title: A common variant on chromosome 4q25 is associated with prolonged PR interval in subjects with and without atrial fibrillation.
abstract: Single nucleotide polymorphisms (SNPs) at chromosome 4q25 (near PITX2) are strongly associated with atrial fibrillation (AF). We assessed whether a 4q25-tagging SNP (rs2200733) is associated with PR interval duration in patients with lone and typical AF and controls. Patients with lone (n = 169) and typical (n = 269) AF enrolled in the Vanderbilt AF registry and controls (n = 1,403) derived from the Vanderbilt DNA Biobank were studied. Carriage of the rs2200733T allele (CT or TT genotype) was more common in patients with lone (39%) than typical (25%) AF or controls (21%, p <0.01 for both comparisons). In both AF cohorts, we observed an association between genotype and PR interval duration (median PR interval for CC, CT, and TT: 162, 178, and 176 ms, respectively, for lone, p = 0.038 and 166, 180, and 196 ms, respectively, for typical, p = 0.001). After adjustment for covariates, the association between T allele and PR prolongation persisted, with mean effect size of 10.9, 12.8, and 4.4 ms for patients with lone and typical AF and controls, respectively (p <0.05 for each comparison). We found that a common 4q25 AF susceptibility allele (rs2200733) is associated with PR interval prolongation in patients with lone and typical AF and controls with no AF. Given that prolonged PR interval is an established risk factor for AF, this observation, in the context of previously described functional effects of PITX2 deficiency, provides further knowledge about the pathophysiological link of 4q25 variants with AF.
authors.affiliation: Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Kolek
authors.affiliation: Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Babar
authors.initials: B
authors.lastname: Parvez
authors.affiliation: Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Raafia
authors.initials: R
authors.lastname: Muhammad
authors.affiliation: Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: M Benjamin
authors.initials: MB
authors.lastname: Shoemaker
authors.affiliation: Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Marcia A
authors.initials: MA
authors.lastname: Blair
authors.affiliation: Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Tanya
authors.initials: T
authors.lastname: Stubblefield
authors.affiliation: Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Gayle A
authors.initials: GA
authors.lastname: Kucera
authors.affiliation: Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Denny
authors.affiliation: Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
authors.affiliation: Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee. Electronic address: dawood.darbar@vanderbilt.edu.
authors.forename: Dawood
authors.initials: D
authors.lastname: Darbar
mesh_terms: D000368:Aged; D000483:Alleles; D001281:Atrial Fibrillation / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D002894:Chromosomes, Human, Pair 4; D004247:DNA / Q000235:genetics*; D004562:Electrocardiography; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D011446:Prospective Studies; D012307:Risk Factors; D014481:United States / Q000453:epidemiology
chemical_list: D004247:DNA