Javad Jabbari1, Morten S Olesen1, Lei Yuan1, Jonas B Nielsen1, Bo Liang1, Vincenzo Macri1, Ingrid E Christophersen1, Nikolaj Nielsen1, Ahmad Sajadieh1, Patrick T Ellinor1, Morten Grunnet1, Stig Haunsø1, Anders G Holst1, Jesper H Svendsen1, Thomas Jespersen2. 1. From the The Danish National Research Foundation Centre for Cardiac Arrhythmia (DARC), Department of Biomedical Sciences (J.J., M.S.O., L.Y., J.B.N., B.L., N.N., M.G., S.H., A.G.H., J.H.S., T.J.), Laboratory for Molecular Cardiology, Department of Cardiology, Rigshospitalet (J.J., M.S.O., J.B.N., S.H., A.G.H., J.H.S.), and Department of Clinical Medicine (S.H., J.H.S.), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA (M.V., P.T.E) and Program in Medical and Population Genetics, The Broad Institute of Harvard and MIT, Cambridge, MA (P.T.E); Department of Medical Research, Bærum Hospital, Vestre Viken Hospital Trust, Rud, Norway (I.E.C.); Department of Cardiology, Copenhagen University Hospital of Bispebjerg, Bispebjerg, Denmark (A.S.); and LuCamp, The Lundbeck Foundation Centre for Applied Medical Genomics in Personalized Disease Prediction, Prevention and Care, Copenhagen, Denmark (S.H.). 2. From the The Danish National Research Foundation Centre for Cardiac Arrhythmia (DARC), Department of Biomedical Sciences (J.J., M.S.O., L.Y., J.B.N., B.L., N.N., M.G., S.H., A.G.H., J.H.S., T.J.), Laboratory for Molecular Cardiology, Department of Cardiology, Rigshospitalet (J.J., M.S.O., J.B.N., S.H., A.G.H., J.H.S.), and Department of Clinical Medicine (S.H., J.H.S.), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA (M.V., P.T.E) and Program in Medical and Population Genetics, The Broad Institute of Harvard and MIT, Cambridge, MA (P.T.E); Department of Medical Research, Bærum Hospital, Vestre Viken Hospital Trust, Rud, Norway (I.E.C.); Department of Cardiology, Copenhagen University Hospital of Bispebjerg, Bispebjerg, Denmark (A.S.); and LuCamp, The Lundbeck Foundation Centre for Applied Medical Genomics in Personalized Disease Prediction, Prevention and Care, Copenhagen, Denmark (S.H.). thojes@sund.ku.dk.
Abstract
BACKGROUND: Genome-wide association studies have shown that the common single nucleotide polymorphism rs6800541 located in SCN10A, encoding the voltage-gated Nav1.8 sodium channel, is associated with PR-interval prolongation and atrial fibrillation (AF). Single nucleotide polymorphism rs6800541 is in high linkage disequilibrium with the nonsynonymous variant in SCN10A, rs6795970 (V1073A, r(2)=0.933). We therefore sought to determine whether common and rare SCN10A variants are associated with early onset AF. METHODS AND RESULTS: SCN10A was sequenced in 225 AF patients in whom there was no evidence of other cardiovascular disease or dysfunction (lone AF). In an association study of the rs6795970 single nucleotide polymorphism variant, we included 515 AF patients and 2 control cohorts of 730 individuals free of AF and 6161 randomly sampled individuals. Functional characterization of SCN10A variants was performed by whole-cell patch-clamping. In the lone AF cohort, 9 rare missense variants and 1 splice site donor variant were detected. Interestingly, AF patients were found to have higher G allele frequency of rs6795970, which encodes the alanine variant at position 1073 (described from here on as A1073, odds ratio =1.35 [1.16-1.54]; P=2.3×10(-5)). Both of the common variants, A1073 and P1092, induced a gain-of-channel function, whereas the rare missense variants, V94G and R1588Q, resulted in a loss-of-channel function. CONCLUSIONS: The common variant A1073 is associated with increased susceptibility to AF. Both rare and common variants have effect on the function of the channel, indicating that these variants influence susceptibility to AF. Hence, our study suggests that SCN10A variations are involved in the genesis of AF.
RCT Entities:
BACKGROUND: Genome-wide association studies have shown that the common single nucleotide polymorphism rs6800541 located in SCN10A, encoding the voltage-gated Nav1.8sodium channel, is associated with PR-interval prolongation and atrial fibrillation (AF). Single nucleotide polymorphism rs6800541 is in high linkage disequilibrium with the nonsynonymous variant in SCN10A, rs6795970 (V1073A, r(2)=0.933). We therefore sought to determine whether common and rare SCN10A variants are associated with early onset AF. METHODS AND RESULTS:SCN10A was sequenced in 225 AFpatients in whom there was no evidence of other cardiovascular disease or dysfunction (lone AF). In an association study of the rs6795970 single nucleotide polymorphism variant, we included 515 AFpatients and 2 control cohorts of 730 individuals free of AF and 6161 randomly sampled individuals. Functional characterization of SCN10A variants was performed by whole-cell patch-clamping. In the lone AF cohort, 9 rare missense variants and 1 splice site donor variant were detected. Interestingly, AFpatients were found to have higher G allele frequency of rs6795970, which encodes the alanine variant at position 1073 (described from here on as A1073, odds ratio =1.35 [1.16-1.54]; P=2.3×10(-5)). Both of the common variants, A1073 and P1092, induced a gain-of-channel function, whereas the rare missense variants, V94G and R1588Q, resulted in a loss-of-channel function. CONCLUSIONS: The common variant A1073 is associated with increased susceptibility to AF. Both rare and common variants have effect on the function of the channel, indicating that these variants influence susceptibility to AF. Hence, our study suggests that SCN10A variations are involved in the genesis of AF.
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