Association of PON1, P2Y12 and COX1 with Recurrent Ischemic Events in Patients with Extracranial or Intracranial Stenting

Abstract

Background and PurposeShort-term combined use of clopidogrel and aspirin improves cerebrovascular outcomes in patients with symptomatic extracranial or intracranial stenosis. Antiplatelet non-responsiveness is related to recurrent ischemic events, but the culprit genetic variants responsible for the non-responsiveness have not been well studied. We aimed to identify the genetic variants associated with poor clinical outcomes.MethodsPatients with symptomatic extracranial or intracranial stenosis scheduled for stenting and receiving dual antiplatelets (clopidogrel 75 mg and aspirin 100 mg daily) for at least 5 days before intervention were enrolled. Ischemic events including recurrent transient ischemic attack, stroke, myocardial infarction, and vascular-related mortality within 12 months follow-up were recorded. We examined the influence of genetic polymorphisms on treatment outcome in our patients.ResultsA total of 268 patients were enrolled into our study and ischemic events were observed in 39 patients. For rs662 of paraoxonase 1 (PON1), allele C was associated with an increased risk of ischemic events (OR = 1.64, 95%CI = 1.03–2.62, P = 0.029). The A-allele carriers of rs2046934 of P2Y12 had a significant association with adverse events (OR = 2.01, 95%CI = 1.10–3.67, P = 0.041). The variant T-allele of cyclooxygenase-1 (COX1) rs1330344 significantly increased the risk of recurrent clinical events (OR = 1.85, 95%CI = 1.12–3.03, P = 0.017). The other single nucleotide polymorphism (SNP) had no association with ischemic events.ConclusionsPON1, P2Y12 and COX1 polymorphisms were associated with poorer vascular outcomes. Testing for these polymorphisms may be valuable in the identification of patients at risk for recurrent ischemic events.

Haplotype of platelet receptor P2RY12 gene is associated with residual clopidogrel on-treatment platelet reactivity

“…Most studies focused on rs2046934 (T744C) or rs6809699 (G52T) representing dbSNP rs10935838, rs2046934, rs5853517 and rs6809699, and rs6785930 (C34T). Some found that it can modulate platelet response to clopidogrel or affect patients' outcomes (Fontana et al, 2003;Zee et al, 2008;Staritz et al, 2009;Shalia et al, 2013;Zoheir et al, 2013;Li et al, 2016), but most results were negative (Angiolillo et al, 2005;Smith et al, 2006;Cuisset et al, 2007;Lev et al, 2007;Bierend et al, 2008;Bonello et al, 2010;Jang et al, 2012;Namazi et al, 2012;Kar et al, 2013;Kim et al, 2013;Jana et al, 2014). Our results show that the P2RY12 allele rs2046934 (T744C) was not significantly associated with HTPR neither in the total study population nor in nonsmokers.…”

“…As well as CYP2C19, other genetic factors may contribute to the inter-individual variability of clopidogrel, among which P2RY12, which encodes the P2Y12 receptor on platelets, is of importance. Previous studies have implied that P2RY12 single nucleotide polymorphism (SNP) might play a role on the large variability in clopidogrel response, but the results were inconsistent and controversial (Angiolillo et al, 2007;Zee et al, 2008;Jana et al, 2014;Oestreich et al, 2014;Li et al, 2016;Zhang et al, 2016). Most of those studies focused on single haplotype-tagging SNPs (ht-SNPs), such as rs2046934 (i-T744C) or rs6785930, or two common haplotypes H 1 and H 2 (constituted by single nucleotide polymorphism database (dbSNP) rs10935838, rs2046934, rs5853517, and rs6809699), especially the previous studies in the Chinese population (Chen et al, 2014;Zhang et al, 2016).…”

Study of the Association of <b><i>PEAR1</i></b>,<b><i> P2Y12</i></b>, and <b><i>UGT2A1</i></b> Polymorphisms with Platelet Reactivity in Response to Dual Antiplatelet Therapy in Chinese Patients

“…Voora et al [29] also investigated the association of PEAR1 polymorphisms with cardiovascular events but failed to find such an association during aspirin treatment in American patients with CAD. Similarly, the association of P2Y12 with recurrent ischemic events in patients with extracranial or intracranial stenting was confirmed [30], but none of the selected SNPs in P2Y12 were associated with adverse outcomes in 426 patients with minor ischemic stroke [31]. Thus, these findings show that the effects of genetic variants on clinical outcomes remain elusive.…”

New genetic variants associated with major adverse cardiovascular events in patients with acute coronary syndromes and treated with clopidogrel and aspirin

“…To our knowledge, the present study is the first genome-wide and large-scale association analysis that integrates whole exome and targeted sequencing to identify novel genetic variants associated with MACE in patients with clopidogrel and aspirin treatment after PCI. By combining the two-stage sequencing data, we investigated five commonly reported SNPs [4,[6][7][8][21][22][23] and confirmed PON1 (HR 1.45; P = 0.003) but not CYP2C19 genetic variants contributed to cardiovascular outcomes in Han Chinese patients (Table S10). Moreover, we identified six novel genetic variants associated with MACE: MYOM2 (rs17064642), KRTAP10-4 (rs201441480), WDR24 (rs11640115), ECHS1 (rs140410716), AGAP3 (rs75750968) and NECAB1 (rs74569896).…”