The GPIIIa (beta(3) integrin) P1(A) polymorphism in the early development of coronary atherosclerosis

The GPIIIa (beta (3) integrin) is an integral part of two glycoprotein rece ptors - the GP(IIb/IIIa) fibrinogen receptors in platelets and the GP(V/III a) vitronectin receptors in endothelium and vascular smooth muscle cells (V SMC). The pl(A) polymorphism of the gene for GPIIIa (beta (3) integrin) has been suggested to play an important role in the progression of coronary ar tery disease (CAD) and in coronary thrombosis. Whether the action of the Pl (A) polymorphism is due to differences in platelet aggregability or functio n of the VSMC and endothelial GPIIIa is not known. The association of the P l(A) polymorphism with the early, non-complicated atherosclerosis and CAD w as studied in the Helsinki Sudden Death Study (HSDS) comprising two indepen dent, autopsy series of altogether 700 middle-aged Caucasian Finnish men (3 3-70 year) suffering sudden out-of-hospital death. The burden of complicate d lesions was greater in men with the A2 allele (heterozygotes or homozygot es for A2) (P = 0.01) compared with Pl(A1/A1) homozygotes in the entire ser ies. To further estimate the role of platelet-independent GPIIIa receptors, we excluded all cases with coronary thrombosis and thrombus-overlaid compl icated lesions. In this subset of men, fibrous coronary lesions were more f requent (OR 2.9. P < 0.01) in the coronary arteries of Pl(A1/A1) homozygote s compared with men with the Pl(A2) allele. Moreover, men with the Pl(A1/A1 ) genotype also had more stenotic coronary arteries (P < 0.05) compared wit h men with the A2 allele at this early, non-complicated stage of atheroscle rosis. The findings of this study suggest that Pl(A1/A1) homozygotes may be prone to early atherosclerosis and more rapid progression of stable CAD wh ereas carriers of the Pl(A2) allele are more prone to thrombotic complicati ons. We hypothesize that the Pl(A) polymorphism may account for the early a therosclerosis by affecting the function of endothelial and vSMC GP(V/IIIa) receptors, whereas the Pl(A) polymorphism on platelet GP(IIb/IIIa) recepto rs may play a major role in coronary thrombosis. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.