The Inconclusive Results of the Studies on Glycoprotein IIIa Platelet Receptor Gene Polymorphism and Coronary Artery Disease

We read with great interest the article entitled ‘‘Relationship between glycoprotein IIIa platelet receptor gene polymorphism and coronary artery disease’’ by Verdoia et al. The authors investigated whether a single-nucleotide polymorphism of IIIa subunit (Leu 33 platelet antigen 1 and 2 [PlA/PlA]) is associated with the extent of coronary artery disease (CAD) and carotid atherosclerosis. The main finding of this study is that the PlA allele was not associated with the prevalence and extent of CAD and carotid atherosclerosis. The platelet glycoprotein (GP) IIb/IIIa receptor composed of 2 subunits is an essential component of platelet aggregation and plug formation. As Verdoia et al mentioned, in the subunit IIIa, the substitution of a cytosine for a thymidine at position 1565 in exon 2 results in a change in the 33rd position of the amino acid chain (Leu ! Pro). This single-nucleotide polymorphism is responsible for the PlA/PlA, in which the ancestor gene is PlA and the variant gene is PlA. Bottiger et al evaluated the role of human platelet antigen (HPA) 1 and HPA-3 as risk factors for myocardial infarction (MI) and CAD, and this study consisted of a different patient population from Verdoia et al with control groups. Indeed, study of Park et al consisted of patients who had minimal CAD or normal coronary arteries and significant CAD. They found an association between HPA-3 polymorphism and MI. In the present study, the percentage of patients with acute coronary syndrome (ACS) is considerably high. It is well known that ACS and stabile CAD are different disorders, as in ACS, the underlying lesion may be stenotic or nonstenotic and more importantly nonstenotic lesions are far more frequent than stenotic plaques and account for the majority of ruptured culprit plaques. In this context, prevalence or extent of CAD may not give sufficient estimated risk prediction of MI. Indeed, the possibility of pharmacogenomic interaction and a possible effect of medication on atherosclerotic process and clinical events cannot be certainly excluded. In a meta-analysis, the PlA/ PlA variant was significantly associated with aspirin resistance only in healthy individuals. Another study, which included patients with stabil CAD treated with aspirin, demonstrated that GPIIIa PlA/PlA genotype carriers have a significantly increased risk of acute vascular ischemic events associated with a poor prognosis at 1 year. Also, it is important to know whether these polymorphisms alter platelet function or not. Andrioli et al demonstrated that in individuals carrying the PlA allele, there was a significantly lower platelet response through thromboxane A2 pathway compared with PlA/PlA genotype carriers. Lopes et al reported a significant increase in major cardiovascular event incidence in patients with stable CAD who were PlA carriers and smokers. Although Verdoia et al mentioned about the possible reason for association between GPIIIa PlA/PlA gene polymorphism and the development of atherosclerosis, there is no sufficient explanation for their contrasting results. Additionally, we wonder about the scientific reason to consider the vessel that was previously treated by percutaneous coronary intervention and no stenosis as significantly diseased. There may be several reasons for the differences observed between all these studies including the variable prevalence of PlA variant in the different patient populations, influence of ethnic and genetic background, the possible link between PlA polymorphism and other true cardiovascular risk factors (eg, smoking) as in the present study, the possible role of this polymorphism in such a variability of response to either antiplatelet treatment or other drug, some medical conditions that could have a major influence on CAD, and the bias of patient selection and genotype mistyping. In conclusion, further studies are needed to address the relationship between single-nucleotide polymorphism in components of each of the plaque, blood, and myocardial vulnerabilities and future outcomes. As atherosclerosis is a diffuse and multisystem disorder, it is important to recognize the total burden of vulnerable plaques and patients other than the extent of CAD.