Aspirin resistance; Gene polymorphism
Aspirin, as an effective anti-platelet aggregation drug, is widely used in the prevention and treatment of cardiovascular and cerebrovascular diseases. Clinical observation shows that aspirin can reduce the recurrence rate of cardiovascular and cerebrovascular diseases by about 25%. However, not all patients can benefit from aspirin treatment. Studies have shown that 0.4% ~ 83.3% of individuals are insensitive to the antiplatelet effect of aspirin, that is, there is aspirin resistance (AR) [1]. The exact mechanism of aspirin resistance is not clear, and heredity may be an important factor. In this paper, the research on AR and gene polymorphism in recent years is summarized as follows.
1 aspirin resistance
1. 1 definition of aspirin resistance Bhatt[2] et al. divided aspirin resistance into clinical and biochemical. Clinically, ischemic vascular disease still occurs after oral aspirin; Biologically, oral aspirin failed to change the results of platelet function test.
1.2 classification of aspirin resistance [3] Biochemical aspirin resistance can be divided into three types: (1) Type I aspirin resistance (pharmacokinetic type): oral administration of the same dose of aspirin can not inhibit thromboxane (TX) synthesis and collagen-induced platelet aggregation. However, in vitro, adding 100 μmol/L aspirin to platelet-rich plasma can inhibit this effect, suggesting that there are considerable pharmacokinetic differences in the use of low-dose aspirin. (2) Type Ⅱ aspirin resistance (pharmacodynamic type): After oral administration of aspirin in vivo and in vitro, TX synthesis and collagen-induced platelet aggregation were not inhibited, suggesting that the mechanism of this type of aspirin resistance is related to cyclooxygenase (COX) gene polymorphism. (3) Type Ⅲ aspirin resistance (pseudoaspirin resistance): Oral aspirin can inhibit TX synthesis, but it can not inhibit collagen-induced platelet aggregation. Such patients are called "pseudo-resistance" because aspirin can inhibit TX synthesis, but it cannot inhibit platelet aggregation induced by collagen and other substances.
2 aspirin resistance mechanism
The specific mechanism of AR is unclear, which may be related to many factors, such as insufficient drug dosage, gene polymorphism of cyclooxygenase 1(COX 1) and platelet glycoprotein (GP), collagen, smoking, dyslipidemia and so on. Thromboxane A2 (TXA2), adenosine diphosphate (ADP), collagen, thrombin and glycoprotein (GP) Ⅱ b/Ⅲ a receptor can all induce platelet activation pathway, while aspirin can only effectively block thromboxane A2 pathway. At present, the research on the relationship between platelet activation pathway and gene polymorphism and aspirin resistance mainly focuses on the following aspects [5. 6]: (1) cyclooxygenase 1 (cyclooxygenase? 1, Cox 1).(2) Platelet antigen 1/ platelet antigen 2 (PLA 1/PLA2) encodes the polymorphism of platelet membrane gp Ⅲ a in the activation pathway of gp Ⅱ b/Ⅲ a; (3) encodes the polymorphism of platelet membrane gp Ⅰ a/gp Ⅱ a in the activation pathway of collagen 807C/T and 873g/a. (4)5? Gene polymorphism of adenosine diphosphate receptor P2Y 1. These polymorphic loci may affect the antiplatelet effect of aspirin. Analyzing the mechanism of aspirin resistance from the gene level.
2. 1 COX gene polymorphism COX is an important rate-limiting enzyme in prostaglandin synthesis. It has two isoenzymes: COX? 1 and COX? 2。 Cox? 1 is the first enzyme in the pathway of transforming arachidonic acid into prostaglandin G/H. It has two enzyme activities, one is cyclooxygenase, and the other is hydroperoxide (HOX), which reduces prostaglandin G to generate prostaglandin H. Prostaglandin H is further catalyzed by COX to become prostaglandin and thromboxane [7]. The antiplatelet mechanism of aspirin is mainly to make COX? 1 serine 530 is irreversibly acetylated, thus inactivating the enzyme and blocking the formation of TXA2. At present, many COX gene polymorphism sites have been found [8]. Different single nucleotide polymorphisms (SNPs) of COX can affect the protein structure or conformation of COX, making its sensitivity to aspirin inhibition extremely uneven, which constitutes the structural basis of AR in some patients.
