OBJECTIVE Genetic variants in the pharmacokinetic(PK)mechanism are the main underlying factors that modify the antiplatelet efficacy of clopidogrel.Hence,joint analysis of genetic variants that modify pharmacodynamic(...OBJECTIVE Genetic variants in the pharmacokinetic(PK)mechanism are the main underlying factors that modify the antiplatelet efficacy of clopidogrel.Hence,joint analysis of genetic variants that modify pharmacodynamic(PD)and PK responses to clopidogrel should be effective for identifying the genetic variants affecting the antiplatelet response to the drug.METHODS A genome-wide association study was conducted to identify new genetic loci that modify PD responses to clopidogrel and its active metabolite H4 in 115 Chinese patients with coronary heart disease(CHD).RESULTS We identified novel variants in two transporter genes(rs12456693 in SLC14A2 and rs2487032 in ABCA1)and in N6AMT1(rs2254638)associated with clopidogrel-treated P2Y12reaction unit(PRU)and plasma H4 concentration.The associations between these single nucleotide polymorphisms(SNPs)and PK parameters of clopidogrel and H4 were observed in 31 additional CHD patients(P<0.05).The new variants,together with CYP2C19*2 and clinical factors,dramatically improved the predictability of PRU variability to 37.7%compared with the published value of approximately 20%.The function of these SNPs on the activation of clopidogrel was validated in 32 liver S9 fractions,and the N6AMT1 rs2254638 T variant was found to be associated with decreased formation of H4(P=0.0386).Meanwhile,N6AMT1 rs2254638 was further identified to exert a marginal risk effect for MACE in an independent CHD patient cohort(OR:1.428,95%CI:0.978-2.086,P=0.0653,FDR=0.4726).In conclusion,we systematically identified new genetic variants as risk factors for the reduced efficacy of clopidogrel.CONCLUSION Our study findings enhanced the understanding of the absorption and metabolic mechanisms that influence PD responses to clopidogrel treatment.展开更多
Highly active antiretroviral therapy （HAART） for HIV/AIDS has efficiently controlled the progression of the disease, extended life expectancy and decreased HIV/AIDS related morbidity and mortality since the advent o...Highly active antiretroviral therapy （HAART） for HIV/AIDS has efficiently controlled the progression of the disease, extended life expectancy and decreased HIV/AIDS related morbidity and mortality since the advent of HIV protease inhibitors in 1996.1 Recent emergence of HIV resistance has severely affected the efficacy of antiretroviral therapy. The prevalence of HIV resistance has been increasing from the usage of AZT. Studies in US indicated that the prevalence was approximately 50% in patients who had experienced antiretroviral therapy.2 Antiviral regimens based on resistance tests could efficiently decrease viral load, increase CD4 cell counts and significantly improve the efficacy of antiretroviral therapy.3 There are two methods commonly used to test HIV resistance at present： one is genotypic resistance assay which predict HIV resistance based on resistance mutations in the viral genome; the other is a phenotypic resistance assay which directly evaluates HIV resistance through analyzing drug sensitivity in vitro.展开更多
Background This study was aim to explore the characteristics of phenotypic resistance of resistant strains of HIV type-1 （HIV-1） subtype B and to compare the concordance between the phenotypic resistance and genotyp...Background This study was aim to explore the characteristics of phenotypic resistance of resistant strains of HIV type-1 （HIV-1） subtype B and to compare the concordance between the phenotypic resistance and genotypic resistance. Methods The genotypic resistance assay for the HIV-1 clinical isolates was performed. One isolate without resistance mutation was chosen as a drug-sensitive reference strain and seven subtype B isolates with resistance mutations were phenotypically tested. Fifty percent inhibitory concentrations （IC50） between resistant and sensitive viruses were compared. The resistance extent was determined by the folds of the increased IC50. The concordance between the phenotypic resistance and genotypic resistance was also analyzed. Results IC50 of resistant isolates were 0.0006--0.1300 μmol/L for zidovudine （AZT）, 0.0016--0.0390 μmol/L for lamivudine （3TC）, 0.0104--0.4234 μmol/L for nevirapine （NVP）, and 0.0163--0.1142 μmol/L for indinavir （IDV）, respectively. Genotypic and phenotypic resistance assays indicated that the resistant strains were intermediately and highly resistant to nucleotide analog reverse transcriptase inhibitors and non-nucleotide analog reverse transcriptase inhibitors. The phenotypic assay was consistent with the genotypic assay. For measuring the potential resistance, the genotypic assay was more sensitive than the phenotypic. In evaluating the resistance to protease inhibitors, these two assays were discrepant. Conclusions Both the phenotypic and genotypic assays indicate that the resistant viruses exist in HIV-infected patients in China who have received treatment. Phenotypic and genotypic assays have high concordance, and the genotypic assay could replace the phenotypic assay to predict the HIV- 1 resistance.展开更多
