A genome-wide association study to identify genomic modulators of rate control therapy in patients with atrial fibrillation

Matthew J. Kolek, Todd L. Edwards, Raafia Muhammad, Adnan Balouch, M. Benjamin Shoemaker, Marcia A. Blair, Kaylen C. Kor, Atsushi Takahashi, Michiaki Kubo, Dan M. Roden, Toshihiro Tanaka, Dawood Darbar

Research output: Contribution to journalArticle

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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 × 10-6. Sixty-three SNPs with p < 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 × 10-6), 4q12 (IGFBP7, p = 1.75 × 10-6), 6q22.33 (C6orf174, p = 4.86 × 10-6), 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.

Original languageEnglish
Pages (from-to)593-600
Number of pages8
JournalAmerican Journal of Cardiology
Volume114
Issue number4
DOIs
Publication statusPublished - 15-08-2014

Fingerprint

Genome-Wide Association Study
Atrial Fibrillation
Single Nucleotide Polymorphism
Therapeutics
Genome
Gene Frequency
Quality Control
Haplotypes
Meta-Analysis
Heart Rate
Phenotype

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

Kolek, M. J., Edwards, T. L., Muhammad, R., Balouch, A., Shoemaker, M. B., Blair, M. A., ... Darbar, D. (2014). A genome-wide association study to identify genomic modulators of rate control therapy in patients with atrial fibrillation. American Journal of Cardiology, 114(4), 593-600. https://doi.org/10.1016/j.amjcard.2014.05.040
Kolek, Matthew J. ; Edwards, Todd L. ; Muhammad, Raafia ; Balouch, Adnan ; Shoemaker, M. Benjamin ; Blair, Marcia A. ; Kor, Kaylen C. ; Takahashi, Atsushi ; Kubo, Michiaki ; Roden, Dan M. ; Tanaka, Toshihiro ; Darbar, Dawood. / A genome-wide association study to identify genomic modulators of rate control therapy in patients with atrial fibrillation. In: American Journal of Cardiology. 2014 ; Vol. 114, No. 4. pp. 593-600.
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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 × 10-6. Sixty-three SNPs with p < 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 × 10-6), 4q12 (IGFBP7, p = 1.75 × 10-6), 6q22.33 (C6orf174, p = 4.86 × 10-6), 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.",
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Kolek, MJ, Edwards, TL, Muhammad, R, Balouch, A, Shoemaker, MB, Blair, MA, Kor, KC, Takahashi, A, Kubo, M, Roden, DM, Tanaka, T & Darbar, D 2014, 'A genome-wide association study to identify genomic modulators of rate control therapy in patients with atrial fibrillation', American Journal of Cardiology, vol. 114, no. 4, pp. 593-600. https://doi.org/10.1016/j.amjcard.2014.05.040

A genome-wide association study to identify genomic modulators of rate control therapy in patients with atrial fibrillation. / Kolek, Matthew J.; Edwards, Todd L.; Muhammad, Raafia; Balouch, Adnan; Shoemaker, M. Benjamin; Blair, Marcia A.; Kor, Kaylen C.; Takahashi, Atsushi; Kubo, Michiaki; Roden, Dan M.; Tanaka, Toshihiro; Darbar, Dawood.

In: American Journal of Cardiology, Vol. 114, No. 4, 15.08.2014, p. 593-600.

Research output: Contribution to journalArticle

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T1 - A genome-wide association study to identify genomic modulators of rate control therapy in patients with atrial fibrillation

AU - Kolek, Matthew J.

AU - Edwards, Todd L.

AU - Muhammad, Raafia

AU - Balouch, Adnan

AU - Shoemaker, M. Benjamin

AU - Blair, Marcia A.

AU - Kor, Kaylen C.

AU - Takahashi, Atsushi

AU - Kubo, Michiaki

AU - Roden, Dan M.

AU - Tanaka, Toshihiro

AU - Darbar, Dawood

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AB - 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 × 10-6. Sixty-three SNPs with p < 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 × 10-6), 4q12 (IGFBP7, p = 1.75 × 10-6), 6q22.33 (C6orf174, p = 4.86 × 10-6), 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.

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