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. 2018 Mar 6;137(10):1027-1038.
doi: 10.1161/CIRCULATIONAHA.117.031431. Epub 2017 Nov 12.

Genetic Predisposition, Clinical Risk Factor Burden, and Lifetime Risk of Atrial Fibrillation

Lu-Chen Weng  1   2 , Sarah R Preis  3   4 , Olivia L Hulme  1   2 , Martin G Larson  3   4 , Seung Hoan Choi  2 , Biqi Wang  3 , Ludovic Trinquart  3   4 , David D McManus  5 , Laila Staerk  4   6 , Honghuang Lin  4   7 , Kathryn L Lunetta  3   4 , Patrick T Ellinor  1   8   2 , Emelia J Benjamin  4   9 , Steven A Lubitz  10   8   2
Affiliations

Genetic Predisposition, Clinical Risk Factor Burden, and Lifetime Risk of Atrial Fibrillation

Lu-Chen Weng et al. Circulation. .

Abstract

Background: The long-term probability of developing atrial fibrillation (AF) considering genetic predisposition and clinical risk factor burden is unknown.

Methods: We estimated the lifetime risk of AF in individuals from the community-based Framingham Heart Study. Polygenic risk for AF was derived using a score of ≈1000 AF-associated single-nucleotide polymorphisms. Clinical risk factor burden was calculated for each individual using a validated risk score for incident AF comprised of height, weight, systolic and diastolic blood pressure, current smoking status, antihypertensive medication use, diabetes mellitus, history of myocardial infarction, and history of heart failure. We estimated the lifetime risk of AF within tertiles of polygenic and clinical risk.

Results: Among 4606 participants without AF at 55 years of age, 580 developed incident AF (median follow-up, 9.4 years; 25th-75th percentile, 4.4-14.3 years). The lifetime risk of AF >55 years of age was 37.1% and was substantially influenced by both polygenic and clinical risk factor burden. Among individuals free of AF at 55 years of age, those in low-polygenic and clinical risk tertiles had a lifetime risk of AF of 22.3% (95% confidence interval, 15.4-9.1), whereas those in high-risk tertiles had a risk of 48.2% (95% confidence interval, 41.3-55.1). A lower clinical risk factor burden was associated with later AF onset after adjusting for genetic predisposition (P<0.001).

Conclusions: In our community-based cohort, the lifetime risk of AF was 37%. Estimation of polygenic AF risk is feasible and together with clinical risk factor burden explains a substantial gradient in long-term AF risk.

Keywords: atrial fibrillation; epidemiology; genetics; lifetime risk; polygenic risk; risk factor; risk stratification.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr. Ellinor is a principal investigator on a Bayer HealthCare grant to the Broad Institute related to the development of new therapeutics for atrial fibrillation.

Figures

Figure 1
Figure 1. Defining polygenic risk for atrial fibrillation (AF)
In total, we derived 30 candidate polygenic risk scores from the results of a prior genetic association study of AF. Each risk score was comprised of candidate single nucleotide polymorphisms (SNPs) selected based on a varying strength of SNP association with AF in the prior analysis (x-axis) and the degree of linkage disequilibrium between each SNP (y-axis). Polygenic risk scores were then created as outlined in the methods section using a linear weighted approach and tested for association with AF in an independent sample from the UK Biobank (N=120,286 individuals of European ancestry total, 2,987 with AF). The most informative, or optimal, polygenic risk score was defined as that with the best model fit as defined by the lowest Akaike's Information Criterion (AIC). Colors correspond to model fit, with yellow indicating a better fit. All scores were highly associated with AF in the optimization sample (P value range 3.1×10-55 to 1.5×10-146). The optimal score was comprised of 1,168 SNPs.
Figure 2
Figure 2. Lifetime risk of atrial fibrillation (AF) at selected attained ages, adjusted for the competing risk of death
Lifetime risk of AF in Framingham Heart Study participants for a given attained age is cumulative through age 95 years.
Figure 3
Figure 3. Lifetime risk of atrial fibrillation (AF) stratified by polygenic risk or clinical risk factor burden tertiles adjusted for the competing risk of death
Panels display the lifetime risk of AF in Framingham Heart Study participants stratified by low, intermediate, and high polygenic risk (A-C) or clinical risk factor burden (D-F) at attained ages of 55, 65, and 75 years free of AF.
Figure 4
Figure 4. Lifetime risk of atrial fibrillation (AF) stratified by polygenic risk within clinical risk factor burden tertiles adjusted for the competing risk of death
Panels display the lifetime risk of AF in Framingham Heart Study participants stratified by low, intermediate, and high polygenic risk and clinical risk factor burden at attained ages of 55 years (A-C), 65 years (D-F), and 75 years (G-I).
Figure 5
Figure 5. Age of atrial fibrillation (AF) onset stratified by clinical and polygenic risk
Gray dots indicate the age of onset of AF in Framingham Heart Study participants free of AF at age 55 years who subsequently developed AF. The white and dark grey lines represent the mean and median age of AF onset, respectively, boxes represent the interquartile range, and whiskers correspond to range of age of onset of AF. The two-side P values were <0.001 for the associations between clinical risk factor burden and age of AF onset within each tertile of polygenic risk score.
See this image and copyright information in PMC

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