Atrial Fibrillation Associated Chromosome 4q25 Variants Are Not Associated with PITX2c Expression in Human Adult Left Atrial Appendages.docVIP

AtrialFibrillationAssociatedChromosome4q25Variants AreNotAssociatedwithPITX2cExpressioninHuman AdultLeftAtrialAppendages ShamoneR.Gore-Panter1,2,JefferyHsu1,2,PeterHanna3,A.MarcGillinov4,GostaPettersson4, DavidW.Newton6,ChristineS.Moravec5,6,DavidR.VanWagoner5,6*,MinaK.Chung5,6*,JohnBarnard7*, JonathanD.Smith1,2,5 * 1Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, United States of America, 2Department of Molecular Medicine, Cleveland Clinic LernerCollegeofMedicineofCaseWesternReserveUniversity,Cleveland,Ohio,UnitedStatesofAmerica,3ClevelandClinicLernerCollegeofMedicineofCaseWestern ReserveUniversity,Cleveland,Ohio,UnitedStatesofAmerica,4DepartmentofThoracicandCardiovascularSurgery,ClevelandClinic,Cleveland,Ohio,UnitedStatesof America,5DepartmentofMolecularCardiology,ClevelandClinic,Cleveland,Ohio,UnitedStatesofAmerica,6DepartmentofCardiovascularMedicine,ClevelandClinic, Cleveland,Ohio,UnitedStatesofAmerica,7DepartmentofQuantitativeHealthSciences,ClevelandClinic,Cleveland,Ohio,UnitedStatesofAmerica Abstract AtrialFibrillation(AF),themostcommonsustainedarrhythmia,hasastronggeneticcomponent,butthemechanismby whichcommongeneticvariantsleadtoincreasedAFsusceptibilityisunknown.Genome-wideassociationstudies(GWAS) have identified that the single nucleotide polymorphisms (SNPs) most strongly associated with AF are located on chromosome 4q25 in an intergenic region distal to the PITX2 gene. Our objective was to determine whether the AF- associated SNPs on chromosome 4q25 were associated with PITX2c expression in adult human left atrial appendages. Analysis of a lone AF GWAS identified four independent AF risk SNPs at chromosome 4q25. Human adult left atrial appendagetissuewasobtainedfrom239subjectsofEuropeanAncestryandusedforSNPanalysisofgenomicDNAand determinationofPITX2cRNAexpressionlevelsbyquantitativePCR.Subjectsweredividedintothreegroupsbasedontheir historyofAFandpre-operativerhythm.AFrhythmsubjectshadhigherPITX2cexpressionthanthosewit