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
Background: Cotton fiber yield is a complex trait,which can be influenced by multiple agronomic traits.Unravelling the genetic basis of cotton fiber yield-related traits contributes to genetic improvement of cotton.Re...Background: Cotton fiber yield is a complex trait,which can be influenced by multiple agronomic traits.Unravelling the genetic basis of cotton fiber yield-related traits contributes to genetic improvement of cotton.Results: In this study,503 upland cotton varieties covering the four breeding stages(BS1–BS4,1911–2011)in China were used for association mapping and domestication analysis.One hundred and forty SSR markers significantly associated with ten fiber yield-related traits were identified,among which,29 markers showed an increasing trend contribution to cotton yield-related traits from BS1 to BS4,and 26 markers showed decreased trend effect.Four favorable alleles of 9 major loci(R^(2)≥3)were strongly selected during the breeding stages,and the candidate genes of the four strongly selected alleles were predicated according to the gene function annotation and tissue expression data.Conclusions :The study not only uncovers the genetic basis of 10 cotton yield-related traits but also provides genetic evidence for cotton improvement during the cotton breeding process in China.展开更多
Background Cotton is an economically important crop.It is crucial to find an effective method to improve cotton yield,and one approach is to decrease the abscission of cotton bolls and buds.However,the lack of knowled...Background Cotton is an economically important crop.It is crucial to find an effective method to improve cotton yield,and one approach is to decrease the abscission of cotton bolls and buds.However,the lack of knowledge of the genetic and molecular mechanisms underlying cotton boll abscission traits has hindered genetic improvements.Results Pearson’s correlation analysis revealed a significant positive correlation between boll abscission rates 1(AR1)and boll abscission rates 2(AR2).A genome-wide association study was conducted on 145 loci that exhibited high polymorphism and were uniformly distributed across 26 chromosomes(pair).The study revealed 18,46,and 62 markers that were significantly associated with boll abscission,fiber quality,and yield traits(P<0.05),explaining 1.75%–7.13%,1.16%–9.58%,and 1.40%–5.44%of the phenotypic variation,respectively.Notably,the marker MON_SHIN-1584b was associated with the cotton boll abscission trait,whereas MON_CGR5732a was associated with cotton boll abscission and fiber quality traits.Thirteen of the marker loci identified in this study had been previously reported.Based on phenotypic effects,six typical cultivars with elite alleles related to cotton boll abscission,fiber quality,and yield traits were identified.These cultivars hold great promise for widespread utilization in breeding programs.Conclusions These results lay the foundation for understanding the molecular regulatory mechanism of cotton boll abscission and provide data for the future improvement of cotton breeding.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.
基金This work was supported by the National Natural Science Foundation of China(31760402)Young and Middle-aged Science and Technology Leading Talents of Xinjiang Production and Construction Corps(2019CB027).
文摘Background: Cotton fiber yield is a complex trait,which can be influenced by multiple agronomic traits.Unravelling the genetic basis of cotton fiber yield-related traits contributes to genetic improvement of cotton.Results: In this study,503 upland cotton varieties covering the four breeding stages(BS1–BS4,1911–2011)in China were used for association mapping and domestication analysis.One hundred and forty SSR markers significantly associated with ten fiber yield-related traits were identified,among which,29 markers showed an increasing trend contribution to cotton yield-related traits from BS1 to BS4,and 26 markers showed decreased trend effect.Four favorable alleles of 9 major loci(R^(2)≥3)were strongly selected during the breeding stages,and the candidate genes of the four strongly selected alleles were predicated according to the gene function annotation and tissue expression data.Conclusions :The study not only uncovers the genetic basis of 10 cotton yield-related traits but also provides genetic evidence for cotton improvement during the cotton breeding process in China.
基金Key Laboratory of Cotton Biology Open Fund(CB2022A11)National Natural Science Foundation of China(32260510)+3 种基金Innovation talent Program in Sciences and Technologies of Xinjiang Production and Construction Corps,China(2021CB028)Key Programs for Science and Technology Development of Shihezi city,Xinjiang Production and Construction Crops,China(2022NY01)Science and Technology Planning of Shuanghe city,Xinjiang Production and Construction Crops,China(2021NY02)key programs for science and technology development in agricultural field of Xinjiang Production and Construction Corps,China.
文摘Background Cotton is an economically important crop.It is crucial to find an effective method to improve cotton yield,and one approach is to decrease the abscission of cotton bolls and buds.However,the lack of knowledge of the genetic and molecular mechanisms underlying cotton boll abscission traits has hindered genetic improvements.Results Pearson’s correlation analysis revealed a significant positive correlation between boll abscission rates 1(AR1)and boll abscission rates 2(AR2).A genome-wide association study was conducted on 145 loci that exhibited high polymorphism and were uniformly distributed across 26 chromosomes(pair).The study revealed 18,46,and 62 markers that were significantly associated with boll abscission,fiber quality,and yield traits(P<0.05),explaining 1.75%–7.13%,1.16%–9.58%,and 1.40%–5.44%of the phenotypic variation,respectively.Notably,the marker MON_SHIN-1584b was associated with the cotton boll abscission trait,whereas MON_CGR5732a was associated with cotton boll abscission and fiber quality traits.Thirteen of the marker loci identified in this study had been previously reported.Based on phenotypic effects,six typical cultivars with elite alleles related to cotton boll abscission,fiber quality,and yield traits were identified.These cultivars hold great promise for widespread utilization in breeding programs.Conclusions These results lay the foundation for understanding the molecular regulatory mechanism of cotton boll abscission and provide data for the future improvement of cotton breeding.
