(Circulation. 2001;103:3051.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Genetic and Environmental Contributions to Platelet Aggregation
The Framingham Heart Study
From the National Heart, Lung, and Blood Institute’s Framingham Heart Study (C.J.O., M.G.L., P.A.S., D.L.), Framingham, Mass; the Cardiology Division (C.J.O.), Department of Medicine, Massachusetts General Hospital; the Institute for Prevention of Cardiovascular Disease (D.F., G.H.T.) and the Division of Cardiology (D.L., G.H.T.), Beth Israel Deaconess Medical Center; the Cardiovascular Division (K.L.), Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; the Departments of Neurology (R.H.M.) and Preventive Medicine and Epidemiology (M.G.L., D.L.), Boston University School of Medicine, Boston, Mass; the Department of Mathematics (R.A.D.), Boston University, Boston, Mass; F. Hoffman-LaRoche (K.L.), Basel, Switzerland; and the National Heart, Lung, and Blood Institute, National Institutes of Health (C.J.O., D.L.), Bethesda, Md.
Correspondence to Christopher J. O’Donnell, MD, MPH, Framingham Heart Study, 5 Thurber Street, Framingham, MA 01701. E-mail chris{at}fram.nhlbi.nih.gov
Background—Platelet aggregation plays an important role in arterial thrombosis in coronary heart disease, stroke, and peripheral arterial disease. However, the contribution of genetic versus environmental influences on interindividual variation in platelet aggregability is poorly characterized.
Methods and Results—We studied the heritability of platelet aggregation responses in 2413 participants in the Framingham Heart Study. The threshold concentrations of epinephrine and ADP required to produce biphasic platelet aggregation and collagen lag time were determined. Mixed-model linear regression was used to calculate correlation coefficients within sibships and within spouse pairs. Variance and covariance component methods were used to estimate the proportion of platelet aggregation attributable to measured covariates versus additive genetic effects. After accounting for environmental covariates, the adjusted sibling correlations for epinephrine, ADP, and collagen lag time were 0.24, 0.22, and 0.31, respectively (P=0.0001 for each). In contrast, adjusted correlations for spouse-pairs were -0.01, 0.05, and -0.02, respectively (all P>0.30). The estimated heritabilities were 0.48, 0.44, and 0.62, respectively. Measured covariates accounted for only 4% to 7% of the overall variance in platelet aggregation, and heritable factors accounted for 20% to 30%. The platelet glycoprotein IIIa PlA2 polymorphism and the fibrinogen Hind III ß-148 polymorphism contributed <1% to the overall variance.
Conclusions—In our large, population-based sample, heritable factors play a major role in determining platelet aggregation, and measured covariates play a lesser role. Future studies are warranted to identify the key genetic variants that regulate platelet function and to lay the groundwork for rational pharmacogenetic approaches.
Key Words: platelets • genetics • glycoproteins • fibrinogen
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