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

• Published in: PLoS medicine Vol. 15; no. 3; p. e1002525
• Main Authors: Muse, Evan D, Wineinger, Nathan E, Spencer, Emily G, Peters, Melissa, Henderson, Riley, Zhang, Yunyue, Barrett, Paddy M, Rivera, Steven P, Wohlgemuth, Jay G, Devlin, James J, Shiffman, Dov, Topol, Eric J
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 13.03.2018; Public Library of Science (PLoS)
• Subjects: Adhesion tests; Aged; Aminopeptidases - genetics; Analysis; Arrhythmia; Atrial fibrillation; Atrial Fibrillation - complications; Atrial Fibrillation - diagnosis; Atrial Fibrillation - genetics; Body mass; Cardiovascular disease; Caveolin 1 - genetics; Cerebral infarction; Cohort analysis; Cohort Studies; Diabetes mellitus; Diagnosis; Echocardiography; EKG; Electrocardiography; Electrocardiography, Ambulatory - methods; Female; Fibrillation; Genetic aspects; Genetic screening; Genetic Testing - methods; Health risk assessment; Health risks; Heart diseases; Homeobox Protein PITX2; Homeodomain Proteins - genetics; Humans; Male; Medicine and Health Sciences; Middle Aged; Morbidity; Myocardial infarction; Patients; Physical Sciences; Polymorphism, Single Nucleotide; Prospective Studies; Research and Analysis Methods; Risk assessment; Risk Assessment - methods; Risk Factors; Single-nucleotide polymorphism; Small-Conductance Calcium-Activated Potassium Channels - genetics; Smoking; Stroke - etiology; Stroke - prevention & control; Systematic review; Time Factors; Transcription Factors - genetics; La Jolla California; California; United States > US; San Juan Capistrano California
• ISSN: 1549-1676; 1549-1277; 1549-1676
• DOI: 10.1371/journal.pmed.1002525

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. 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. 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. ClinicalTrials.gov NCT01970969.