A functional variant in the promoter region regulates the C-reactive protein gene and is a potential candidate for increased risk of atrial fibrillation

Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan.
Journal of Internal Medicine (Impact Factor: 6.06). 02/2012; 272(3):305-15. DOI: 10.1111/j.1365-2796.2012.02531.x
Source: PubMed


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 Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Genome-wide association studies (GWAS) have identified common variants in nine genomic regions associated with AF (KCNN3, PRRX1, PITX2, WNT8A, CAV1, C9orf3, SYNE2, HCN4 and ZFHX3 genes); however, the genetic variability of these risk variants does not explain the entire genetic susceptibility to AF. Rare variants missed by GWAS may also contribute to genetic risk of AF. Methods We used an extreme trait design to sequence carefully selected probands with extreme phenotypes and their unaffected parents to identify rare de novo variants or mutations. Based on the hypothesis that common and rare variants may colocate in the same disease susceptibility gene, we used next-generation sequencing to sequence these nine published AF susceptibility genes identified by GWAS (a total of 179 exons) in 20 trios, 200 unrelated patients with AF and 200 non-AF controls. Results We identified a novel mutation in the 5′ untranslated region of the PITX2 gene, which localised in the transcriptionally active enhancer region. We also identified one missense exon mutation in KCNN3, two in ZFHX3 and one in SYNE2. None of these mutations were present in other unrelated patients with AF, healthy controls, unaffected parents and are thus novel and de novo (p<10−4). Functional study showed that the mutation in the 5′ untranslated region of the PITX2 gene significantly downregulated PITX2 expression in atrial myocytes, either in basal condition or during rapid pacing. In silico analysis showed that the missense mutation in ZFHX3 results in damage of the ZFHX3 protein structure. Conclusions The genetic architecture of subjects with extreme phenotypes of AF is similar to that of rare or Mendelian diseases, and mutations may be the underlying cause.
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