Very early-onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation

TY - JOUR

T1 - Very early-onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation

AU - Olesen, Morten S

AU - Andreasen, Laura

AU - Jabbari, Javad

AU - Refsgaard, Lena

AU - Haunsø, Stig

AU - Olesen, Søren-Peter

AU - Nielsen, Jonas B

AU - Schmitt, Nicole

AU - Svendsen, Jesper H

N1 - © 2013 Published by Heart Rhythm Society on behalf of Heart Rhythm Society.

PY - 2014/2

Y1 - 2014/2

N2 - Background Atrial fibrillation (AF) is the most common cardiac arrhythmia. Currently, 14 genes important for ion channel function, intercellular signaling, and homeostatic control have been associated with AF. Objective We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early-onset lone AF patients than in the background population. Methods Sequencing results of KCNQ1, KCNH2, SCN5A, KCNA5, KCND3, KCNE1, 2, 5, KCNJ2, SCN1-3B, NPPA, and GJA5 from 192 early-onset lone AF patients were compared with data from the National Heart, Lung, and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies. Results Among the lone AF patients, 29 (7.6%) alleles harbored a novel or very rare variant (minor allele frequency <0.1 in the Exome Variant Server), a frequency that was significantly higher than what was found in the reference database (4.1%; with minor allele frequency <0.1; P =.0012). Previously published electrophysiological data showed that 96% (n = 23) of the rare variants that has been functionally investigated (n = 24) displayed significant functional changes. Conclusions We report a much higher prevalence of rare variants in genes associated with AF in early-onset lone AF patients than in the background population. By presenting these data, we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF.

AB - Background Atrial fibrillation (AF) is the most common cardiac arrhythmia. Currently, 14 genes important for ion channel function, intercellular signaling, and homeostatic control have been associated with AF. Objective We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early-onset lone AF patients than in the background population. Methods Sequencing results of KCNQ1, KCNH2, SCN5A, KCNA5, KCND3, KCNE1, 2, 5, KCNJ2, SCN1-3B, NPPA, and GJA5 from 192 early-onset lone AF patients were compared with data from the National Heart, Lung, and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies. Results Among the lone AF patients, 29 (7.6%) alleles harbored a novel or very rare variant (minor allele frequency <0.1 in the Exome Variant Server), a frequency that was significantly higher than what was found in the reference database (4.1%; with minor allele frequency <0.1; P =.0012). Previously published electrophysiological data showed that 96% (n = 23) of the rare variants that has been functionally investigated (n = 24) displayed significant functional changes. Conclusions We report a much higher prevalence of rare variants in genes associated with AF in early-onset lone AF patients than in the background population. By presenting these data, we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF.

U2 - 10.1016/j.hrthm.2013.10.034

DO - 10.1016/j.hrthm.2013.10.034

M3 - Journal article

C2 - 24144883

SN - 1547-5271

VL - 11

SP - 246

EP - 251

JO - Heart Rhythm

JF - Heart Rhythm

IS - 2

ER -