Heart disease is one of the leading causes of death in adults. Its prevalence has been linked with aging and a number of environmental and dietary risk factors, such as lack of exercise, consumption of high levels of saturated fat, and lack of antioxidants in the diet. However, every year, individuals who do not fit these established risk profiles fall victim to the disease in its many forms. Especially puzzling are those cases of heart disease among relatively young persons, for example persons under 60 years of age.
It is known that formation of a platelet aggregate at the site of a ruptured coronary plaque is implicated in the pathogenesis of myocardial infarction (MI)and unstable angina (USA) (Y. Jang et al., J. Am Coll. Cardiol. 24:1591-1601, 1994; N. A. Flores et al., Cardiovasc. Res. 28:295-302, 1994; Chandler, et al., Amer J Card. 34:823, 1974; Fuster, et al., N Engl J Med, 3:242, 1992; DeWood, et al., N Engl J Med., 31:417, 1986). Formation of platelet aggregates requires binding of fibrinogen, and in some situations, von Willebrand factor, to the glycoprotein IIb-IIIa (GPIIb-IIIa) receptor. Over the past ten years, large trials of various inhibitors of platelet function, such as aspirin and antibodies, particularly monoclonal antibody directed against the platelet GPIIb/IIIa receptor complex, have demonstrated a significant benefit both in preventing and in reducing the mortality and morbidity of unstable coronary syndromes such as MI, USA, and restenosis after angioplasty. Additional studies have linked ex vivo platelet reactivity to outcome in post-MI patients (M. D. Trip et al., N. Engl. J. Med. 322:1549-54, 1990).
The fibrinogen receptor, GPIIb-IIIa, has been studied in connection with alloimmune-mediated platelet destruction by antibodies to platelet-specific antigens in well-known clinical conditions, including neonatal alloimmune thrombocytopenia, posttransfusion purpura, and refractoriness to platelet transfusions. These studies have resulted in the discovery that amino acid substitutions in platelet membrane glycoproteins result in formation of alloantigens. Thus, identification of these and other polymorphisms in cell surface glycoproteins is important in the study of pathogenesis of alloimmune-mediated disorders.
Platelet membrane glycoproteins are highly polymorphic, and can be recognized as allo- or self-antigens. Five major platelet alloantigen systems have now been identified. Incompatibility of epitopes on the various platelet surface glycoproteins has been recognized as responsible for the alloimmune thrombocytopenias; most commonly, these syndromes of immune mediated platelet destruction are induced by alloantibodies against the Pl.sup.A alloantigen on GPIIIa(P. J. Newman et al., J. Loscalzo et al., eds. Blackwell Scientific Publications, Cambridge, Mass., 1994, 529-54).
The DNA polymorphisms responsible for the five major platelet alloantigen systems have now been identified and are summarized in Table 1 below. In all cases, a single nucleotide substitution results in an amino acid change that, in turn, alters the antigenicity of the glycoprotein. The molecular basis for the Pl.sup.A1 /Pl.sup.A2 polymorphism, which is responsible for immune mediated platelet destruction in humans, is characterized by a difference in a single amino acid at residue 33 of the mature GPIIIa protein. Pl.sup.A1 has a leucine at position 33 of the mature GPIIIa; while Pl.sup.A2 has a praline at this position as the result of a T to C nucleotide substitution at nucleotide 156 of the GPIIIa gene.
TABLE 1 ______________________________________ Human Platelet Alloantigens Alloantigen Glycoprotein Location ______________________________________ Pl.sup.A1, Zw.sup.a IIIa Leucine/33 Pl.sup.A2, Zw.sup.b IIIa Proline/33 Ko.sup.b Ib Threonine/145 Ko.sup.a Ib Methionine/145 Bak.sup.a, Sib.sup.a IIb Isoleucine/843 Bak.sup.b, Sib.sup.a IIb Serine/843 Pen.sup.a, Yuk.sup.b IIIa Arginine/143 Pen.sup.b, Yuk.sup.a IIIa Glutamine/143 Br.sup.b, Zav.sup.b Ia Glutamic acid/505 Br.sup.a, Zav.sup.a Ia Lysine/505 ______________________________________