Genetic and environmental contributions to platelet aggregation: the Framingham heart study.
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.


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 Pl(A2) polymorphism and the fibrinogen Hind III beta-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.
O'Donnell
C J
CJ
National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA. chris@fram.nhlbi.nih.gov
Larson
M G
MG
Feng
D
D
Sutherland
P A
PA
Lindpaintner
K
K
Myers
R H
RH
D'Agostino
R A
RA
Levy
D
D
Tofler
G H
GH
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D001665:Binding Sites / Q000235:genetics; D003094:Collagen / Q000494:pharmacology; D004247:DNA / Q000235:genetics / Q000378:metabolism; D015247:Deoxyribonuclease HindIII / Q000378:metabolism; D004837:Epinephrine / Q000494:pharmacology; D005260:Female; D005340:Fibrinogen / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010974:Platelet Aggregation / Q000187:drug effects / Q000235:genetics*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000235:genetics*; D011110:Polymorphism, Genetic; D012737:Sex Factors; D013997:Time Factors
D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D000244:Adenosine Diphosphate; D005340:Fibrinogen; D003094:Collagen; D004247:DNA; D015247:Deoxyribonuclease HindIII; D004837:Epinephrine