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

. Chang S‐N, Tsai C‐T, Wu C‐K, Lee J‐K, Lai L‐P, Huang S‐W, Huang L‐Y, Tseng C‐D, Lin J‐L, Chiang F‐T, Hwang J‐J (National Taiwan University Hospital Yun‐Lin Branch, Yun‐Lin; National Taiwan University Hospital, Taipei; National Taiwan University Hospital, Taipei; Institute of Pharmacology, Taipei; and Graduate Institute of Biomedical Engineering, Taipei, Taiwan). A functional variant in the promoter region regulates the C‐reactive protein gene and is a potential candidate for increased risk of atrial fibrillation. J Intern Med 2012; 272: 305–315. Objectives. 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. Methods. 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. Results. 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. Conclusion. 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.

C‐reactive protein gene polymorphism predicts the risk of thromboembolic stroke in patients with atrial fibrillation: a more than 10‐year prospective follow‐up study

“…In our previous study, we found that patients with AF had higher plasma CRP levels than control subjects . We also found that the triallelic polymorphism (C‐390A and C‐390T) in the CRP promoter determined the basal CRP promoter activities and plasma CRP level, and was functionally related to the mechanism of AF . To date little evidence is available regarding the impact of genetic polymorphisms on the risk of thromboembolic stroke in patients with AF.…”

Inflammation and C-Reactive Protein in Atrial Fibrillation: Cause or Effect?

“…It is likely that AF involves a sequestration of inflammatory cytokines in atrial tissue: Marcus and associates 25 found that the difference between left atrial and coronary sinus CRP levels was significantly greater in patients who had AF at the time of the blood draw than in patients who were in sinus rhythm during that time. Chang and coworkers 28 showed that changes in the promoter region regulated the CRP gene that influences the risk of AF: the -390A variant was associated with greater CRP gene-promoter activity, a higher plasma CRP level, and a higher risk of AF. Further analysis showed that CRP significantly increased the inward L-type Ca current in atrial myocytes with no changes in other ionic currents and without affecting expressions of gene-encoding procollagens in atrial fibroblasts.…”

Next-generation sequencing of nine atrial fibrillation candidate genes identified novel de novo mutations in patients with extreme trait of atrial fibrillation

“…Consecutive patients who were admitted to our adult cardiology ward with a history of AF were collected, as reported in our previous studies 19 20. To identify patients with AF with extreme phenotypes for exon sequencing, we selected patients with extremely symptomatic AF attacks (more than once per day) who were refractory to at least three classes of antiarrhythmic drugs (including class I and class III antiarrhythmic drugs) and to catheter ablation therapy.…”