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Multicenter Study
. 2014 Aug 15;114(4):593-600.
doi: 10.1016/j.amjcard.2014.05.040. Epub 2014 Jun 6.

A Genome-Wide Association Study to Identify Genomic Modulators of Rate Control Therapy in Patients With Atrial Fibrillation

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Free PMC article
Multicenter Study

A Genome-Wide Association Study to Identify Genomic Modulators of Rate Control Therapy in Patients With Atrial Fibrillation

Matthew J Kolek et al. Am J Cardiol. .
Free PMC article

Abstract

For many patients with atrial fibrillation, ventricular rate control with atrioventricular (AV) nodal blockers is considered first-line therapy, although response to treatment is highly variable. Using an extreme phenotype of failure of rate control necessitating AV nodal ablation and pacemaker implantation, we conducted a genome-wide association study (GWAS) to identify genomic modulators of rate control therapy. Cases included 95 patients who failed rate control therapy. Controls (n = 190) achieved adequate rate control therapy with ≤2 AV nodal blockers using a conventional clinical definition. Genotyping was performed on the Illumina 610-Quad platform, and results were imputed to the 1000 Genomes reference haplotypes. A total of 554,041 single-nucleotide polymorphisms (SNPs) met criteria for minor allele frequency (>0.01), call rate (>95%), and quality control, and 6,055,224 SNPs were available after imputation. No SNP reached the canonical threshold for significance for GWAS of p <5 × 10(-8). Sixty-three SNPs with p <10(-5) at 6 genomic loci were genotyped in a validation cohort of 130 cases and 157 controls. These included 6q24.3 (near SAMD5/SASH1, p = 9.36 × 10(-8)), 4q12 (IGFBP7, p = 1.75 × 10(-7)), 6q22.33 (C6orf174, p = 4.86 × 10(-7)), 3p21.31 (CDCP1, p = 1.18 × 10(-6)), 12p12.1 (SOX5, p = 1.62 × 10(-6)), and 7p11 (LANCL2, p = 6.51 × 10(-6)). However, none of these were significant in the replication cohort or in a meta-analysis of both cohorts. In conclusion, we identified several potentially important genomic modulators of rate control therapy in atrial fibrillation, particularly SOX5, which was previously associated with heart rate at rest and PR interval. However, these failed to reach genome-wide significance.

Conflict of interest statement

Conflicts of interest: none.

Figures

Figure 1
Figure 1
Manhattan plot of results for genome-wide association with failure of rate control therapy in patients with atrial fibrillation. The canonical threshold for genome-wide significance, P <5 × 10−8, is indicated by the red line. The threshold for inclusion of variants in the validation experiment, P<5 × 10−5, is indicated by the blue line.
Figure 2
Figure 2
Plots of the top five most significant genomic regions associated with failure of rate control therapy in patients with atrial fibrillation: a) Chr6q24.3 (near SAMD5/SASH1); b) 4q12 (IGFBP7); c) 6q22.33 (C6orf174); d) 3p21.31 (CDCP1); and e) 12p12.1 (SOX5).
Figure 2
Figure 2
Plots of the top five most significant genomic regions associated with failure of rate control therapy in patients with atrial fibrillation: a) Chr6q24.3 (near SAMD5/SASH1); b) 4q12 (IGFBP7); c) 6q22.33 (C6orf174); d) 3p21.31 (CDCP1); and e) 12p12.1 (SOX5).
Figure 2
Figure 2
Plots of the top five most significant genomic regions associated with failure of rate control therapy in patients with atrial fibrillation: a) Chr6q24.3 (near SAMD5/SASH1); b) 4q12 (IGFBP7); c) 6q22.33 (C6orf174); d) 3p21.31 (CDCP1); and e) 12p12.1 (SOX5).
Figure 2
Figure 2
Plots of the top five most significant genomic regions associated with failure of rate control therapy in patients with atrial fibrillation: a) Chr6q24.3 (near SAMD5/SASH1); b) 4q12 (IGFBP7); c) 6q22.33 (C6orf174); d) 3p21.31 (CDCP1); and e) 12p12.1 (SOX5).
Figure 2
Figure 2
Plots of the top five most significant genomic regions associated with failure of rate control therapy in patients with atrial fibrillation: a) Chr6q24.3 (near SAMD5/SASH1); b) 4q12 (IGFBP7); c) 6q22.33 (C6orf174); d) 3p21.31 (CDCP1); and e) 12p12.1 (SOX5).

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