基金The project supported by National Natural Science Foundation of China(81373486)Science and Technology Development Projects of Guangdong Province,China(2016B090918114,2013B021800157)Science and Technology Development Projects of Guangzhou,Guangdong,China(201510010236,201604020096)
文摘OBJECTIVE Genetic variants in the pharmacokinetic(PK)mechanism are the main underlying factors that modify the antiplatelet efficacy of clopidogrel.Hence,joint analysis of genetic variants that modify pharmacodynamic(PD)and PK responses to clopidogrel should be effective for identifying the genetic variants affecting the antiplatelet response to the drug.METHODS A genome-wide association study was conducted to identify new genetic loci that modify PD responses to clopidogrel and its active metabolite H4 in 115 Chinese patients with coronary heart disease(CHD).RESULTS We identified novel variants in two transporter genes(rs12456693 in SLC14A2 and rs2487032 in ABCA1)and in N6AMT1(rs2254638)associated with clopidogrel-treated P2Y12reaction unit(PRU)and plasma H4 concentration.The associations between these single nucleotide polymorphisms(SNPs)and PK parameters of clopidogrel and H4 were observed in 31 additional CHD patients(P<0.05).The new variants,together with CYP2C19*2 and clinical factors,dramatically improved the predictability of PRU variability to 37.7%compared with the published value of approximately 20%.The function of these SNPs on the activation of clopidogrel was validated in 32 liver S9 fractions,and the N6AMT1 rs2254638 T variant was found to be associated with decreased formation of H4(P=0.0386).Meanwhile,N6AMT1 rs2254638 was further identified to exert a marginal risk effect for MACE in an independent CHD patient cohort(OR:1.428,95%CI:0.978-2.086,P=0.0653,FDR=0.4726).In conclusion,we systematically identified new genetic variants as risk factors for the reduced efficacy of clopidogrel.CONCLUSION Our study findings enhanced the understanding of the absorption and metabolic mechanisms that influence PD responses to clopidogrel treatment.
文摘Highly active antiretroviral therapy （HAART） for HIV/AIDS has efficiently controlled the progression of the disease, extended life expectancy and decreased HIV/AIDS related morbidity and mortality since the advent of HIV protease inhibitors in 1996.1 Recent emergence of HIV resistance has severely affected the efficacy of antiretroviral therapy. The prevalence of HIV resistance has been increasing from the usage of AZT. Studies in US indicated that the prevalence was approximately 50% in patients who had experienced antiretroviral therapy.2 Antiviral regimens based on resistance tests could efficiently decrease viral load, increase CD4 cell counts and significantly improve the efficacy of antiretroviral therapy.3 There are two methods commonly used to test HIV resistance at present： one is genotypic resistance assay which predict HIV resistance based on resistance mutations in the viral genome; the other is a phenotypic resistance assay which directly evaluates HIV resistance through analyzing drug sensitivity in vitro.
基金This study was supported by a grant from the "Tenth Five-Year" Key Project (No. 2004-BA-719A-05).
文摘Background This study was aim to explore the characteristics of phenotypic resistance of resistant strains of HIV type-1 （HIV-1） subtype B and to compare the concordance between the phenotypic resistance and genotypic resistance. Methods The genotypic resistance assay for the HIV-1 clinical isolates was performed. One isolate without resistance mutation was chosen as a drug-sensitive reference strain and seven subtype B isolates with resistance mutations were phenotypically tested. Fifty percent inhibitory concentrations （IC50） between resistant and sensitive viruses were compared. The resistance extent was determined by the folds of the increased IC50. The concordance between the phenotypic resistance and genotypic resistance was also analyzed. Results IC50 of resistant isolates were 0.0006--0.1300 μmol/L for zidovudine （AZT）, 0.0016--0.0390 μmol/L for lamivudine （3TC）, 0.0104--0.4234 μmol/L for nevirapine （NVP）, and 0.0163--0.1142 μmol/L for indinavir （IDV）, respectively. Genotypic and phenotypic resistance assays indicated that the resistant strains were intermediately and highly resistant to nucleotide analog reverse transcriptase inhibitors and non-nucleotide analog reverse transcriptase inhibitors. The phenotypic assay was consistent with the genotypic assay. For measuring the potential resistance, the genotypic assay was more sensitive than the phenotypic. In evaluating the resistance to protease inhibitors, these two assays were discrepant. Conclusions Both the phenotypic and genotypic assays indicate that the resistant viruses exist in HIV-infected patients in China who have received treatment. Phenotypic and genotypic assays have high concordance, and the genotypic assay could replace the phenotypic assay to predict the HIV- 1 resistance.
