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Fox CS, Parise H, D'Agostino, Sr RB, et al. Parental Atrial Fibrillation as a Risk Factor for Atrial Fibrillation in Offspring. JAMA. 2004;291(23):2851–2855. doi:10.1001/jama.291.23.2851
Context Atrial fibrillation (AF) is the most common cardiac dysrhythmia in the
United States. Whereas rare cases of familial AF have been reported, it is
unknown if AF among unselected individuals is a heritable condition.
Objective To determine whether parental AF increases the risk for the development
of offspring AF.
Design, Setting, and Participants Prospective cohort study (1983-2002) within the Framingham Heart Study,
a population-based epidemiologic study. Participants were 2243 offspring (1165
women, 1078 men) at least 30 years of age and free of AF whose parents had
both been evaluated in the original cohort.
Main Outcome Measures Development of new-onset AF in the offspring was prospectively examined
in association with previously documented parental AF.
Results Among 2243 offspring participants, 681 (30%) had at least 1 parent with
documented AF; 70 offspring participants (23 women; mean age, 62 [range, 40-81]
years) developed AF in follow-up. Compared with no parental AF, AF in at least
1 parent increased the risk of offspring AF (multivariable-adjusted odds ratio
[OR], 1.85; 95% confidence interval [CI], 1.12-3.06; P =
.02). These results were stronger when age was limited to younger than 75
years in both parents and offspring (multivariable-adjusted OR, 3.23; 95%
CI, 1.87-5.58; P<.001) and when the sample was
further limited to those without antecedent myocardial infarction, heart failure,
or valve disease (multivariable-adjusted OR, 3.17; 95% CI, 1.71-5.86; P<.001).
Conclusions Parental AF increases the future risk for offspring AF, an observation
supporting a genetic susceptibility to developing this dysrhythmia. Further
research into the genetic factors predisposing to AF is warranted.
Atrial fibrillation (AF) is the most common cardiac dysrhythmia in the
United States, affecting approximately 2.3 million adults1 and
resulting in substantial societal costs.2 Atrial
fibrillation increases the risk of stroke,3 heart
failure,3,4 and mortality.3,5 The prevalence of AF is increasing
and is projected to affect 5.6 million Americans by 2050.1 Known
risk factors for AF include male sex, advancing age, diabetes, hypertension,
heart failure, myocardial infarction, and valvular heart disease.4,6,7
However, much of the variability in risk for AF remains unexplained,6 leading investigators to look for novel and genetic
risk factors for AF. Rare familial forms of AF have been reported, and loci
have been mapped to chromosomes 10q22-248 and
6q14-16.9 A gain-of-function mutation in the KCNQ1 gene has been implicated in a family with persistent
AF.10 Although a genetic basis of AF in selected
patients has been described, it is unknown if there is a genetic component
to AF in the general population. Thus, we sought to test whether documented
parental AF was associated with increased risk of AF in a community-based
Beginning in 1948, 5209 men and women aged 28 to 62 years were enrolled
into the "original" (ie, "parental") cohort of the Framingham Heart Study.
Offspring and their spouses (n = 5124) were enrolled in the "offspring" cohort
starting in 1971. The design of the study11,12 and
methods of risk factor measurement have been described in detail elsewhere.13 Routine clinic examinations included structured interviews,
physical examinations, laboratory tests, and electrocardiograms. The Boston
Medical Center institutional review board approved the study, and all participants
provided written informed consent.
Framingham Offspring Study participants were included for study in this
investigation if they had 2 biological parents in the original cohort, were
at least 30 years of age, and were free of AF at the baseline examination
(occurring after 1982). Because offspring participants were examined every
4 years, covariates were updated at each examination cycle, and 4-year follow-up
windows between examinations were studied for development of AF. Once participants
developed AF, they were censored from further follow-up.
Participants in the offspring and original cohorts were considered to
have AF if either atrial fibrillation or atrial flutter was confirmed on electrocardiogram.