Maree et al [9] classified 144 patients with coronary heart disease according to COX? The single nucleotide polymorphisms of 1 were divided into five groups [A842G, C22T(R8W), G 128A(Q4 1Q), C644A(G2 13G) and C714a (L237m). With a mutant? Compared with wild-type A842, arachidonic acid-induced platelet activation and serum thromboxane B2 (downstream product of TXB2 and TXA2) are more obvious in patients with 842G allele, which indicates that they carry mutants. Patients with 842G allele are not sensitive to aspirin therapy. Show Cox? The genetic variation of 1 can affect arachidonic acid-induced platelet aggregation and thrombosis, and the patient's response to aspirin is partly determined by COX? Genotype 1. Gonzalez? Cornejero et al. [10] research shows that Cox? Allele 1 50T may be related to aspirin resistance.
2.2 platelet glycoprotein (gp) Ⅱ b/Ⅲ a gene polymorphism platelet glycoprotein gp Ⅱ b/Ⅲ a is a member of cell adhesion receptor integrin family, which contains specific binding sites of adhesion proteins such as fibrin, fibronectin and von willbrand factor, and participates in platelet adhesion and aggregation. AR may be related to the polymorphism of gp ⅱ b/ⅲ a receptor complex on platelet membrane, and gp ⅱ b/ⅲ a receptor is the last way of platelet activation. The gene encoding gp Ⅱ b/Ⅲ a is highly polymorphic. Mutation, deletion or insertion of gp Ⅱ b/Ⅲ a gene (including genes encoding gp Ⅱ b and gp Ⅲ a) leads to phenotypic changes, which in turn leads to changes in platelet function. Up to now, many gp ⅲ a polymorphic sites have been found, such as C 157T, a163c, A 1553G, T 1565C, and the most common one is exon 21. 1a), and the site code Pro is called PLA2 (HPA? 1b). There are few studies on gp Ⅱ b gene polymorphism, mainly gp Ⅱ bmax? /Max +(G2603A, V837M), HPA3a/3b(T2622G, Ile843Ser), gp Ⅱ bg1063a (glu324lys) and other polymorphic phenomena, among which the variation of Ile/Ser at position 843 of gp Ⅱ b residue is the most extensive and in-depth study, which is similar to that of human platelet antigen 3 (HPA). 3) correlation.
A large number of evidences show that GP receptor polymorphism is a genetic risk factor for arterial thrombosis, which can cause diversity of adhesion receptor composition expression, function and immunogenetics. Platelet agonists (such as TXA2) activate GP Ⅱ b/Ⅲ a receptors through intracellular signals, mediate the binding of fibrinogen and its receptors, and then promote platelet aggregation. Aspirin inhibits the activation of gp ⅱ b/ⅲ a by interfering with COX-independent intracellular signal transduction and acetylating gp ⅱ b and gp ⅲ a molecules. Although not fully understood, the known COX-independent signal transduction pathways may include transmembrane protein receptor, phospholipase, Ca2+ release, adenylate cyclase, guanylate cyclase and protein kinase C, etc. Aspirin can partially inhibit the activation of GPⅱb/ⅲa by some weak agonists (such as ADP, adrenaline and collagen). In the presence of PLA2 genotype, the reduction of this alternative pathway can reduce the antiplatelet effect.
Aguenier Ska Szlovik et al. [1 1] found that PLA2 allele is an independent risk factor for stroke caused by macroangiopathy in male patients. In this study, 92 patients with stroke caused by macrovascular diseases and the control group 184, 206 patients with stroke caused by small vascular diseases 103 and the control group 182, patients with cardiogenic stroke and the control group 182 were selected respectively. The results showed that the frequency of PLA2 allele in patients with small vascular disease and cardiogenic stroke was similar to that in the control group, and there was no statistical significance. The frequency of PLA2 in male stroke patients caused by macroangiopathy is higher (39.7% compared with 23.0%; P=0.003，OR = 2.5 1； CI is 1.2 1 ~ 5.20). Grove et al. [12] detected the PLA2 frequency of 1 1 healthy people and10/9 patients with coronary heart disease, among which 529 patients had a history of myocardial infarction. Results 28% of healthy people were PLA2 genotype, 28% of patients with coronary heart disease (except myocardial infarction) were PLA2 genotype, and 35% of patients with myocardial infarction were PLA2 positive. The frequency of PLA2 gene is significantly different between healthy people and patients with myocardial infarction. Therefore, they believe that Scandinavian PLA2 genotype is related to the increased risk of myocardial infarction, not coronary heart disease. The results of Szczeklik A study suggest that compared with PLA 1, PLA2 allele is more inclined to promote thrombosis, thus participating in the occurrence of aspirin resistance. Papp E et al [13] also found that the frequency of PLA2 allele in patients with aspirin resistance was significantly higher than that in patients with good response to aspirin, and all PLA2/A2 genotype patients in this study had poor antiplatelet response to aspirin. This suggests that the PLA2 allele may be related to the inadequate and insensitive response to aspirin therapy. However, Macchi et al. [14] found that PLA 1 allele was more resistant to low-dose aspirin therapy.
