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1、周慧君 博士,Personalized Hypertension Treatment in Community Cares in China 基因指导社区高血压精细管理,为什么要进行个体化用药 美国药物基因组计划 基因指导社区高血压用药,为什么要个体化用药,据联合国世界卫生组织统计，全球死亡患者中，三分之一是死于不合理用药，而非死于自然疾病本身。 据粗略估计，对于一种特定的药物而言，只有三分之一的医生处方真正是“对症下药”；剩余的三分之二，不是药物无效，就是有毒副作用。由此可见，安全用药已成为世界性的公共医疗卫生问题。 药物不良反应成为除了癌症、脑溢血和心脏病外的第四大死因。,4,6.7%的住
2、院病人曾发生过严重药物不良反应（ADR)，其中0.32%是致命的,对美国39所医院的预期分析研究表明:,ADR导致了美国每年10万人死亡,ADR是住院病人第四至第六大死亡原因,个体化用药，就是药物治疗“因人而异”、“量体裁衣”，在充分考虑每个病人的遗传因素（即药物代谢基因类型）、性别、年龄、体重、生理病理特征以及正在服用的其它药物等综合情况的基础上制定安全、合理、有效、经济的药物治疗方案。,什么是个体化安全用药,7,什么是个体化安全用药,8,什么是个体化安全用药,进入卫生部医疗机构临床检验项目目录,11,NIH - Pharmacogenetics Research Network,www.p
3、harmgkb.org,12,13,PharmGKB Facilitates Pharmacogenomic Studies,PharmGKB: www.pharmgkb.org,The Pharmacogenetics Knowledgebase to collect, encode, and disseminate knowledge about the impact of human genetic variations on drug response.,1,316,994 Genotype-Phenotype Pairs 5540 Unique Variants 12710 Subj
4、ects with Genotypes 5305 Subjects with Genotype and Phenotype 141,759 Phenotypes Measured 1391 Literature Annotations,Nicotine Metabolism Pathway,From: Ring（周慧君）, Lou, Thorn and Benowitz (www.PharmGKB.org),Goals of Research in The PGRN,Discovery genetic predictors of variation in drug response in et
5、hnically diverse human populations Understand biological mechanisms responsible for variation in drug response,17,Pharmacogenetics of Nicotine Addiction and Treatment (PNAT),18,UGT Haplotypes and Nicotine Glucuronidation,UGT1A9 promoter haplotypes are associated with lower rate of 3-hydroxycotinine
6、glucuronidation. Ring HZ et al., SRNT (2006),19,Combined Effect of Dopamine Pathway Genes on Smoking Cessation Outcome,Smoking cessation trial using antidepressant bupropion The effects of DRD2 genotype are depending on DAT1 genotype Swan, Valdes, Ring, et al Pharmacogenomics (2005) Swan, Jack, Vald
7、es , Ring, et al Health Psychology (in press),N=51 N=124,N=64 N=89,20,Uses Multiple Sources of Information and Methodologies for Discovery,Discovery Strategies,HapMap,Linkage,Association,Model systems,Expression array,Cell assays,益基生物科技 (www.iDNA),2009年：科技部国家科技平台重大专项子课题“基因指导艾滋病安全用药” 2009年：与中国疾病控制中心合
8、作“基因指导社区高血压用药” 2010年：科技部创新基金“基因指导儿童安全用药” 2010年度中国最具潜力中小企业（创业家） 2010年度中国健康大事记（时尚健康）,Background,高血压是一种严重的慢性疾病，也是世界范围内的公共健康问题 药物治疗是控制高血压的主要手段，然而个体差异性导致了药物的疗效有所不同。,Calcium channel blockers Angiotensin II receptor blockers (ARBs) Beta-blockers Angiotensin-converting enzyme inhibitors (ACEI) Diuretics,Dru
9、gs to Treat High Blood Pressure,Common antihypertension drugs:,2019/5/9,24,Common Antihypertension Drugs,Life Cycle of Drug in Human Body,Liver: Cytochrome P450 represents a major set of drug metabolising enzymes,Pharmacokinetics,Proportion of drug metabolized by P450 Enzyme System,Drug Safety Gene
