Genetic Risk Prediction of Atrial Fibrillation
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Published:2017-04-04
Issue:14
Volume:135
Page:1311-1320
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ISSN:0009-7322
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Container-title:Circulation
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language:en
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Short-container-title:Circulation
Author:
Lubitz Steven A.1, Yin Xiaoyan1, Lin Henry J.1, Kolek Matthew1, Smith J. Gustav1, Trompet Stella1, Rienstra Michiel1, Rost Natalia S.1, Teixeira Pedro L.1, Almgren Peter1, Anderson Christopher D.1, Chen Lin Y.1, Engström Gunnar1, Ford Ian1, Furie Karen L.1, Guo Xiuqing1, Larson Martin G.1, Lunetta Kathryn L.1, Macfarlane Peter W.1, Psaty Bruce M.1, Soliman Elsayed Z.1, Sotoodehnia Nona1, Stott David J.1, Taylor Kent D.1, Weng Lu-Chen1, Yao Jie1, Geelhoed Bastiaan1, Verweij Niek1, Siland Joylene E.1, Kathiresan Sekar1, Roselli Carolina1, Roden Dan M.1, van der Harst Pim1, Darbar Dawood1, Jukema J. Wouter1, Melander Olle1, Rosand Jonathan1, Rotter Jerome I.1, Heckbert Susan R.1, Ellinor Patrick T.1, Alonso Alvaro1, Benjamin Emelia J.1
Affiliation:
1. From Cardiac Arrhythmia Service (S.A.L., P.T.E.), Cardiovascular Research Center (S.A.L., L.-C.W., S.K., P.T.E.), J. Philip Kistler Stroke Research Center, Department of Neurology (N.S.R., C.D.A., J.R.), and Center for Human Genetic Research (C.D.A., S.K., J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge (S.A.L., C.D.A., L.-C.W., S.K., C.R., J.R., P.T.E.); Boston University and...
Abstract
Background:
Atrial fibrillation (AF) has a substantial genetic basis. Identification of individuals at greatest AF risk could minimize the incidence of cardioembolic stroke.
Methods:
To determine whether genetic data can stratify risk for development of AF, we examined associations between AF genetic risk scores and incident AF in 5 prospective studies comprising 18 919 individuals of European ancestry. We examined associations between AF genetic risk scores and ischemic stroke in a separate study of 509 ischemic stroke cases (202 cardioembolic [40%]) and 3028 referents. Scores were based on 11 to 719 common variants (≥5%) associated with AF at
P
values ranging from <1×10
−3
to <1×10
−8
in a prior independent genetic association study.
Results:
Incident AF occurred in 1032 individuals (5.5%). AF genetic risk scores were associated with new-onset AF after adjustment for clinical risk factors. The pooled hazard ratio for incident AF for the highest versus lowest quartile of genetic risk scores ranged from 1.28 (719 variants; 95% confidence interval, 1.13–1.46;
P
=1.5×10
−4
) to 1.67 (25 variants; 95% confidence interval, 1.47–1.90;
P
=9.3×10
−15
). Discrimination of combined clinical and genetic risk scores varied across studies and scores (maximum C statistic, 0.629–0.811; maximum ΔC statistic from clinical score alone, 0.009–0.017). AF genetic risk was associated with stroke in age- and sex-adjusted models. For example, individuals in the highest versus lowest quartile of a 127-variant score had a 2.49-fold increased odds of cardioembolic stroke (95% confidence interval, 1.39–4.58;
P
=2.7×10
−3
). The effect persisted after the exclusion of individuals (n=70) with known AF (odds ratio, 2.25; 95% confidence interval, 1.20–4.40;
P
=0.01).
Conclusions:
Comprehensive AF genetic risk scores were associated with incident AF beyond associations for clinical AF risk factors but offered small improvements in discrimination. AF genetic risk was also associated with cardioembolic stroke in age- and sex-adjusted analyses. Efforts are warranted to determine whether AF genetic risk may improve identification of subclinical AF or help distinguish between stroke mechanisms.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Physiology (medical),Cardiology and Cardiovascular Medicine
Cited by
89 articles.
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