2.3 the polymorphism of platelet glycoprotein gp1a/IIA receptor gene gp1a/IIA (integrin α2β 1) is located in the middle of the divalent cation bond connecting platelets with collagen fibers (types ⅰ and ⅱ) or non-collagen fibers (types ⅲ and ⅳ). The expression of GPIA/IIA on platelet surface is different between normal people and people with four alleles of α2 gene. GPIa gene is located on chromosome 5. Some related studies on this gene have revealed some symptomatic or asymptomatic polymorphisms, and the changes of receptor structure and function caused by them, as well as the differences between multiple copies of GPIA/IIA receptors on platelet surface. α2GPIa polymorphism -—807C? T(phe224) and 873G? It has been proved that A(Thr246) is related to the different expression of platelet surface receptors. Genotype 807TT(873AA) is associated with high-density expression of receptor, while 807CC(873GG) is associated with low-density expression. Heterozygosity is related to the expression level of intermediate receptor. The third polymorphism was caused by the substitution of G for A at 1648, which also caused the substitution of Glu/Lys at 505 (Br system). At the same time, GPIa807C/T is genetically related to Glu505 lys, and the polymorphism of Br is related to nucleotide cyclase 837(C? T), people who carry allele I(807T/873T/873A /Brb) show a high level of GPIA/IIA, while those who carry alleles II (807C/837T/873G/BRB) and III (807C/837C/873G/BRB) show a high level. Collagen is an important inducer of platelet aggregation. The increase of platelet membrane glycoprotein1a/IIA density may be a potential risk factor for thrombosis and the cause of aspirin resistance. The polymorphism of platelet membrane glycoprotein1a/IIA gene can increase the density of platelet membrane collagen receptor [15], thus reducing the efficacy of aspirin.
2.4 changes of ADP receptor P2Y 1 gene ADP is an important mediator of platelet aggregation, and its regulation is realized by connecting with P2Y receptor coupled with G protein on platelet surface. So far, eight subtypes of P2Y receptor have been cloned, and P2Y 1 and P2Y 12 have been studied clearly. Gαq coupled P2Y 1 receptor binds to ADP, releasing calcium ions, changing the shape of platelets and making platelets aggregate. Another major receptor, P2Y 12, is coupled with G protein Gi, which inhibits adenylate cyclase, activates creatine phosphokinase 3 and activates GP Ⅱ B/Ⅲ A receptor. The inhibition of any receptor will cause a significant decline in platelet aggregation.
ADP stimulates platelet activation and aggregation through P2Y 1 and P2Y 12 receptors. The mutation of these receptors is related to abnormal hemostasis, and the inhibition of any receptor will cause a significant decline in platelet aggregation. Aspirin reduces these conditions in a synergistic way [16]. The compound antagonism between P2Y 12 and aspirin has been clinically proved to significantly reduce the occurrence of thrombotic events [17]. Therefore, the corresponding functional changes of ADP receptor P2Y 1 gene can change the signal function of ADP, reduce the reactivity to aspirin (including P2Y 12 inhibitors, such as ticlopidine and clopidogrel), lead to prethrombotic state and reduce the reactivity to aspirin.
Fontana et al. [18] found five polymorphisms of P2Y 12 receptor in 98 healthy subjects, four of which were complete linkage imbalance. This resulted in two haplotypes, H 1 (86%) and H2 (14%). Subjects with H2 haploid used low concentration ADP (2 microns), and platelet aggregation increased. The average aggregation rate of homozygote H 1 (H 1 /H 1) was 34. The aggregation rate of an H2 allele (H 1 /H2, n= 2 1) was 67. 9%. This suggests that P2Y 12 polymorphism may play a role in aspirin resistance. Recently, it has been found that the polymorphism of P2Y 1 receptor A 1622G is related to the different responses of platelets to ADP. Carrying rare G allele is more sensitive to ADP. Jefferson et al [19] studied 332 male patients with a history of myocardial infarction, and found that aspirin resistance patients were closely related to P2Y 1 gene C893T polymorphism. The aspirin resistance rate of patients with heterozygote C893T allele is three times that of patients with common homozygote C893 allele, and its mechanism is not clear.
This paper reviews the research results on the relationship between gene polymorphism and aspirin resistance in recent years. Because there is no internationally recognized definition of aspirin resistance, most of the research samples are small, and there are still many contradictions between the research results. So far, the role of heredity in aspirin resistance is not clear. Therefore, it is still necessary to carry out large-scale and prospective studies of different nationalities to confirm that these gene polymorphisms are related to AR.
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