Influence of platelet collagen receptor polymorphisms on risk for arterial thrombosis.
BACKGROUND
Collagens are major components of the vascular subendothelium, and the interaction of platelets with collagens initiates normal hemostasis or pathologic arteriothrombosis. Genetic factors that affect the interaction of platelets with collagens could represent risk factors for either arteriothrombosis or excessive hemorrhage. In this regard, we first found that platelet levels of one of the major platelet collagen receptors, integrin alpha(2)beta(1), vary up to 10-fold in normal healthy individuals and that the higher-level phenotype is associated with allele 1 (807T) of the integrin alpha(2) gene. More recently, we found that there is roughly a fivefold range in platelet glycoprotein VI content among normal individuals, which may also influence risk for thromboembolism.


OBJECTIVE
To determine if genetic polymorphisms of platelet glycoproteins involved in collagen-related function are associated with higher risk for thrombotic disorders, such as coronary heart disease, myocardial infarction, or stroke.


METHODS
We examined the genetic mechanisms responsible for variation in expression levels of the collagen receptor integrin alpha(2)beta(1) and the potential influence of this variation on risk for thrombotic diseases.


RESULTS
We found that patients with arteriothrombotic diseases have a higher frequency of alpha(2) allele 1 (associated with higher levels of platelet integrin alpha(2)beta(1)). We further found that platelet glycoprotein VI content directly correlates with platelet prothrombinase activity, suggesting that a higher phenotype of platelet glycoprotein VI also may contribute to increased risk of arteriothrombotic diseases.


CONCLUSIONS
Genetic polymorphisms that influence the level or function of platelet collagen receptors need to be seriously considered as genetic risk factors for arteriothrombotic diseases.
Furihata
Kenichi
K
Roon Research Center for Arteriosclerosis and Thrombosis, Division of Experimental Hemostasis and Thrombosis, Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Nugent
Diane J
DJ
Kunicki
Thomas J
TJ
D001157:Arterial Occlusive Diseases / Q000235:genetics* / Q000378:metabolism; D001792:Blood Platelets / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000096:biosynthesis / Q000235:genetics*; D010980:Platelet Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D038981:Receptors, Collagen; D012307:Risk Factors; D013923:Thromboembolism / Q000235:genetics* / Q000378:metabolism
D016023:Integrins; D010980:Platelet Membrane Glycoproteins; D038981:Receptors, Collagen; C098341:platelet membrane glycoprotein VI; D003094:Collagen