A Genome-Wide Association Comparative Analysis of Response of AF Patients to Rate Control Therapy; A Collaboration between the NIH Pharmacogenomics Research Network and the RIKEN Yokohama Institute Center for Genomic Medicine

The goal of this study was to identify genetic predictors of response to rate control therapy in patients with AF. We conducted a genome-wide association study (GWAS) focusing on subjects with a history of atrial fibrillation. Rate control therapy for AF uses a range of drugs (beta-adrenergic receptor blockers, calcium channel blockers, and digitalis) to depress conduction through the AV node, thereby preventing rapid rates and minimizing symptoms. In large groups of patients, such as the Vanderbilt AF Registry (a clinical and genetic repository with over 1200 patients with ECG-confirmed AF) from which these study subjects were drawn, approximately 5% display failure of aggressive AV nodal-blocking therapy to control ventricular rate. In these patients, interruption of the AV node by ablation and pacemaker implantation are necessary for adequate rate control.

Study cases were individuals who underwent AV node ablation and pacemaker implantation after combined therapy with 3 AV nodal-blocking agents was ineffective in rate control. Controls for this study were individuals who met standardized rate-control efficacy criteria (as described in AFFIRM study, Wyse et al, NEJM 2002; PMID: 12466506) for optimal rate control with 2 or fewer AV nodal-blocking agents. Two additional groups were genotyped by RIKEN: An additional group of patients with AF as well as subjects undergoing cardiac surgery in whom AF did not occur post-operatively. All study participants were recruited and treated/evaluated at Vanderbilt University Medical Center.

This study was conducted by the Pharmacogenomics of Arrhythmia Therapy subgroup of the Pharmacogenetics Research Network, a nationwide collaboration of scientists studying the genetic contributions to drug response variability. Genotyping was performed by the RIKEN research institute in Japan using the Illumina 610 Quad Beadchip platform.

• Study Design:
  • Case-Control
• Study Type:
  • Case-Control
• dbGaP estimated ancestry using GRAF-pop
• Total number of consented subjects: 1888
• Subject Sample Telemetry Report (SSTR)

Inclusion criteria for all AF subjects: Must be between 18 and 100 years old with a diagnosis of atrial fibrillation. Additionally, subject must have a family member with known AF.

Exclusion criteria for all AF subjects: New onset AF occurring within 3 months of CABG or valve surgery; AF occurring post heart transplant; Post allogeneic bone marrow transplant.

Controls were defined as those subjects who satisfied the following criteria (AFFIRM) after treatment with 2 or fewer AV nodal-blocking agents: average heart rate (HR) ≤ 80 bpm at rest, in addition to either an average 24-hour HR ≤ 100 bpm and no maximal 24-hr HR > 110% of the predicted age-adjusted maximum exercise HR, or a HR ≤ 110 bpm during a 6-minute walk test.

Cases were defined as those subjects who failed to satisfy the AFFIRM criteria after combined therapy with 3 AV nodal-blocking agents and required AV node ablation and pacemaker implantation.

Criteria for post-op patients with no AF: All adult patients scheduled for elective cardiothoracic surgery who are capable of providing informed consent will be eligible for the study. Emergency patients or hemodynamically unstable patients for whom discussion of consent would delay surgery or who are incapable of providing consent will be excluded.

• Primary Phenotype: Atrial Fibrillation

• BioProject
• BioSample
• MeSH

• Principal Investigator
  • Dawood Darbar, MD, PhD. Vanderbilt University Medical Center, Nashville, TN, USA.
• Institute
  • Vanderbilt University PGRN Group (PAT). Vanderbilt University Medical Center, Nashville, TN, USA.
  • Yokohama Center for Genomic Medicine (CGM), RIKEN, Japan.
• Funding Source
  • National Institutes of Health, Bethesda, MD, USA.