title: A genome-wide association study to identify genomic modulators of rate control therapy in patients with atrial fibrillation.
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.
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Kolek
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee.
authors.forename: Todd L
authors.initials: TL
authors.lastname: Edwards
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Raafia
authors.initials: R
authors.lastname: Muhammad
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Adnan
authors.initials: A
authors.lastname: Balouch
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: M Benjamin
authors.initials: MB
authors.lastname: Shoemaker
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Marcia A
authors.initials: MA
authors.lastname: Blair
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Kaylen C
authors.initials: KC
authors.lastname: Kor
authors.affiliation: Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.affiliation: Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
authors.affiliation: 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.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee. Electronic address: dawood.darbar@vanderbilt.edu.
authors.forename: Dawood
authors.initials: D
authors.lastname: Darbar
mesh_terms: D000368:Aged; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D001283:Atrioventricular Node / Q000187:drug effects / Q000503:physiopathology; D004247:DNA / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006339:Heart Rate / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D055755:SOXD Transcription Factors / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors
chemical_list: D000889:Anti-Arrhythmia Agents; C490301:SOX5 protein, human; D055755:SOXD Transcription Factors; D004247:DNA