Validation of a genetic risk score for atrial fibrillation: A prospective multicenter cohort study

Evan D Muse, Nathan E Wineinger, Emily G Spencer, Melissa Peters, Riley Henderson, Yunyue Zhang, Paddy M Barrett, Steven P Rivera, Jay G Wohlgemuth, James J Devlin, Dov Shiffman, Eric J Topol, Evan D Muse, Nathan E Wineinger, Emily G Spencer, Melissa Peters, Riley Henderson, Yunyue Zhang, Paddy M Barrett, Steven P Rivera, Jay G Wohlgemuth, James J Devlin, Dov Shiffman, Eric J Topol

Abstract

Background: Atrial fibrillation (AF) is the most commonly encountered arrhythmia and is associated with an elevated risk of stroke. Improving the identification of patients with the highest risk for AF to enable appropriate surveillance and treatment, if necessary, is critical to reducing AF-associated morbidity and mortality. Multiple common single nucleotide polymorphisms (SNPs) are unequivocally associated with the lifetime risk of AF. In the current study we aimed to prospectively validate an AF genetic risk score (GRS) in previously undiagnosed patients at risk for AF.

Methods and findings: Individuals 40 years of age or older with 1 clinical risk factor for AF, presenting with symptoms of AF, or with a first diagnosis of AF, were enrolled for genetic testing and ambulatory cardiac rhythm monitoring with an adhesive patch monitor or a long-term Holter monitor (mean wear time 10 days 21 hours and 13 days 18 hours, respectively). An AF event was the first diagnosis of AF by ECG, patch monitor, or long-term Holter monitor. The AF GRS was determined for each participant based on the weighted contribution of 12 genetic risk loci. Of 904 participants, 85 manifested AF. Their mean age was 66.2 (SD 11.8) years; 38% of participants were male. Participants in the highest quintile of AF GRS were more likely (odds ratio 3.11; 95% CI 1.27-7.58; p = 0.01) to have had an AF event than participants in the lowest quintile after adjusting for age, sex, smoking status, BMI, hypertension, diabetes mellitus, heart failure, and prior myocardial infarction. Study limitations included an ethnically homogenous population, a restricted rhythm monitoring period, and the evolving discovery of SNPs associated with AF.

Conclusions: Prospective assessment of a GRS for AF identified participants with elevated risk of AF beyond established clinical criteria. Accordingly, a GRS for AF could be incorporated into overall risk assessment to better identify patients at the highest risk of developing AF, although further testing in larger populations is needed to confirm these findings.

Trial registration: ClinicalTrials.gov NCT01970969.

Conflict of interest statement

JGW is an employee of Quest Diagnostics and receives stock and stock options from Quest Diagnostics. SPR, JJD and DS are employees of Quest Diagnostics.

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