ABSTRACT
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.
Subject(s)
ATP Binding Cassette Transporter 1/genetics , Coronary Disease/drug therapy , Genetic Loci , Pharmacogenomic Variants , Platelet Aggregation Inhibitors/pharmacokinetics , Polymorphism, Single Nucleotide , Purinergic P2Y Receptor Antagonists/pharmacokinetics , Site-Specific DNA-Methyltransferase (Adenine-Specific)/genetics , Ticlopidine/analogs & derivatives , ATP Binding Cassette Transporter 1/metabolism , Aged , Biotransformation , China , Clopidogrel , Coronary Disease/diagnosis , Coronary Disease/genetics , Female , Genome-Wide Association Study , Humans , Male , Microsomes, Liver/metabolism , Middle Aged , Models, Biological , Nonlinear Dynamics , Platelet Aggregation Inhibitors/administration & dosage , Platelet Aggregation Inhibitors/adverse effects , Platelet Function Tests , Purinergic P2Y Receptor Antagonists/administration & dosage , Purinergic P2Y Receptor Antagonists/adverse effects , Receptors, Purinergic P2Y12/blood , Receptors, Purinergic P2Y12/drug effects , Risk Assessment , Risk Factors , Site-Specific DNA-Methyltransferase (Adenine-Specific)/metabolism , Ticlopidine/administration & dosage , Ticlopidine/adverse effects , Ticlopidine/pharmacokinetics , Treatment OutcomeABSTRACT
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.