Genetic risk prediction of atrial fibrillation

Steven A. Lubitz, Xiaoyan Yin, Henry J. Lin, Matthew Kolek, J. Gustav Smith, Stella Trompet, Michiel Rienstra, Natalia S. Rost, Pedro L. Teixeira, Peter Almgren, Christopher D. Anderson, Lin Y. Chen, Gunnar Engström, Ian Ford, Karen L. Furie, Xiuqing Guo, Martin G. Larson, Kathryn L. Lunetta, Peter W. Macfarlane, Bruce M. PsatyElsayed Z. Soliman, Nona Sotoodehnia, David J. Stott, Kent D. Taylor, Lu Chen Weng, Jie Yao, Bastiaan Geelhoed, Niek Verweij, Joylene E. Siland, Sekar Kathiresan, Carolina Roselli, Dan M. Roden, Pim Van Der Harst, Dawood Darbar, J. Wouter Jukema, Olle Melander, Jonathan Rosand, Jerome I. Rotter, Susan R. Heckbert, Patrick T. Ellinor, Alvaro Alonso, Emelia J. Benjamin

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

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 ageand 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.

Original languageEnglish (US)
Pages (from-to)1311-1320
Number of pages10
JournalCirculation
Volume135
Issue number14
DOIs
StatePublished - Apr 4 2017

Keywords

  • atrial fibrillation
  • atrial flutter
  • forecasting
  • genetic association studies
  • stroke

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