Offspring AF cases were detected in the hospital (69%), by an outside physician
(14%), at the Framingham Heart Study examination (11%), or by careful review
of the participant's history only (6%), and confirmed upon review by 1 of
2 Framingham heart Study cardiologists. Parental AF had to occur temporally
before the onset of offspring AF; cases of first parental AF occurring after
development of AF in offspring were excluded (n = 5). We accrued parental
AF cases from 1949-2002 and offspring AF cases from 1983-2002. In prespecified
analyses, the overall sample was restricted to parental and offspring participants
younger than 75 years (ie, the median age of AF incidence14);
the offspring sample was additionally restricted to participants without antecedent
clinically overt heart disease (defined as myocardial infarction, heart failure,
or clinical valve disease [identified as any diastolic murmur, or systolic
murmur ≥3/6 on Framingham visit physician-administered physical examination]).
Among parents who did not develop AF during the study, 83% (n = 853) of mothers
and 69% (n = 688) of fathers were older than 70 years at death or at the end
of follow-up in 2002. Similarly, 62% (n = 638) of mothers and 39% (n = 386)
of fathers were older than 80 years at death or the end of follow-up.
Pooled logistic regression was used to examine the 4-year risk of incident
offspring AF associated with documented parental AF; pooled logistic regression
provides similar estimates to time-dependent Cox regression analysis.15 Person-examination observations were pooled over
a total of 4 baseline examinations, each with 4 years of follow-up; covariates
and outcome status were updated every 4 years over a total of 16 years. The
generalized estimating equations procedure in SAS version 816 was
used to account for correlations among family members. Odds ratios (ORs) and
95% confidence intervals (CIs) were calculated; the referent group consisted
of participants without parental AF. P<.05 (2-sided)
was used to determine statistical significance. Models were unadjusted, age-
and sex-adjusted, and multivariable-adjusted. Multivariable covariates were
chosen a priori based on standard risk factors for AF6 and
included age, sex, systolic blood pressure, hypertension treatment, diabetes,
and clinically overt heart disease (defined above).
To provide a visual display of the additional predictive information
conferred by parental AF status in the context of known risk factors, we computed
the 4-year predicted risk of AF per 1000 person-years over each follow-up
interval. Sex-specific values were constructed from the original models, based
on combinations of risk factor profiles (see Figure 1 legend).
The offspring study sample included 1165 women and 1078 men free of
AF at baseline (defined as the first examination attended after 1982). During
the offspring study period (1983-2002), 30% (681/2243) had at least 1 parent
with documented AF. Baseline clinical characteristics of offspring participants
did not vary by parental AF status (Table
Of eligible offspring participants, 70 (23 women) developed AF in follow-up,
with a mean age at onset of 62 years (range, 40-81). Offspring participants
with at least 1 parent with AF had an incidence rate of 4.5 per 1000 person-years,
compared with 3.0 per 1000 person-years in participants without parental AF
After multivariable adjustment, offspring AF was associated with maternal
AF (Table 2), particularly when
the parental and offspring samples were restricted to participants younger
than 75 years, as well as when further limited to offspring participants without
clinically overt heart disease, defined as antecedent myocardial infarction,
heart failure, or valve disease. Paternal AF was nonsignificantly associated
with offspring AF (Table 2) but
was significantly associated with offspring AF when the parental and offspring
samples were limited to those younger than 75 years and when offspring participants
with antecedent clinically overt heart disease were additionally removed.
Offspring AF was independently associated with at least 1 parent with
AF, especially when the parental and offspring samples were limited to participants
younger than 75 years and when offspring participants with antecedent clinically
overt heart disease were excluded.
Only 5 offspring AF cases had both parents with AF. Overall, the multivariable-adjusted
OR was 3.20 (95% CI, 1.15-8.91). The wide CIs reflect the very small number
of cases in this group.
Results were not substantively different if cases of atrial flutter
as the only documented atrial dysrhythmia (n = 3) were not considered cases
in the AF analyses. Similarly, when we considered smoking, body mass index,
and electrocardiographic evidence of left ventricular hypertrophy as additional
confounders, there were no material changes in the independent associations
of parental and offspring AF.
The 4-year predicted risk of AF based on the model for at least 1 affected
parent in the setting of different risk factor profiles was estimated assuming
an offspring mean age of 55 years (Figure
1). Having at least 1 affected parent approximately doubled the
risk of predicted AF when compared with models with either absent or present
coexisting risk factors.
