title: Genetic polymorphisms confer risk of atrial fibrillation in patients with heart failure: a population-based study.
abstract: OBJECTIVE
  Atrial fibrillation (AF) is a frequent co-morbidity in heart failure (HF) associated with increased mortality, but little is known about the mechanisms underlying AF onset in HF patients. We evaluated the association of cardiovascular and genetic risk factors with AF in HF patients.
  
  
  RESULTS
  Individuals hospitalized for HF (n = 1040; 500 with AF) were identified from a large, population-based cohort study (n = 30 447; 2339 with AF). Genetic polymorphisms in the chromosomal regions 4q25 (rs2200733) and 16q22 (rs2106261) associated with AF in genome-wide association studies were genotyped. Association of cardiovascular risk factors and polymorphisms with AF was tested in HF patients and the entire cohort using both prospective and non-time-dependent models. Cardiovascular risk factors-hypertension, body mass index, sex, smoking, diabetes, and myocardial infarction-were associated with AF in the entire cohort but not in HF patients. In contrast, polymorphisms on chromosomes 16q22 and 4q25 were associated with AF both in the entire cohort and in HF patients, conferring 75% [95% confidence interval (CI) 35-126, P = 2 × 10(-5)] and 57% (95% CI 18-109, P = 0.002) increased risk of AF per copy in HF patients, respectively. In the entire cohort, AF risk in the presence of HF was multiplicatively magnified by genotype for 16q22 (P for interaction = 7 × 10(-4)) but not 4q25 (P = 0.83). In prospective analyses excluding patients with AF diagnosis prior to or simultaneously with HF diagnosis, 16q22 but not 4q25 remained robustly associated with AF (hazard ratio 1.96, 95% CI 1.40-2.73, P = 8 × 10(-5)). The proportion of AF diagnoses in HF patients attributable to polymorphisms was 19% and 12%, respectively.
  
  
  CONCLUSIONS
  A polymorphism in the ZFHX3 gene, encoding a cardiac transcription factor, was associated with increased AF risk in HF patients, and the genetic association with AF was more pronounced in HF patients than in the general population.
authors.affiliation: Department of Cardiology, Lund University, Lund, Sweden. gustav.smith@med.lu.se
authors.forename: J Gustav
authors.initials: JG
authors.lastname: Smith
authors.forename: Olle
authors.initials: O
authors.lastname: Melander
authors.forename: Marketa
authors.initials: M
authors.lastname: Sjögren
authors.forename: Bo
authors.initials: B
authors.lastname: Hedblad
authors.forename: Gunnar
authors.initials: G
authors.lastname: Engström
authors.forename: Christopher
authors.initials: C
authors.lastname: Newton-Cheh
authors.forename: Pyotr G
authors.initials: PG
authors.lastname: Platonov
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001281:Atrial Fibrillation / Q000150:complications / Q000235:genetics*; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006333:Heart Failure / Q000150:complications*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors; D013548:Sweden
chemical_list: D018398:Homeodomain Proteins; C071660:ZFHX3 protein, human