with G1059C polymorphism in exon 2. The -390A variant was associated with a higher CRP gene promoter activity, a higher plasma CRP level and a higher risk of AF. Patients with AF also had a higher plasma CRP level than controls. CRP significantly increased the inward L-type calcium current in atrial myocytes with no changes in other ionic currents. CRP did not affect the expressions of type I alpha 1 (COL1A1), type III alpha 1 (COL3A1) and type 1 alpha 2 (COL1A2) procollagens in atrial fibroblasts.
A CRP gene promoter triallelic polymorphism was associated with CRP gene promoter activity, determined the plasma level of CRP, and predicted the risk of AF. The mechanism of this may be via augmention of calcium influx by CRP in atrial myocytes, but not because of atrial fibrosis.
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ABSTRACT: BACKGROUND: Inflammatory biomarkers are reported as risk factors for atrial fibrillation (AF), but their impact is uncertain. OBJECTIVE: We investigated the associations between inflammatory biomarkers and future AF in a large general cohort. METHODS: Available markers were white blood cells (WBCs) with subgroups, fibrinogen, high-sensitivity C-reactive protein (hs-CRP), and osteoprotegerin (OPG). A total of 6315 men and women from a population survey in Tromsø, Norway in 1994 to 1995 were followed for a mean of 10.9 years. Mean age at baseline was 60 years. Measurements of height, weight, blood pressure, heart rate, total cholesterol, high-density lipoprotein (HDL) cholesterol, WBC count, and information on diabetes, angina, myocardial infarction, and antihypertensive treatment, were obtained at baseline. Fibrinogen, hs-CRP, and OPG were obtained at a follow-up visit. The outcome measure was first-ever AF, documented on an electrocardiogram. The Cox proportional hazards regression model was used to estimate hazard ratios of AF. RESULTS: In the multivariable analysis, adjusted for traditional cardiovascular risk factors and other inflammatory biomarkers, hs-CRP was associated with AF in men only (hazard ratio = 1.14 for a 1 SD increase; 95% CI, 1.02-1.28). There was a significant increase in AF across quartiles of WBCs in men (P = 0.007) and in the total study population (P = 0.004). OPG was associated with AF in patients free of coronary heart disease at baseline. Fibrinogen and subgroups of WBCs showed no significant association with AF. CONCLUSION: This population-based cohort study showed that hs-CRP was independently associated with AF in men, but apparently not in women, and that patients with WBCs in the upper quartile had increased risk of AF.Gender Medicine 10/2012; · 1.55 Impact Factor
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ABSTRACT: Atrial fibrillation is associated with substantial morbidity and mortality rates. The incompletely understood pathogenesis of this cardiac dysrhythmia makes it difficult to improve approaches to primary and secondary prevention. Evidence has accumulated in regard to a relationship between inflammation and atrial fibrillation. Investigators have correlated the dysrhythmia with myocarditis, pericardiotomy, and C-reactive protein levels, suggesting that inflammation causes atrial fibrillation or participates in its onset and continuation. Conversely, other investigators suggest that atrial fibrillation induces an inflammatory response. In this review, we summarize and critically discuss the nature and clinical role of inflammation and C-reactive protein in atrial fibrillation.09/2014; 41(5):461-468.