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Am J Cardiol. 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.

Author information

1
Department of Medicine, Vanderbilt University, Nashville, Tennessee.
2
Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee.
3
Department of Pharmacology, Vanderbilt University, Nashville, Tennessee.
4
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
5
Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
6
Department of Medicine, Vanderbilt University, Nashville, Tennessee; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee.
7
Laboratory for Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
8
Department of Medicine, Vanderbilt University, Nashville, Tennessee. Electronic address: dawood.darbar@vanderbilt.edu.

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.

PMID:
25015694
PMCID:
PMC4119836
DOI:
10.1016/j.amjcard.2014.05.040
[Indexed for MEDLINE]
Free PMC Article

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