Table 3.
The influence of chosen genetic polymorphism on the platelet reactivity and the efficacy of the antiplatelet treatment
| Reference | Studied P2Y12 SNPs | Study group | Drug tested | Observed effects | Pharmacodynamic assessment | Results |
|---|---|---|---|---|---|---|
| In vitro assessment only | ||||||
| [13] | T744C, C139T, 801A, G52T, C34T | 98 healthy volunteers (Caucasian origin) | None (ADP reactivity test only) | Assessment of maximal platelet aggregation between P2Y12 genotypes and haplotypes | Photometric method | The H2 haplotype was related to increased maximal platelet aggregation after ADP exposition |
| [38] | T744C, C139T, 801A, G52T, C34T | 158 healthy volunteers (of Korean origin) | None (ADP reactivity test only) | Assessment of the relationship between ADP-induced MPA and studied SNPs | LTA/platelet-rich plasma turbidimetry | ADP-induced maximal platelet aggregation was not affected by three intronic P2Y12 and C34T polymorphisms. However, the authors noticed a correlation between the TT genotype of G52T polymorphism and higher ADP-induced maximal platelet aggregation |
| [33] | T744C, G52T, C34T, rs1907637, rs79320243, rs10935842, rs6787801, rs6801273, rs16863323 | 196 healthy volunteers (Chinese origin) | Ticagrelor, in vitro test only | Assessment of MPA and relative inhibition of platelet aggregation | LTA/platelet-rich plasma turbidimetry | Any genetic variations both in the P2Y12 and G-protein beta 3 subunit were not related to differences in platelet inhibition after partial ex vivo blockade using ticagrelor. Several P2Y12 polymorphisms and one haplotype (haplotype D) were related to differences in baseline platelet aggregation, but no studied polymorphism affected response to ticagrelor in the ex vivo study |
| [36] | T744C, rs6798347, rs6787801, rs9859552, rs6801273 | 242 healthy volunteers (mostly of Caucasian origin) | Cangrelor, in vitro test only | Assessment of MPA and relative inhibition of platelet aggregation | LTA/platelet-rich plasma turbidimetry | The minor C allele of rs6787801 was related to lower ADP-induced maximal platelet aggregation. rs9859552 AA genotype was related to decreased response to cangrelor therapy when compared with CC genotype. Haplotypes analysis presented results similar to the results of SNPs |
| [37] | T744C, C34T | 29 healthy volunteers (mostly of Caucasian origin) | Cangrelor, in vitro test only | Assessment of TRAP-mediated platelet activation by PAC1 binding and CD62P expression, and relative inhibition of platelet aggregation | Flow cytometry, VerifyNow P2Y12 assay | Patients with H2/H2 haplotypes showed greater platelet inhibition during cangrelor exposition. No consistent effects of the C34T and T744C polymorphisms separately were found |
| Influence of studied P2Y12 SNPs on platelet reactivity or clinical outcome | ||||||
| [39] | T744C | 77 ACS patients & 101 healthy volunteers (of Moroccan origin) | Clopidogrel, 300 mg LD & 75 mg MD | Association between genotypes and ACS risk and CR, defined as 208 PRU and above or < 20% inhibition of platelet aggregation after 7 days of treatment | VerifyNow P2Y12 assay | The C allele of studied polymorphism was more frequent among patients resistant to therapy. Relation of C allele to observed ACS was statistically significant |
| [35] | T744C, rs7428575, rs3732759 | 178 CHD patients and 182 healthy controls (Chinese origin) | Clopidogrel, 300 mg LD & 75 mg MD | Assessment of the decrease in MPA. CR defined as a < 10% decrease from baseline after 10 days of treatment | LTA/platelet-rich plasma turbidimetry | Significant differences in genotype and allele frequencies of T744C and rs3732759 between the case and control groups were observed. Haplotype TCA was related to increased coronary artery disease risk. Responsive to clopidogrel therapy group consisted of coronary artery disease patients with higher frequencies of TT genotype of T744C and lower frequencies of GG genotype of rs3732759 compared to patients with CR |
| [40] | T744C | 40 ACS patients and 40 age-matched healthy controls (origin unspecified) | Clopidogrel; exact dosing regimen unspecified |
CR defined as persistence of HPR (ADP-Ag > 70%) Comparison of allele frequencies between patients and controls; prevalence of CR according to the genotype C |
LTA/platelet-rich plasma turbidimetry | Carriers of T744C C allele showed increased platelet reactivity after ADP activation |
| [41] | T744C | 191 patients with ischemic stroke (Chinese origin) | Clopidogrel 300 mg LD & 75 mg MD | CR defined as a < 10% decrease in MPA after 5 days of treatment | LTA/platelet-rich plasma turbidimetry | The C allele in T744C P2RY12 polymorphism was considered to decrease the risk of CR. Additionally, CR was found to be related to increased risk of hypertension |
