Atrial Fibrillation associated chromosome 4q25 variants are not associated with PITX2c expression in human adult left atrial appendages.
Atrial Fibrillation (AF), the most common sustained arrhythmia, has a strong genetic component, but the mechanism by which common genetic variants lead to increased AF susceptibility is unknown. Genome-wide association studies (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 appendage tissue was obtained from 239 subjects of European Ancestry and used for SNP analysis of genomic DNA and determination of PITX2c RNA expression levels by quantitative PCR. Subjects were divided into three groups based on their history of AF and pre-operative rhythm. AF rhythm subjects had higher PITX2c expression than those with history of AF but in sinus rhythm. PITX2c expression was not associated with the AF risk SNPs in human adult left atrial appendages in all subjects combined or in each of the three subgroups. However, we identified seven SNPs modestly associated with PITX2c expression located in the introns of the ENPEP gene, ∼54 kb proximal to PITX2. PITX2c expression in human adult left atrial appendages is not associated with the chromosome 4q25 AF risk SNPs; thus, the mechanism by which these SNPs are associated with AF remains enigmatic.
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, United States of America ; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, United States of America.
Shamone R
SR
Gore-Panter
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, United States of America ; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, United States of America.
Jeffery
J
Hsu
Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, United States of America.
Peter
P
Hanna
Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic, Cleveland, Ohio, United States of America.
A Marc
AM
Gillinov
Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic, Cleveland, Ohio, United States of America.
Gosta
G
Pettersson
Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio, United States of America.
David W
DW
Newton
Department of Molecular Cardiology, Cleveland Clinic, Cleveland, Ohio, United States of America ; Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio, United States of America.
Christine S
CS
Moravec
Department of Molecular Cardiology, Cleveland Clinic, Cleveland, Ohio, United States of America ; Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio, United States of America.
David R
DR
Van Wagoner
Department of Molecular Cardiology, Cleveland Clinic, Cleveland, Ohio, United States of America ; Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio, United States of America.
Mina K
MK
Chung
Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio, United States of America.
John
J
Barnard
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, United States of America ; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, United States of America ; Department of Molecular Cardiology, Cleveland Clinic, Cleveland, Ohio, United States of America.
Jonathan D
JD
Smith
D000328:Adult; D000368:Aged; D020517:Atrial Appendage / Q000378:metabolism*; D001281:Atrial Fibrillation / Q000235:genetics*; D002894:Chromosomes, Human, Pair 4; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D014157:Transcription Factors / Q000235:genetics*; D000097577:Homeobox Protein PITX2
D018398:Homeodomain Proteins; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; C484664:SHOX2 protein, human