Association Between Familial Atrial Fibrillation and Risk of New-Onset Atrial Fibrillation
Open accessAbstract
CONTEXT: 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. DESIGN, SETTING, AND PARTICIPANTS: 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. MAIN OUTCOME MEASURES: 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.
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Information about family history of AF was not routinely available for this cohort.
“And information about family history of AF was not routinely available for this cohort.40”
From Twelve-single nucleotide polymorphism genetic risk score identifies individuals at increased risk for future atrial fibrillation and stroke (2014) · cites this paper as [40]
The KCNE5 variant might contribute to the lower prevalence of AF in women because women have two copies of the X chromosome whereas men have one.
“Since women have two copies of the X chromosome whereas men have one, the investigators suggested that the variant might contribute to the lower prevalence of AF in women.”
From Atrial fibrillation in women: epidemiology, pathophysiology, presentation, and prognosis (2016) · cites this paper as [57]
A genetic variant in the X-linked gene KCNE5 was more frequent in controls than in patients with AF and was found to be protective of AF.
“In 2005, Ravn et al. discovered a genetic variant in the X-linked gene KCNE5 that was more frequent in 96 controls than in 158 patients with AF, and that was found to be protective of AF.57”
From Atrial fibrillation in women: epidemiology, pathophysiology, presentation, and prognosis (2016) · cites this paper as [57]
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- Authors
- Lubitz, S. A., Yin, X., Fontes, J. D., Magnani, J. W., Rienstra, M., Pai, M., Villalon, M. L., Vasan, R. S., Pencina, M. J., Levy, D., Larson, M. G., Ellinor, P. T., & Benjamin, E. J.
- Affiliations
- Massachusetts General Hospital (US)
- Framingham Heart Study (US)
- Boston University (US)
- University Medical Center Groningen (NL)
- National Heart, Lung, and Blood Institute (US)
- Harvard University (US)
- ORCID
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2010-11-24
- Volume
- 304
- Issue
- 20
- Pages
- 2263
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- PMC
- PMC3073054
- OpenAlex
- W2133128268
- Cited by
- 313
- References
- 36
- Citations by year
- 2026: 9 · 2025: 7 · 2024: 18 · 2023: 13 · 2022: 16 · 2021: 21 · 2020: 23 · 2019: 22 · 2018: 20 · 2017: 27 · 2016: 32 · 2015: 15 · 2014: 23 · 2013: 26 · 2012: 26
- FWCI
- 14.27
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JAMA (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (825.09.020)
- National Institutes of Health
- National Institute on Aging (R01AG028321)
- National Heart, Lung, and Blood Institute (HL104156, L30 HL097675, RC1-HL01056, R01HL104156, R01HL102214, HL092577, Z01HL001056, T32HL007575, R01HL092577)
- National Institute on Drug Abuse (DA027021, R21DA027021)
- National Institute of Neurological Disorders and Stroke (6R01NS17950, R01NS017950)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Atrial Fibrillation Management and Outcomes
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cardiovascular and Diving-Related Complications
- Keywords
- atrial fibrillation, familial atrial fibrillation, new-onset atrial fibrillation, heritability, risk prediction model, risk factors, Framingham Heart Study, genetic variants, integrated discrimination improvement, net reclassification improvement, cardiovascular risk stratification, atrial fibrillation prevention, anticoagulation
- MeSH terms
- Adult, Aged, Atrial Fibrillation, Female, Humans, Male, Middle Aged, Risk, United States, Cohort Studies, Genetic Predisposition to Disease, White People
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