| [42] | T744C | 268 patients with ischemic stroke (Chinese origin) | Clopidogrel, 75 mg | Primary endpoints: transient ischemic attack, ischemic stroke, myocardial infarction or vascular-related mortality | - | There was significant association between A allele of the T744C P2Y12 polymorphism and present adverse effects |
| [32] | T744C, C34T, rs6798347, rs6787801, rs6801273 | 180 patients with ACS (Chinese origin) | Clopidogrel, 75 mg MD, with or without 300/600 mg LD | HTPR defined by platelet inhibition > 30% | Thromboelastography | Authors determined six haplotypes on basis of the selected P2RY12 and CYP2C19 polymorphisms (named as H0—H5). They discovered, that combination of few P2RY12 variations rather than T744C alone, associated with different response to treatment with clopidogrel |
| [43] | T744C, G52T, C34T | 146 patients with CAD (Han Chinese origin) | Clopidogrel, 75 mg MD | HTPR defined by MPA > = 50% | LTA/platelet-rich plasma turbidimetry | There was no association between studied polymorphism and HTPR or recurrence of major adverse cardiac events |
| [44] | T744C, C34T | 124 patients with acute myocardial infarction (Caucasian origin) | Clopidogrel, 75 mg MD | CR defined as values > 45% in LTA or 298 AUC/min in Multiplate | LTA/platelet-rich plasma turbidimetry and Multiplate analyzer | There was not any statistically significant association between P2RY12 receptor polymorphisms (T744C, C34T) and response to antiplatelet therapy with clopidogrel |
| [45] | T744C | 60 patients with ACS (Mexican origin) | Clopidogrel 300 mg LD & 75 mg MD | CR defined as persistence of HPR (ADP-Ag > 70%) | LTA/platelet-rich plasma turbidimetry | T744C polymorphism showed no association with clopidogrel resistance |
| [46] | T744C | 100 patients with CAD and ACS or chronic stable angina (North Indian origin) | Clopidogrel 75 mg MD, 300 mg LD in one subject | Assessment of the decrease in MPA. CR defined as a < 10% decrease from baseline, semi-responders as 10–29% reduction, responders as > 30% reduction | LTA/platelet-rich plasma turbidimetry | H1/H1 haplotype (P2Y12 polymorphism) was related to CR. CR was not related to single ADP receptor P2Y1 and P2Y12 gene polymorphisms |
| [47] | T744C | 1419 ACS patients (origin unspecified) | Clopidogrel 600 mg LD & 75 mg MD | CR defined as persistence of HPR (ADP-Ag > 70% or Arachidonic acid-AG > 20%) after 6 days | LTA/platelet-rich plasma turbidimetry | T744C polymorphism was not associated with higher platelet reactivity |
| [48] | T744C | 597 patients with ACS (origin unspecified) | Clopidogrel 600 mg LD | CR defined as persistence of HPR (ADP-Ag > 70%) after LD; also VASP value and P-selectin surface expression | LTA/platelet-rich plasma turbidimetry, VASP phosphorylation, flow cytometry | T774C polymorphism was not associated with CR |
| [49] | T744C | 120 patients scheduled for elective PCI (mixed origin) | Clopidogrel 300 mg LD & 75 mg MD | CR defined as a < 10% decrease from baseline after 3 months | LTA/platelet-rich plasma turbidimetry, flow cytometry | No divergence in polymorphism frequencies between resistant and nonresistant patients was observed. No significant differences were observed also in response to aspirin or to clopidogrel in patients grouped accordingly to their genotype |
| [50] | T744C | 119 patients with CAD (origin unspecified) | Clopidogrel 300 mg LD & 75 mg MD or 75 mg MD only | MPA assessment and platelet activation with fibrinogen, and P-selectin expression | LTA/platelet-rich plasma turbidimetry, flow cytometry | T744C polymorphism was not related to differences in response to clopidogrel at early or late stage of therapy |
| [51] | T744C, C34T | 222 patients with ACS (Chinese Han origin) | Clopidogrel 300 mg LD & 75 mg MD | HPR cut-off point has been described as ≥ 208 PRU | VerifyNow P2Y12 assay | Poor response to clopidogrel was based on coexistence of CYP2B6*9 and T744C and coexistence of CYP2B6*1B and T744C |
| [52] | G52T, C34T | 503 STEMI patients (Chinese Han origin) | Clopidogrel 300 mg LD & 75 mg MD | Primary endpoint was a composite of cardiovascular death, nonfatal MI, vessel revascularization, and S. Safety endpoint was incidence of major bleeding events | - | G52T minor allele was factor responsible for major bleedings |
| [53] | G52T, C34T | 473 patients with PAD | Clopidogrel, 75 mg (in 137 patients) | Primary endpoint of neurological events (ischemic stroke, carotid endartectomy, carotid stenting) | - | Clopidogrel treated patients with at least one C34T T allele showed 4.02-fold higher risk for neurological events comparing to carriers of only C34T C alleles. None of the studied polymorphisms was related to all-cause mortality |
| [54] | G52T, C34T | 498 patients with ACS | Clopidogrel 300 mg LD & 75 mg MD | CR defined as < 10% decrease from baseline after 7 days of treatment. Secondary outcome comprised adverse cardiovascular events | AggRAM system | Patients with T allele at G52T or C34T polymorphisms, presented significantly higher risk of CR* and presence of cardiovascular events in comparison to wild-type patients. Patients with the T variations in C34T presented also significantly increased risk of post percutaneous coronary intervention and higher recurrence risk of cardiovascular diseases |
