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. 2014 Oct;45(10):2856-2862.
doi: 10.1161/STROKEAHA.114.006072. Epub 2014 Aug 14.

Twelve-single nucleotide polymorphism genetic risk score identifies individuals at increased risk for future atrial fibrillation and stroke

Hayato Tada #  1   2   3 , Dov Shiffman #  4 , J Gustav Smith  5 , Marketa Sjögren  6 , Steven A Lubitz  1   7 , Patrick T Ellinor  1   3   7 , Judy Z Louie  4 , Joseph J Catanese  4 , Gunnar Engström  6 , James J Devlin  4 , Sekar Kathiresan #  1   2   3 , Olle Melander #  6   8
Affiliations

Twelve-single nucleotide polymorphism genetic risk score identifies individuals at increased risk for future atrial fibrillation and stroke

Hayato Tada et al. Stroke. 2014 Oct.

Abstract

Background and purpose: Atrial fibrillation (AF) is prevalent and there is a clinical need for biomarkers to identify individuals at higher risk for AF. Fixed throughout a life course and assayable early in life, genetic biomarkers may meet this need. Here, we investigate whether multiple single nucleotide polymorphisms together as an AF genetic risk score (AF-GRS) can improve prediction of one's risk for AF.

Methods: In 27 471 participants of the Malmö Diet and Cancer Study, a prospective, community-based cohort, we used Cox models that adjusted for established AF risk factors to assess the association of AF-GRS with incident AF and ischemic stroke. Median follow-up was 14.4 years for incident AF and 14.5 years for ischemic stroke. The AF-GRS comprised 12 single nucleotide polymorphisms that had been previously shown to be associated with AF at genome-wide significance.

Results: During follow-up, 2160 participants experienced a first AF event and 1495 had a first ischemic stroke event. Participants in the top AF-GRS quintile were at increased risk for incident AF (hazard ratio, 2.00; 95% confidence interval, 1.73-2.31; P=2.7×10(-21)) and ischemic stroke (hazard ratio, 1.23; 95% confidence interval, 1.04-1.46; P=0.02) when compared with the bottom quintile. Addition of the AF-GRS to established AF risk factors modestly improved both discrimination and reclassification (P<0.0001 for both).

Conclusions: An AF-GRS can identify 20% of individuals who are at ≈2-fold increased risk for incident AF and at 23% increased risk for ischemic stroke. Targeting diagnostic or therapeutic interventions to this subset may prove clinically useful.

Keywords: atrial fibrillation; polymorphism, single nucleotide; stroke.

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Figures

Figure 1
Figure 1. Cumulative incident atrial fibrillation events according to AF-GRS quintile
Black: GRS Quintile 1. Red: GRS Quintile 2. Green: GRS Quintile 3. Blue: GRS Quintile 4. Light blue: GRS Quintile 5.
Figure 2
Figure 2. Cumulative incident atrial fibrillation events according to median age, AFGRS quintile, and hypertension status
Panel A: Subgroup with age greater than median. Blue: The highest GRS (Quintile 5) with hypertension. Green: The lowest GRS (Quintile 1) with hypertension. Red: The highest GRS (Quintile 5) without hypertension. Black: The lowest GRS (Quintile 1) without hypertension. Median age for this older group is 64.2, IQR 61.1 to 67.6. Panel B: Subgroup with age below median. Blue: The highest GRS (Quintile 5) with hypertension. Green: The lowest GRS (Quintile 1) with hypertension. Red: The highest GRS (Quintile 5) without hypertension. Black: The lowest GRS (Quintile 1) without hypertension. Median age for this group is 51.1 IQR 48.8 to 54.2.
Figure 2
Figure 2. Cumulative incident atrial fibrillation events according to median age, AFGRS quintile, and hypertension status
Panel A: Subgroup with age greater than median. Blue: The highest GRS (Quintile 5) with hypertension. Green: The lowest GRS (Quintile 1) with hypertension. Red: The highest GRS (Quintile 5) without hypertension. Black: The lowest GRS (Quintile 1) without hypertension. Median age for this older group is 64.2, IQR 61.1 to 67.6. Panel B: Subgroup with age below median. Blue: The highest GRS (Quintile 5) with hypertension. Green: The lowest GRS (Quintile 1) with hypertension. Red: The highest GRS (Quintile 5) without hypertension. Black: The lowest GRS (Quintile 1) without hypertension. Median age for this group is 51.1 IQR 48.8 to 54.2.
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