10、Test,CYPs are the major enzymes involved in drug metabolism and bioactivation.,Individual Difference of Drug Response,The genetic variations of drug related proteins including drug metabolism enzymes, drug transport proteins, and drug active receptors and/or targets are basic factors resulting in in
11、dividual and ethnic differences in drug response.,DNA,RNA,Protein,Enzyme,Individual difference caused by genetic variations of P450 genes.,poor metabolizer,normal metabolizer,2019/5/9,28,Possible designs: heritability estimates genome wide scans candidate gene studies Types of studies: sib pairs fam
12、ily studies association studies,Research Designs for Human Genetic Studies,Selected genes affecting hypertension drug metabolism:,Candidate Gene Selection,CYP2C9*3 CYP2C19*2/*3 CYP2D6*10,与中国疾控中心及武汉市卫生局合作， 我们在武汉五个社区医疗中心挑选了350个原发性高血压患者，并确定了这些患者的P450基因的基因型，随后我们对基因型与降压药物的反应做了关联分析。,Patient Selection,Age:
13、 37-71 years old Gender: men and women, half and half Sample collection: blood,Processes,genotyping,DNA preparation,Sample collection,bioinformatics analysis,reports,Genotype,Frequency,Genotype Results,Frequency,Allele,RESULT,Case 1,Poor metaboliser - these subjects have little or no metabolism func
14、tion Intermediate metabolizers - these subjects metabolize drugs at a rate somewhere between the poor and normal metabolizers Normal/extensive metaboliser - these subjects have normal function,Case 1,Poor metaboliser - these subjects have little or no metabolism function Intermediate metabolizers -
15、these subjects metabolize drugs at a rate somewhere between the poor and normal metabolizers Normal/extensive metaboliser - these subjects have normal function,Case 2,Case 2,Poor metaboliser - these subjects have little or no metabolism function Intermediate metabolizers - these subjects metabolize
16、drugs at a rate somewhere between the poor and normal metabolizers Normal/extensive metaboliser - these subjects have normal function,我们能为减少高血压患者对降压药产生的不良反应提供有效的方法。,初步研究显示：不同的药物代谢基因的基因型不同，导致了对药物的不同反应，这种基因型的不同也帮助解释了降压药对不同个体的疗效和副作用都会存在差异。,如果社区医疗中心将这种基因的差异性能够划在考虑范围之内，就能够有效地减少降压药对高血压患者的不良反应。,Summary,基因指
17、导儿童安全用药,药物基因检测将成为新生儿接受的一个常规程序, 人们将像知道自己的血型一样，很容易知道自己哪些药物应该谨慎使用。 一个简单明了的个体化医疗的流程是：病人就医时随身带上一张智能卡，上面除了姓名、性别、年龄、生活史等常规资料外，还存储着与药物代谢和药物效应有关的各种基因型资料。,“个体化医疗”,个体化医疗在未来将具备以下四大特征: 预测性，预防性，个体化，和参与性 (P4 Medicine: predictive, preventative, personalized and participatory)。 预测性：基于个人特异性DNA序列与蛋白水平上的健康预测。 预防性：在疾病未发
18、病时，即对个人有可能获得的疾病进行预防性治疗，阻止疾病的发生或最大限度的降低疾病造成的损害。 个体化：根据每个人独特的基因组对疾病进行有针对性的治疗，对预测、预防进行补充。 参与性：患者积极参与治疗的全过程，与医生一起制定治疗方案。,2019/5/9,Dr. Jiang Xia Wuhan Centers for Disease Prevention and Control, Wuhan Dr. Chenghua Hu Dr. Xia Feng Dr. Yumin Liu Dr. Shuyi Liang Dr. Fucheng Fan Dr. Ning Zhang Wuhan local community health cares, Wuhan,Acknowledgement,Dr. Li Su Huazhong University of Science and Technology Dr. Ma Xuejun CDC Hongtao Zhang Du Zheng YiGene Inc,