Advanced

Genetic Risk Prediction of Atrial Fibrillation

Lubitz, Steven A; Yin, Xiaoyan; Lin, Henry J.; Kolek, Matthew; Smith, Gustav G. LU ; Trompet, Stella; Rienstra, Michiel; Rost, Natalia S.; Teixeira, Pedro L. and Almgren, Peter LU , et al. (2017) In Circulation 135(14). p.1311-1320
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 five 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 3,028 referents. Scores were based on 11 to 719 common variants (≥5%) associated with AF at P-values ranging from <1x10 to <1x10 in a prior independent genetic association... (More)

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 five 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 3,028 referents. Scores were based on 11 to 719 common variants (≥5%) associated with AF at P-values ranging from <1x10 to <1x10 in a prior independent genetic association study. RESULTS—: Incident AF occurred in 1,032 (5.5%) individuals. AF genetic risk scores were associated with new-onset AF after adjusting 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%CI, 1.13-1.46; P=1.5x10) to 1.67 (25 variants; 95%CI, 1.47-1.90; P=9.3x10). 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%CI, 1.39-4.58; P=2.7x10). The effect persisted after excluding individuals (n=70) with known AF (odds ratio, 2.25; 95%CI, 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, though 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.

(Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Circulation
volume
135
issue
14
pages
1311 - 1320
publisher
Lippincott Williams and Wilkins
external identifiers
  • scopus:85014184817
  • wos:000398053500013
ISSN
0009-7322
DOI
10.1161/CIRCULATIONAHA.116.024143
language
English
LU publication?
yes
id
bfa7eeb8-7800-4294-87e3-afc319bc831a
date added to LUP
2017-03-17 15:36:25
date last changed
2018-01-07 11:56:17
@article{bfa7eeb8-7800-4294-87e3-afc319bc831a,
  abstract     = {<p>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 five 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 3,028 referents. Scores were based on 11 to 719 common variants (≥5%) associated with AF at P-values ranging from &lt;1x10 to &lt;1x10 in a prior independent genetic association study. RESULTS—: Incident AF occurred in 1,032 (5.5%) individuals. AF genetic risk scores were associated with new-onset AF after adjusting 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%CI, 1.13-1.46; P=1.5x10) to 1.67 (25 variants; 95%CI, 1.47-1.90; P=9.3x10). 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%CI, 1.39-4.58; P=2.7x10). The effect persisted after excluding individuals (n=70) with known AF (odds ratio, 2.25; 95%CI, 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, though 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.</p>},
  author       = {Lubitz, Steven A and Yin, Xiaoyan and Lin, Henry J. and Kolek, Matthew and Smith, Gustav G. and Trompet, Stella and Rienstra, Michiel and Rost, Natalia S. and Teixeira, Pedro L. and Almgren, Peter and Anderson, Christopher D. and Chen, Lin Y. and Engström, Gunnar and Ford, Ian and Furie, Karen L. and Guo, Xiuqing and Larson, Martin G. and Lunetta, Kathryn L. and Macfarlane, Peter W and Psaty, Bruce M. and Soliman, Elsayed Z and Sotoodehnia, Nona and Stott, David J. and Taylor, Kent D and Weng, Lu Chen and Yao, Jie and Geelhoed, Bastiaan and Verweij, Niek and Siland, Joylene E. and Kathiresan, Sekar and Roselli, Carolina and Roden, Dan M and van der Harst, Pim and Darbar, Dawood and Jukema, J. Wouter and Melander, Olle and Rosand, Jonathan and Rotter, Jerome I. and Heckbert, Susan R and Ellinor, Patrick T and Alonso, Alvaro and Benjamin, Emelia J and , },
  issn         = {0009-7322},
  language     = {eng},
  month        = {03},
  number       = {14},
  pages        = {1311--1320},
  publisher    = {Lippincott Williams and Wilkins},
  series       = {Circulation},
  title        = {Genetic Risk Prediction of Atrial Fibrillation},
  url          = {http://dx.doi.org/10.1161/CIRCULATIONAHA.116.024143},
  volume       = {135},
  year         = {2017},
}