The GPIIIa (β3 integrin) P1A polymorphism in the early development of coronary atherosclerosis

The GPIIIa (beta (3) integrin) is an integral part of two glycoprotein receptors - the GP(IIb/IIIa) fibrinogen receptors in platelets and the GP(V/IIIa) vitronectin receptors in endothelium and vascular smooth muscle cells (VSMC). 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 artery disease (CAD) and in coronary thrombosis. Whether the action of the Pl(A) polymorphism is due to differences in platelet aggregability or function of the VSMC and endothelial GPIIIa is not known. The association of the Pl(A) polymorphism with the early, non-complicated atherosclerosis and CAD was studied in the Helsinki Sudden Death Study (HSDS) comprising two independent, autopsy series of altogether 700 middle-aged Caucasian Finnish men (33-70 year) suffering sudden out-of-hospital death. The burden of complicated lesions was greater in men with the A2 allele (heterozygotes or homozygotes for A2) (P = 0.01) compared with Pl(A1/A1) homozygotes in the entire series. To further estimate the role of platelet-independent GPIIIa receptors, we excluded all cases with coronary thrombosis and thrombus-overlaid complicated lesions. In this subset of men, fibrous coronary lesions were more frequent (OR 2.9. P < 0.01) in the coronary arteries of Pl(A1/A1) homozygotes 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 with men with the A2 allele at this early, non-complicated stage of atherosclerosis. The findings of this study suggest that Pl(A1/A1) homozygotes may be prone to early atherosclerosis and more rapid progression of stable CAD whereas carriers of the Pl(A2) allele are more prone to thrombotic complications. We hypothesize that the Pl(A) polymorphism may account for the early atherosclerosis by affecting the function of endothelial and vSMC GP(V/IIIa) receptors, whereas the Pl(A) polymorphism on platelet GP(IIb/IIIa) receptors may play a major role in coronary thrombosis. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.