title: Association between familial atrial fibrillation and risk of new-onset atrial fibrillation.
abstract: BACKGROUND
  Although the heritability of atrial fibrillation (AF) is established, the contribution of familial AF to predicting new-onset AF remains unknown.
  
  
  OBJECTIVE
  To determine whether familial occurrence of AF is associated with new-onset AF beyond established risk factors.
  
  
  METHODS
  The Framingham Heart Study, a prospective community-based cohort study started in 1948. Original and Offspring Cohort participants were aged at least 30 years, were free of AF at the baseline examination, and had at least 1 parent or sibling enrolled in the study. The 4421 participants in this analysis (mean age, 54 [SD, 13] years; 54% women) were followed up through December 31, 2007.
  
  
  METHODS
  Incremental predictive value of incorporating different features of familial AF (any familial AF, premature familial AF [onset ≤65 years old], number of affected relatives, and youngest age of onset in a relative) into a risk model for new-onset AF.
  
  
  RESULTS
  Across 11,971 examinations during the period 1968-2007, 440 participants developed AF. Familial AF occurred among 1185 participants (26.8%) and premature familial AF occurred among 351 participants (7.9%). Atrial fibrillation occurred more frequently among participants with familial AF than without familial AF (unadjusted absolute event rates of 5.8% and 3.1%, respectively). The association was not attenuated by adjustment for AF risk factors (multivariable-adjusted hazard ratio, 1.40; 95% confidence interval [CI], 1.13-1.74) or reported AF-related genetic variants. Among the different features of familial AF examined, premature familial AF was associated with improved discrimination beyond traditional risk factors to the greatest extent (traditional risk factors, C statistic, 0.842 [95% CI, 0.826-0.858]; premature familial AF, C statistic, 0.846 [95% CI, 0.831-0.862]; P = .004). Modest changes in integrated discrimination improvement were observed with premature familial AF (2.1%). Net reclassification improvement (assessed using 8-year risk thresholds of <5%, 5%-10%, and >10%) did not change significantly with premature familial AF (index statistic, 0.011; 95% CI, -0.021 to 0.042; P = .51), although categoryless net reclassification was improved (index statistic, 0.127; 95% CI, 0.064-0.189; P = .009).
  
  
  CONCLUSIONS
  In this cohort, familial AF was associated with an increased risk of AF that was not attenuated by adjustment for AF risk factors including genetic variants. Assessment of premature familial AF was associated with a very slight increase in predictive accuracy compared with traditional risk factors.
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Lubitz
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Yin
authors.forename: João D
authors.initials: JD
authors.lastname: Fontes
authors.forename: Jared W
authors.initials: JW
authors.lastname: Magnani
authors.forename: Michiel
authors.initials: M
authors.lastname: Rienstra
authors.forename: Manju
authors.initials: M
authors.lastname: Pai
authors.forename: Mark L
authors.initials: ML
authors.lastname: Villalon
authors.forename: Ramachandran S
authors.initials: RS
authors.lastname: Vasan
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Pencina
authors.forename: Daniel
authors.initials: D
authors.lastname: Levy
authors.forename: Martin G
authors.initials: MG
authors.lastname: Larson
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Ellinor
authors.forename: Emelia J
authors.initials: EJ
authors.lastname: Benjamin
mesh_terms: D000328:Adult; D000368:Aged; D001281:Atrial Fibrillation / Q000453:epidemiology / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D012306:Risk; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics