Effect of common single-nucleotide polymorphisms in acetylsalicylic acid metabolic pathway genes on platelet reactivity in patients with diabetes

Abstract

BackgroundPlatelet reactivity in patients on acetylsalicylic acid (ASA) therapy can be influenced by physiological or pathological conditions affecting ASA pharmacokinetics or pharmacodynamics. The mechanism of such variability in the therapeutic response to ASA, particularly in diabetic patients, is poorly understood. The rate of elimination of ASA and its metabolite, salicylic acid (SA), is likely a major factor determining drug efficacy. The objective of this study was to investigate the effect of genetic polymorphisms in the selected candidate genes within the ASA metabolic pathway on the platelet reactivity and concentration of ASA and thromboxane A2 (TxA2) metabolites in a population of patients with type 2 diabetes mellitus (T2DM).Material/MethodsThe study cohort consisted of 287 Caucasians with T2DM who had been taking ASA tablets at the dose of 75 mg per day for at least 3 months. Platelet reactivity analyses were performed using VerifyNow Aspirin and PFA-100 assays. The measured ASA metabolite included salicylic acid (ASA), and TxA2 metabolites included serum TxB2 and urinary 11-dh-TxB2. Genotyping for the selected 18 single-nucleotide polymorphisms (SNPs) within 5 genes of the ASA metabolic pathway was performed using a Sequenom iPLEX platform.ResultsNo statistically significant association was observed between the investigated SNPs genotypes, platelet reactivity, and measured metabolites in the investigated cohort of patients.ConclusionsThe results of our study failed to confirm that the selected variants in the genes within the ASA metabolic pathway might contribute to platelet reactivity in a diabetic population treated with ASA.

Serum Brain-Derived Neurotrophic Factor is Related to Platelet Reactivity but not to Genetic Polymorphisms within BDNF Encoding Gene in Patients with Type 2 Diabetes

“…ELISA kits were also used to determine concentrations of the following parameters: serum TXB2 (EIA kits, Cayman Chemicals, Ann Arbor, MI, USA), von Willebrand factor (vWF) molecule (vWF: Ag), tumor necrosis factor (TNF)-α (Quantikine ® HS ELISA Human TNF-α Immunoassay), interleukin (IL)-6 (Quantikine ® HS ELISA Human IL-6 Immunoassay; both R&D Systems, Inc., Minneapolis, USA), soluble CD40 ligand (sCD40L; Human soluble CD40 Ligand Immunoassay, R&D Systems, Inc., NE, USA), and soluble P-selectin (human P-selectin/CD62P ELISA kit R&D Systems, Inc., Minneapolis, USA). High-sensitivity C-reactive protein (hsCRP) concentrations were assessed using a Cobas Integra 800 device (Roche, Basel, Switzerland), as previously described [ 21 , 22 ]. The compliance with ASA treatment was defined according to previously described criteria [ 20 ].…”

The OSR1 rs12329305 Polymorphism Contributes to the Development of Congenital Malformations in Cases of Stillborn/Neonatal Death

“…Some studies defined variants with MAFs between 0.1% and 3% as rare variants and concluded that rare variants associated with complex phenotypes sometimes have larger effect sizes to the trait than common variants [ 24 ]. Associations of rare variants with complex phenotypes, metabolic pathways, or polygenetic disease are under-investigated [ 25 ]. However, a recent study has shown that Osr1 has an essential role in the early stages of kidney and heart development in an animal model [ 16 ].…”

Blood Coagulation and Beyond: Position Paper from the Fourth Maastricht Consensus Conference on Thrombosis

“…And it is well known that major bleeding has a similar impact on patient outcome as a recurrent thrombotic event e.g myocardial infarction (144,145). Aspirin is metabolized by different enzymes, but up to now none of the genetic polymorphisms has impacted clinical outcome (146). Ticagrelor is a direct-acting drug, while both clopidogrel and prasugrel need activation by cytochrome CYPP450 genes (147).…”

“… 165 166 Aspirin is metabolized by different enzymes, but up to now none of the genetic polymorphisms has impacted clinical outcome. 167 Ticagrelor is a direct-acting drug, while both clopidogrel and prasugrel need activation by cytochrome CYPP450 genes. 168 The active compound of ticagrelor is metabolized by CYP3A4, which can also directly bind to the P2Y12 receptor.…”