Association of polymorphisms of platelet membrane integrins αIIbβ3 (HPA‐1b/PlA2) and α2β1 (α2807TT) with premature myocardial infarction

Abstract

Summary. Conflicting results of an association of the human platelet antigen 1b (HPA-1b/Pl A2 ), localized on the b-subunit of the integrin a IIb b 3 , and the a 2 807TT genotype of the integrin a 2 b 1 with coronary atherosclerosis and myocardial infarction have been reported. Both platelet receptor polymorphisms were genotyped in 3261 patients who had undergone coronary angiography, including 1175 survivors of a myocardial infarction, 1211 individuals with coronary artery disease but no history of myocardial infarction, and 571 control patients without angiographic coronary artery disease, and in 793 blood donors. In a case-control design, the prevalence of HPA-1b and a 2 807TT genotypes did not differ significantly between the patient groups with coronary artery disease or myocardial infarction and patient controls or blood donors. By contrast, using a multivariate case-only design, it was found that the median age of onset of myocardial infarction was 5.2 years earlier (P ¼ 0.006) in carriers of the HPA-1b allele and 6.3 years earlier (P ¼ 0.006) in carriers of the a 2 807TT genotype in the 264 survivors of myocardial infarction of recent onset with one-or two-vessel coronary artery disease. A significant interaction with the conventional risk factors hypercholesterolemia, smoking, diabetes, hypertension, and hyperfibrinogenemia was excluded. Human platelet antigen 1b and a 2 807TT are associated with premature myocardial infarction but not with coronary artery disease, suggesting a role of distinct integrin genotypes for increased platelet thrombogenicity. This association requires confirmation in follow-up studies.

The human platelet antigen-1b (Pro33) variant of αIIbβ3 allosterically shifts the dynamic conformational equilibrium of this integrin toward the active state

“…This finding can provide an explanation for the prothrombotic phenotype of Pro33 platelets that has been suggested in several clinical association studies (22)(23)(24)(25) but also in experimental settings (26,38,49). Both clinical and laboratory data regarding a possible impact of the HPA-1 polymorphism of αIIbβ3 on modulating platelet function have been discussed controversially.…”

“…The expression of α2β1 on the platelet surface is genetically controlled and modulated by nucleotide polymorphisms in the α 2 gene (52). Moreover, since the α 2 807TT genotype of α 2 β 1 has also been suggested to be a prothrombotic integrin variant (22), volunteers of this series of experiments were carefully selected by recruiting only carriers of the α 2 807CC genotype. A specific feature of the experiments summarized in Fig.…”

“…Specifically, the domain is believed to have a biomechanical role in the allosteric signal transmission across the structure (21). The human platelet antigen-1 (HPA-1) polymorphism of the β 3 gene of α IIb β 3 arises from a LeuPro exchange at residue 33 of the mature β3 subunit (22,24), resulting in Leu33 (HPA-1a) or Pro33 (HPA-1b) platelets. This amino acid exchange, located within the PSI domain, leads to an inherited dimorphism that can be of clinical relevance (22).…”

“…The human platelet antigen-1 (HPA-1) polymorphism of the β 3 gene of α IIb β 3 arises from a LeuPro exchange at residue 33 of the mature β3 subunit (22,24), resulting in Leu33 (HPA-1a) or Pro33 (HPA-1b) platelets. This amino acid exchange, located within the PSI domain, leads to an inherited dimorphism that can be of clinical relevance (22). For example, the HPA-1b allele was significantly more frequent among young patients with acute coronary syndrome than among agematched healthy subjects (23).…”

“…For example, the HPA-1b allele was significantly more frequent among young patients with acute coronary syndrome than among agematched healthy subjects (23). In the LURIC trial, an association study including more than 4,000 individuals, we documented that patients with coronary artery disease (CAD) 1 , who are carriers of the HPA-1b allele, experience their myocardial infarction five years earlier in life than CAD patients who are HPA-1b negative (22,24). In a prospective study on CAD patients undergoing saphenous-vein coronary-artery bypass grafting, we demonstrated that HPA-1b is a hereditary risk factor for bypass occlusion, myocardial infarction, or death after coronary-artery bypass surgery (25).…”