| [55] | G52T | 557 patients with CAD and 43 healthy volunteers (origin unspecified) | Clopidogrel 300, 450 or 600 mg LD & 75 mg MD (in patients only) | Nonresponsiveness defined as impedance above 5 Ω | Impedance aggregometry | Patients with H2/H2 haplotype were more often nonresponders and showed stronger platelet aggregation than subjects with at least one H1. Haplotype H2/H2 was also related with increased CR |
| [56] | T744C | 26 patients with acute MI and 102 healthy volunteers (Western Indian origin) | Clopidogrel 300 mg LD & 75 mg MD | Assessment of MPA and inhibition of platelet aggregation before, 24 h and 6 days of treatment | LTA/platelet-rich plasma turbidimetry | Beside T744C P2Y12 polymorphism MDR1 and CYP2C19 SNPs were taken into consideration. T744C and CYP2C19*2 mutant alleles were related to clopidogrel resistance, compared to wild type |
| [57] | T744C | 112 patients scheduled for PCI (Iranian origin) | Clopidogrel 600 mg LD & 150 and 75 mg MD | Responsiveness to clopidogrel defined a decrease from baseline value; < 10% for nonresponders, 10 – 30% for semiresponders, > 30% for responders | LTA/platelet-rich plasma turbidimetry | No significant association between response to clopidogrel treatment and P2Y12 polymorphism was observed |
| [56] | T744C | 26 patients with acute MI and 102 healthy volunteers (Western Indian origin) | Clopidogrel 300 mg LD & 75 mg MD | Assessment of MPA and inhibition of platelet aggregation before, 24 h and 6 days of treatment | LTA/platelet-rich plasma turbidimetry | Beside T744C P2Y12 polymorphism MDR1 and CYP2C19 SNPs were taken into consideration. T744C and CYP2C19*2 mutant alleles were related to clopidogrel resistance, compared to wild type |
| Comparison of P2Y12 SNP prevalence in study populations | ||||||
| [58] | T744C, C34T | 696 patients with CAD (Caucasian origin) | Unspecified | Assessment of bleeding complications defined as major bleeding, intercranial bleeding, or clinically over bleeding, minor bleeding relative to studied polymorphisms | - | Studied polymorphisms were related to bleeding incidents |
| [59] | T744C, C34T | 105 patients with premature MI, and 132 patients without CAD (Caucasian origin) | Unspecified | Assessment of SNP frequencies in study groups and evaluation of cardiovascular risk factors | - | No effect of P2Y12 polymorphism was observed |
| [60] | T744C, G52T, rs10935838 rs5853517 | A total of 1982 patients and matched controls: with/without MI, with/without transient ischemic attacks, with/without deep venous thrombosis (mostly Caucasian origin) | Unspecified | Comparison of SNPs prevalence between cases and controls | - | Haplotype H2 was significantly related to lower risk of incident deep vein thrombosis and pulmonary embolism, compared to haplotype H1. There was no association between the P2RY12 polymorphisms or the H2 haplotype with possible myocardial infarction or ischemic stroke |
| [61] | T744C, G52T, rs9859538, rs1491974, rs7637803 | 776 patients with Kawasaki disease and 1335 healthy controls (Southern Chinese origin) | - | Assessment of P2Y12 SNP association with coronary aneurism in Kawasaki disease | - | No significant association between any of studied polymorphism and Kawasaki disease was found. There was however significant association between TT genotype of rs7637803 and higher risk of coronary artery aneurysm risk in Kawasaki disease patients. Authors claimed that it could be used as biomarker for prediction of giant coronary artery aneurysm |
| [62] | T744C, G52T, rs9859538, rs1491974, rs7637803 | 759 patients with Kawasaki disease (Chinese Han origin) | - | Association of studied SNPs with intravenous immunoglobulin resistance | - | After including such factors as gender and age, carriers of the rs6809699 (G52T) C allele were at lower risk of intravenous immunoglobulin resistance. There was no significant association between four other polymorphism and sensitivity to intravenous immunoglobulin |
| [63] | T744C, G52T, rs6801273, rs6798347 | 122 patients with MI (subdivided according to the age when MI occurred) and 235 healthy controls | Unspecified | Assessment of studied SNPs prevalence between study groups | - | Studied P2RY12 polymorphisms did not show any significant correlations to CR |
ACS acute coronary syndrome, CHD coronary heart disease, CR clopidogrel resistance, HTPR high on-treatment platelet reactivity, LD loading dose, LTA light transmittance aggregometry, MD maintenance dose, MPA maximum platelet aggregation rate, PAD peripheral artery disease, PCI percutaneous coronary intervention, STEMI ST-elevation myocardial infarction, ST stent thrombosis