title: Common and rare variants in SCN10A modulate the risk of atrial fibrillation.
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.
  
  
  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.
authors.affiliation: 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.).
authors.forename: Javad
authors.initials: J
authors.lastname: Jabbari
authors.affiliation: 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.).
authors.forename: Morten S
authors.initials: MS
authors.lastname: Olesen
authors.affiliation: 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.).
authors.forename: Lei
authors.initials: L
authors.lastname: Yuan
authors.affiliation: 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.).
authors.forename: Jonas B
authors.initials: JB
authors.lastname: Nielsen
authors.affiliation: 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.).
authors.forename: Bo
authors.initials: B
authors.lastname: Liang
authors.affiliation: 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.).
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Macri
authors.affiliation: 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.).
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Christophersen
authors.affiliation: 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.).
authors.forename: Nikolaj
authors.initials: N
authors.lastname: Nielsen
authors.affiliation: 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.).
authors.forename: Ahmad
authors.initials: A
authors.lastname: Sajadieh
authors.affiliation: 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.).
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Ellinor
authors.affiliation: 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.).
authors.forename: Morten
authors.initials: M
authors.lastname: Grunnet
authors.affiliation: 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.).
authors.forename: Stig
authors.initials: S
authors.lastname: Haunsø
authors.affiliation: 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.).
authors.forename: Anders G
authors.initials: AG
authors.lastname: Holst
authors.affiliation: 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.).
authors.forename: Jesper H
authors.initials: JH
authors.lastname: Svendsen
authors.affiliation: 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.
authors.forename: Thomas
authors.initials: T
authors.lastname: Jespersen
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001281:Atrial Fibrillation / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide
chemical_list: D062559:NAV1.8 Voltage-Gated Sodium Channel; C568317:SCN10A protein, human
keywords: SCN10A; atrial fibrillation arrhythmia; electrophysiology; genetic polymorphism; genome-wide association study; genotyping; voltage-gated sodium channel alpha subunit Nav1.8