RESUMEN
BACKGROUND: CYP2C19 loss-of-function alleles impair clopidogrel effectiveness after percutaneous coronary intervention, but the clinical impact of implementing CYP2C19 genotyping in a real-world setting is unknown. The purpose of the study was to determine whether returning CYP2C19 genotype results along with genotype-guided pharmacotherapy recommendations using a rapid turnaround test would change antiplatelet prescribing following percutaneous coronary intervention.The primary outcome was the rate of prasugrel or ticagrelor prescribing in each arm. Secondary outcomes included agreement to the genotype-guided recommendations. METHODS: At the time of percutaneous coronary intervention, participants were randomly assigned to prospective rapid point-of-care genotyping of CYP2C19 major alleles (*2, *3, *17) via salivary swab (genotyped group) or no genotyping (usual care) to guide antiplatelet drug selection. Interventional cardiologists at 2 cardiac catheterization laboratories within the same health system were provided genotype information along with genotype-guided pharmacotherapy recommendations. RESULTS: A total of 504 participants were randomized, 249 to the genotyped and 255 to the usual care group. The participants were primarily men (73%); age, 63±10 years; and 50% had acute coronary syndromes. In the genotyped group, 28% were carriers of loss-of-function alleles (*2, *3). The use of prasugrel or ticagrelor was significantly higher in the genotyped group compared with the usual care group (30% versus 21%; odds ratio, 1.60 [95% CI, 1.07-2.42]; P=0.03). Within the genotyped group, 53% of loss-of-function allele carriers were started on prasugrel/ticagrelor, while 47% were started on clopidogrel. CONCLUSIONS: In a randomized controlled trial of clinical CYP2C19 genotyping implementation, pharmacogenetic test results significantly influenced antiplatelet drug prescribing; however, almost half of CYP2C19 loss-of-function carriers continued to receive clopidogrel. Interventional cardiologists consider both clinical and genetic factors when selecting antiplatelet therapy following percutaneous coronary intervention. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique Identifier: NCT02508116.
Asunto(s)
Síndrome Coronario Agudo/tratamiento farmacológico , Biomarcadores/análisis , Citocromo P-450 CYP2C19/genética , Intervención Coronaria Percutánea/métodos , Pruebas de Farmacogenómica/métodos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Polimorfismo Genético , Síndrome Coronario Agudo/genética , Síndrome Coronario Agudo/patología , Síndrome Coronario Agudo/cirugía , Femenino , Estudios de Seguimiento , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios ProspectivosRESUMEN
Periodontitis is a common chronic inflammatory condition that results in increased levels of inflammatory cytokines and inflammatory mediators. In addition to oral disease and tooth loss, it also causes low-grade systemic inflammation that contributes to development of systemic conditions including cardiovascular disease, pre-term birth, diabetes and cancer. Chronic inflammation is associated with epigenetic change, and it has been suggested that such changes can alter cell phenotypes in ways that contribute to both ongoing inflammation and development of associated pathologies. Here we show that exposure of human gingival fibroblasts to IL-1ß increases expression of maintenance methyltransferase DNMT1 but decreases expression of de novo methyltransferase DNMT3a and the demethylating enzyme TET1, while exposure to PGE2 decreases expression of all three enzymes. IL-1ß and PGE2 both affect global levels of DNA methylation and hydroxymethylation, as well as methylation of some specific CpG in inflammation-associated genes. The effects of IL-1ß are independent of its ability to induce production of PGE2, and the effects of PGE2 on DNMT3a expression are mediated by the EP4 receptor. The finding that exposure of fibroblasts to IL-1ß and PGE2 can result in altered expression of DNA methylating/demethylating enzymes and in changing patterns of DNA methylation suggests a mechanism through which inflammatory mediators might contribute to the increased risk of carcinogenesis associated with inflammation.