Twelve–Single Nucleotide Polymorphism Genetic Risk Score Identifies Individuals at Increased Risk for Future Atrial Fibrillation and Stroke
Twelve–Single Nucleotide Polymorphism Genetic Risk Score Identifies Individuals at Increased Risk for Future Atrial Fibrillation and Stroke
- Hayato Tada, MD*,
- Dov Shiffman, PhD*,
- J. Gustav Smith, MD, PhD,
- Marketa Sjögren, PhD,
- Steven A. Lubitz, MD, MPH,
- Patrick T. Ellinor, MD, PhD,
- Judy Z. Louie, MSc,
- Joseph J. Catanese, MSc,
- Gunnar Engström, MD, PhD,
- James J. Devlin, PhD,
- Sekar Kathiresan, MD* and
- Olle Melander, MD, PhD*
+ Author Affiliations
From the Center for Human Genetic Research and Cardiovascular Research Center (H.T., S.A.L., P.T.E., S.K.) and Cardiac Arrhythmia Service (S.A.L., P.T.E.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (H.T., S.K.); Department of Medicine, Harvard Medical School, Boston, MA (H.T., P.T.E., S.K.); Quest Diagnostics, Science and Innovation Group, Alameda, CA (D.S., J.Z.L., J.J.C., J.J.D.); Department of Cardiology, Lund University, Lund, Sweden (J.G.S.); Department of Clinical Sciences, Lund University, Malmö, Sweden (M.S., G.E., O.M.); and Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden (O.M.).
- Correspondence to Dov Shiffman, PhD, Quest Diagnostics, Science and Innovation Group, 1401 Harbor Bay Pkwy, Alameda, CA 94502, E-mail dov.shiffman@celera.com; or Sekar Kathiresan, MD, Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, 185 Cambridge Street, CPZN 5.252, Boston, MA 02114, E-mail sekar@broadinstitute.org; or Olle Melander, MD, PhD, Department of Internal Medicine, Skåne University Hospital, SE 205 02 Malmö, Sweden, E-mail olle.melander@med.lu.se
-
↵* Drs Tada, Shiffman, Kathiresan, and Melander contributed equally.
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.
Key Words:
- Received May 7, 2014.
- Revision received July 13, 2014.
- Accepted July 15, 2014.
- © 2014 American Heart Association, Inc.