Morten S Olesen1, Laura Andreasen2, Javad Jabbari3, Lena Refsgaard2, Stig Haunsø2, Søren-Peter Olesen4, Jonas B Nielsen2, Nicole Schmitt4, Jesper H Svendsen2. 1. Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark; Laboratory for Molecular Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: morten.salling.olesen@rh.regionh.dk. 2. Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark; Laboratory for Molecular Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 3. Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark; Laboratory for Molecular Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 4. Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Abstract
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.
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 AFpatients 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 AFpatients 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 AFpatients, 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 AFpatients 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.
Authors: Jeppe D Andersen; Stine B Jacobsen; Linea C Trudsø; Marie-Louise Kampmann; Jytte Banner; Niels Morling Journal: Int J Legal Med Date: 2019-08-07 Impact factor: 2.686
Authors: Gerald S Bloomfield; Tecla M Temu; Constantine O Akwanalo; Peng-Sheng Chen; Wilfred Emonyi; Susan R Heckbert; Myra M Koech; Imran Manji; Changyu Shen; Matteo Vatta; Eric J Velazquez; Jennifer Wessel; Sylvester Kimaiyo; Thomas S Inui Journal: Am Heart J Date: 2015-06-14 Impact factor: 4.749