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
为研究哺乳仔猪抗腹泻的遗传因素和通路,通过对640头腹泻仔猪进行采样和统计分析,选取其中600个样本,包括大白猪453头、长白猪105头和杜洛克猪42头进行低深度重测序(1×),对测序结果质控后开展全基因组关联分析(genome-wide associa...为研究哺乳仔猪抗腹泻的遗传因素和通路,通过对640头腹泻仔猪进行采样和统计分析,选取其中600个样本,包括大白猪453头、长白猪105头和杜洛克猪42头进行低深度重测序(1×),对测序结果质控后开展全基因组关联分析(genome-wide association study,GWAS),在大白猪和长白猪中分别筛选出42个和107个显著SNPs,这些位点上下游20 kb区域分别涉及32个和82个基因,对这些基因进行GO和KEGG富集分析,最终分别确定了6个(PLA2G4A、C1RL、PTPN6、C1R、PPP1R12A和GRID2)和8个(DAPK1、TMC8、ITM2C、CHMP4B、CAST、PDE4D、HSPA4和GRID2)可能与哺乳仔猪腹泻性状相关的重要候选基因,其中GRID2在大白猪和长白猪中同时被筛选到。结果表明,仔猪腹泻性状候选基因与细胞凋亡、免疫、细胞屏障和物质的跨膜运输相关功能有关。展开更多
2型糖尿病(type 2 diabetes,T2D)是一种常见的复杂疾病,其发病受到遗传和环境因素的共同作用.全基因组关联研究(genome-wide association study,GWAS)是一种可在全基因组范围筛查疾病相关的序列变异的新型群体关联研究方法.近年来,采用G...2型糖尿病(type 2 diabetes,T2D)是一种常见的复杂疾病,其发病受到遗传和环境因素的共同作用.全基因组关联研究(genome-wide association study,GWAS)是一种可在全基因组范围筛查疾病相关的序列变异的新型群体关联研究方法.近年来,采用GWAS以及在此基础上展开的meta分析,已分别在TCF7L2、HHEX-IDE、SLC30A8、CDKAL1、CDKN2A-CDKN2B、IGF2BP2、NOTCH2、CDC123-CAMK1D、ADAMTS9、THADA、TSPAN8-LGR5、JAZF1等12个基因区域鉴定出多个T2D相关的多态位点.已有的研究提示,上述多个基因可能在胰岛β细胞发育和功能维持方面扮演着重要角色.本文集中介绍了GWAS的原理及其在T2D研究中的优势;回顾了GWAS在T2D研究中的主要发现;并对运用GWAS在T2D研究中尚需解决的问题进行了总结和展望.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
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.
文摘为研究哺乳仔猪抗腹泻的遗传因素和通路,通过对640头腹泻仔猪进行采样和统计分析,选取其中600个样本,包括大白猪453头、长白猪105头和杜洛克猪42头进行低深度重测序(1×),对测序结果质控后开展全基因组关联分析(genome-wide association study,GWAS),在大白猪和长白猪中分别筛选出42个和107个显著SNPs,这些位点上下游20 kb区域分别涉及32个和82个基因,对这些基因进行GO和KEGG富集分析,最终分别确定了6个(PLA2G4A、C1RL、PTPN6、C1R、PPP1R12A和GRID2)和8个(DAPK1、TMC8、ITM2C、CHMP4B、CAST、PDE4D、HSPA4和GRID2)可能与哺乳仔猪腹泻性状相关的重要候选基因,其中GRID2在大白猪和长白猪中同时被筛选到。结果表明,仔猪腹泻性状候选基因与细胞凋亡、免疫、细胞屏障和物质的跨膜运输相关功能有关。
文摘2型糖尿病(type 2 diabetes,T2D)是一种常见的复杂疾病,其发病受到遗传和环境因素的共同作用.全基因组关联研究(genome-wide association study,GWAS)是一种可在全基因组范围筛查疾病相关的序列变异的新型群体关联研究方法.近年来,采用GWAS以及在此基础上展开的meta分析,已分别在TCF7L2、HHEX-IDE、SLC30A8、CDKAL1、CDKN2A-CDKN2B、IGF2BP2、NOTCH2、CDC123-CAMK1D、ADAMTS9、THADA、TSPAN8-LGR5、JAZF1等12个基因区域鉴定出多个T2D相关的多态位点.已有的研究提示,上述多个基因可能在胰岛β细胞发育和功能维持方面扮演着重要角色.本文集中介绍了GWAS的原理及其在T2D研究中的优势;回顾了GWAS在T2D研究中的主要发现;并对运用GWAS在T2D研究中尚需解决的问题进行了总结和展望.
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.
