Platelet glycoprotein IIIa Pl(a) polymorphism, fibrinogen, and platelet aggregability: The Framingham Heart Study.
BACKGROUND
Recent data suggest that the Pl(A2) allele of the platelet glycoprotein IIIa receptor may be a genetic risk factor for cardiovascular disease. We previously reported that the Pl(A2) allele was associated with increased platelet aggregability, as indicated by lower epinephrine threshold concentrations. Paradoxically, however, it has been reported that Pl(A2)-positive platelets have reduced fibrinogen binding. Because fibrinogen mediates platelet aggregability, we hypothesized that plasma fibrinogen levels may interact with Pl(A) genotype in modulating platelet aggregability. Methods and Results-- Glycoprotein IIIa Pl(A) genotype, fibrinogen level, and platelet aggregability were ascertained in 1340 subjects enrolled into the Framingham Offspring Study. Platelet aggregability was evaluated by the Born method. Higher fibrinogen levels were associated with increased epinephrine-induced aggregation (P=0.002) and a trend for ADP-induced aggregation (P=0.07). The fibrinogen effect was genotype specific, however, in that the increase in platelet aggregability with higher fibrinogen was present for the Pl(A1/A1) genotype (P=0.0005 and P=0.03 for epinephrine- and ADP-induced aggregation, respectively) but not for the Pl(A2)-positive genotype (P>0.90).


CONCLUSIONS
Higher fibrinogen levels were associated with increased platelet aggregability. However, the association between fibrinogen and platelet aggregability was genotype specific. This interaction may be responsible for the conflicting findings regarding Pl(A) genotype and platelet aggregability. Further study of this gene-environment interaction may provide insight into cardiovascular disease risk.
Feng
D
D
Institute for Prevention of Cardiovascular Disease, Beth Israel Deaconess Medical Center, Boston, MA, USA. dfeng2@caregroup.harvard.edu
Lindpaintner
K
K
Larson
M G
MG
O'Donnell
C J
CJ
Lipinska
I
I
Sutherland
P A
PA
Mittleman
M
M
Muller
J E
JE
D'Agostino
R B
RB
Levy
D
D
Tofler
G H
GH
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000483:Alleles; D016824:Antigens, Human Platelet / Q000235:genetics*; D002318:Cardiovascular Diseases / Q000235:genetics; D004837:Epinephrine / Q000494:pharmacology; D000939:Epitopes / Q000235:genetics; D005260:Female; D005340:Fibrinogen / Q000032:analysis / Q000378:metabolism*; D005787:Gene Frequency; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005838:Genotype; D006720:Homozygote; D006801:Humans; D039661:Integrin beta3; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects / Q000235:genetics*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000235:genetics*; D011110:Polymorphism, Genetic; D012307:Risk Factors; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014841:von Willebrand Factor / Q000378:metabolism
D016824:Antigens, Human Platelet; D000939:Epitopes; C061248:ITGB3 protein, human; D039661:Integrin beta3; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D014662:Vasoconstrictor Agents; D014841:von Willebrand Factor; D000244:Adenosine Diphosphate; D005340:Fibrinogen; D004837:Epinephrine