Of the 70 offspring individuals with AF, 4 pairs belonged to the same
extended families. The only related pair of offspring with AF (siblings) did
not have documented parental AF.
In a population-based sample, parental AF independently predicted an
increased risk of offspring AF events after adjustment for standard AF risk
factors, including hypertension,17 diabetes,18,19 and myocardial infarction,20 which are known to have genetic components. This
finding suggests that potentially unaccounted-for genetic mechanisms may contribute
to the pathogenesis of AF. To our knowledge, our study is the first to demonstrate
that a familial component exists for AF among unselected community-based individuals.
Because disorders with a genetic predisposition often occur at a younger
age, or in the absence of major predisposing conditions, we performed analyses
restricting the sample to participants younger than 75 years and subsequently
eliminating those with clinically overt heart disease. Both analyses demonstrated
a lack of attenuation of the increased odds of offspring AF associated with
parental AF, lending further support to the hypothesis that there is a genetic
predisposition to AF.
Most studies to date have focused on families with large numbers of
affected individuals. Genetic linkage analyses have demonstrated logarithm
of odds scores of 3.6 on chromosome 10q22-248 and
4.9 on chromosome 6q12-14.9 Candidate genes
associated with AF have been identified, including a gain-of-function mutation
in KCNQ1, a gene encoding a potassium-channel subunit
associated with long-QT syndrome.10 In addition,
AF has been associated with polymorphisms in KCNE1 (a
gene also involved in potassium-channel physiology)21 and
in the renin-angiotensin system.22 Taken together,
these studies suggest that AF is potentially a heterogeneous disorder with
a significant genetic component.
A recent analysis of AF cases from an arrhythmia clinic found that 5%
of all patients with AF, and 15% of all patients with lone AF, had a family
history of this dysrhythmia.23 We demonstrated
that 30% of offspring were documented as having parents with AF. The higher
prevalence of parental AF in our study likely stemmed from the prospective
cohort design, which enabled us to more completely ascertain parental AF cases
and allowed us to follow the parental cohort to near extinction.
The strengths of this study include prospective collection and validation
of AF events by 1 of 2 Framingham Heart Study cardiologists in both the offspring
and parents, substantially reducing any possibility of recall bias. Moreover,
our sample was community-based and our participants were unselected, reducing
the likelihood that our sample had a unique mechanism underlying the AF cases.
It is unlikely that our results were driven by unusual families with rare
Limitations of our study include a small number of offspring with AF
(n = 70), a predominantly white sample, and a mean age of AF onset younger
than that reported in the United States.14 Because
of our sample's relatively young mean age, our AF cases have a lower prevalence
of hypertension and overt heart disease than the general AF population. Despite
the fact that the younger mean age limits the generalizability of our findings,
it does not limit our findings to younger patients with parental AF, who are
potentially the population most likely to be affected by genetic causes. Our
use of validated cases of parental AF reduces misclassification in our data
but potentially limits the usefulness of a parental history of AF in the clinical
setting, since offspring may incorrectly identify whether their parents had
AF. An additional limitation is that the effects of early family environmental
influences cannot be excluded as an alternate explanation for our findings,
but this appears less likely given the mean age of AF onset in our offspring
sample (62 years). We were unable to account for all potential risk factors
for AF that are known to have genetic components and thus may provide alternative
mechanisms to explain our findings, including C-reactive protein,24 hemostatic factors,25 left
atrial enlargement,26 Graves disease, and use
of alcohol.27 Lastly, we were unable to account
for echocardiographic features that are known to be associated with AF.26
Parental AF increases the risk of future offspring AF events, consistent
with a genetic contribution to the etiology of AF. Further research pertaining
to the etiology of AF, particularly additional basic and clinical investigations
into the genetic mechanisms involved in AF, is warranted. Data from animal
models may be helpful in elucidating genetic underpinnings of AF, particularly
now that mouse models of this dysrhythmia have been established.28 The
identification of genetic mechanisms in the pathophysiology of AF could help
guide research into the causes, prevention, and treatment of AF.
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