RESUMEN
Genetic variants in the pharmacokinetic (PK) mechanism are the main underlying factors affecting the antiplatelet response to clopidogrel. Using a genomewide association study (GWAS) to identify new genetic loci that modify antiplatelet effects in Chinese patients with coronary heart disease, we identified novel variants in two transporter genes (SLC14A2 rs12456693, ATP-binding cassette [ABC]A1 rs2487032) and in N6AMT1 (rs2254638) associated with P2Y12 reaction unit (PRU) and plasma active metabolite (H4) concentration. These new variants dramatically improved the predictability of PRU variability to 37.7%. The associations between these loci and PK parameters of clopidogrel and H4 were observed in additional patients, and its function on the activation of clopidogrel was validated in liver S9 fractions (P < 0.05). Rs2254638 was further identified to exert a marginal risk effect for major adverse cardiac events in an independent cohort. In conclusion, new genetic variants were systematically identified as risk factors for the reduced efficacy of clopidogrel treatment.
Asunto(s)
Transportador 1 de Casete de Unión a ATP/genética , Enfermedad Coronaria/tratamiento farmacológico , Sitios Genéticos , Variantes Farmacogenómicas , Inhibidores de Agregación Plaquetaria/farmacocinética , Polimorfismo de Nucleótido Simple , Antagonistas del Receptor Purinérgico P2Y/farmacocinética , Metiltransferasa de ADN de Sitio Específico (Adenina Especifica)/genética , Ticlopidina/análogos & derivados , Transportador 1 de Casete de Unión a ATP/metabolismo , Anciano , Biotransformación , China , Clopidogrel , Enfermedad Coronaria/diagnóstico , Enfermedad Coronaria/genética , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Microsomas Hepáticos/metabolismo , Persona de Mediana Edad , Modelos Biológicos , Dinámicas no Lineales , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/efectos adversos , Pruebas de Función Plaquetaria , Antagonistas del Receptor Purinérgico P2Y/administración & dosificación , Antagonistas del Receptor Purinérgico P2Y/efectos adversos , Receptores Purinérgicos P2Y12/sangre , Receptores Purinérgicos P2Y12/efectos de los fármacos , Medición de Riesgo , Factores de Riesgo , Metiltransferasa de ADN de Sitio Específico (Adenina Especifica)/metabolismo , Ticlopidina/administración & dosificación , Ticlopidina/efectos adversos , Ticlopidina/farmacocinética , Resultado del TratamientoRESUMEN
Results of identification and classification of 204 strains of Gram negative bacteria isolated from poultry eggs are reported. Among 106 strains of glucose nonfermenting bacteria 105 (99%) strains could be further identified as: pseudomonas (87 strains), including P. fluorescens (63), P. putida (9), P. maltophilia (12), P. putrefaciens (2), and P. stutzeri (1); 2 strains of Alcaligenes, both identified as A. denitrificans; 7 strains of Flavobacterium, including F. multovorum (3) and Flavobacterium sp. (4); and 9 strains of Acinetobacter, including A. lwoffi (7) and A. anitratus (2). Among 98 strains of fermentors, 73 strains (74.5%) could be identified as; Escherichia (9), E. coli (12), Enterobacter Liquefaciens (31), Ent. cloacae (7), Ent. halfnia (8), Ent. aerogenes (1) and proteus (5); while 25 strains (25.5%) which split glucose and lactose or sucrose fermentative with acid but no gaseouse formation remain to be ascertained.
