RESUMO
BACKGROUND: To investigate genes differentially expressed in peripheral blood cells (PBCs) from patients with coronary arterial disease (CAD) under double anti-platelet therapy. METHODS: Twenty-six CAD patients that were submitted to percutaneous coronary intervention (PCI) were selected to participate in this study. These patients took 100mg/day of acetylsalicylic acid (ASA) and 75mg/day of clopidogrel. Blood samples were collected before PCI to evaluate platelet reactivity using VerifyNow ASA and P2Y12 assays (Accumetrics). The patients were stratified into 4 quartiles based on ASA reaction units (ARUs) and P2Y12 reaction units (PRUs). Quartile 1 (Q1) patients were classified as responders and quartile 4 (Q4) patients as non-responders. Global mRNA expression from Q1 to Q4 was analyzed by microarray using the GeneChip Exon 1.0 ST array (Affymetrix) and was confirmed by RT-qPCR. RESULTS: Patients with ARU or PRU values within the first quartile (Q1, ARU<390 and PRU<151) were considered responders, while those who had ARU or PRU within the fourth quartile (Q4, ARU>467 and PRU>260) were considered nonresponders. The risk factors associated for CAD showed expected frequencies and no difference was found between Q1 and Q4. Microarray analysis identified 117 genes differentially expressed for ASA and 29 for clopidogrel between Q1 and Q4 groups (p<0.01, FC>1.2). CONCLUSION: The variation in response to ASA may be related with an increased expression of IGF1 and IGF1R, as well as a response to clopidogrel can be affected by pharmacokinetic change related to the reverse transport pathway by increased expression of ABCC3.
Assuntos
Aspirina/administração & dosagem , Doença da Artéria Coronariana/genética , Expressão Gênica , Leucócitos Mononucleares/química , Inibidores da Agregação Plaquetária/administração & dosagem , Ticlopidina/análogos & derivados , Idoso , Plaquetas/efeitos dos fármacos , Plaquetas/patologia , Clopidogrel , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/patologia , Esquema de Medicação , Perfilação da Expressão Gênica , Humanos , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Agregação Plaquetária/efeitos dos fármacos , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Ticlopidina/administração & dosagem , Resultado do TratamentoRESUMO
BACKGROUND: Genome-wide expression analysis using microarrays has been used as a research strategy to discovery new biomarkers and candidate genes for a number of diseases. We aim to find new biomarkers for the prediction of acute coronary syndrome (ACS) with a differentially expressed mRNA profiling approach using whole genomic expression analysis in a peripheral blood cell model from patients with early ACS. METHODS AND RESULTS: This study was carried out in two phases. On phase 1 a restricted clinical criteria (ACS-Ph1, n=9 and CG-Ph1, n=6) was used in order to select potential mRNA biomarkers candidates. A subsequent phase 2 study was performed using selected phase 1 markers analyzed by RT-qPCR using a larger and independent casuistic (ACS-Ph2, n=74 and CG-Ph2, n=41). A total of 549 genes were found to be differentially expressed in the first 48 h after the ACS-Ph1. Technical and biological validation further confirmed that ALOX15, AREG, BCL2A1, BCL2L1, CA1, COX7B, ECHDC3, IL18R1, IRS2, KCNE1, MMP9, MYL4 and TREML4, are differentially expressed in both phases of this study. CONCLUSIONS: Transcriptomic analysis by microarray technology demonstrated differential expression during a 48 h time course suggesting a potential use of some of these genes as biomarkers for very early stages of ACS, as well as for monitoring early cardiac ischemic recovery.