基因指導(dǎo)社區(qū)高血壓精細(xì)管理-周慧君課件

1、周慧君 博士PersonalizedHypertensionTreatmentinCommunityCaresinChina基因指導(dǎo)社區(qū)高血壓精細(xì)管理 為什么要進(jìn)行個(gè)體化用藥 美國(guó)藥物基因組計(jì)劃 基因指導(dǎo)社區(qū)高血壓用藥為什么要個(gè)體化用藥據(jù)聯(lián)合國(guó)世界衛(wèi)生組織統(tǒng)計(jì)，全球死亡患者中，三分之一是死于不合理用藥，而非死于自然疾病本身。據(jù)粗略估計(jì)，對(duì)于一種特定的藥物而言，只有三分之一的醫(yī)生處方真正是“對(duì)癥下藥”；剩余的三分之二，不是藥物無(wú)效，就是有毒副作用。由此可見(jiàn)，安全用藥已成為世界性的公共醫(yī)療衛(wèi)生問(wèn)題。藥物不良反應(yīng)成為除了癌癥、腦溢血和心臟病外的第四大死因。4 6.7%的住院病人曾發(fā)生過(guò)嚴(yán)重藥物不良反

2、應(yīng)（ADR)，其中0.32%是致命的 對(duì)美國(guó)39所醫(yī)院的預(yù)期分析研究表明:ADR導(dǎo)致了美國(guó)每年10萬(wàn)人死亡ADR是住院病人第四至第六大死亡原因個(gè)體化用藥，就是藥物治療“因人而異”、“量體裁衣”，在充分考慮每個(gè)病人的遺傳因素（即藥物代謝基因類型）、性別、年齡、體重、生理病理特征以及正在服用的其它藥物等綜合情況的基礎(chǔ)上制定安全、合理、有效、經(jīng)濟(jì)的藥物治療方案。什么是個(gè)體化安全用藥7什么是個(gè)體化安全用藥11NIH - Pharmacogenetics Research Network12Goals of Research in The PGRNDiscovery genetic predictors

3、 of variation in drug response in ethnically diverse human populationsUnderstand biological mechanisms responsible for variation in drug responseBetter, safer, personalized medications17Focus Genetics of nicotine metabolism Genetics of individual susceptibility to nicotine addiction Genetics of vari

4、ability in treatment outcomesApproach Genotype-phenotype association analysis Prospective confirmatory trial Long-term Goal Tailor treatment to individual patients Identify novel targets for pharmacologic treatments Reduce impact of smoking as a major public health problemPharmacogenetics of Nicotin

5、e Addiction and Treatment (PNAT) 18UGT Haplotypes and Nicotine Glucuronidation UGT1A9 promoter haplotypes are associated with lower rate of 3-hydroxycotinine glucuronidation. Ring HZ et al., SRNT (2006)19Combined Effect of Dopamine Pathway Genes on Smoking Cessation OutcomeSmoking cessation trial us

6、ing antidepressant bupropionThe effects of DRD2 genotype are depending on DAT1 genotypeSwan, Valdes, Ring, et al Pharmacogenomics (2005)Swan, Jack, Valdes , Ring, et al Health Psychology (in press)N=51 N=124N=64 N=89益基生物科技 (www.iDNA.)2009年：科技部國(guó)家科技平臺(tái)重大專項(xiàng)子課題“基因指導(dǎo)艾滋病安全用藥”2009年：與中國(guó)疾病控制中心合作“基因指導(dǎo)社區(qū)高血壓用藥”2

7、010年：科技部創(chuàng)新基金“基因指導(dǎo)兒童安全用藥”2010年度中國(guó)最具潛力中小企業(yè)（創(chuàng)業(yè)家）2010年度中國(guó)健康大事記（時(shí)尚健康）Background高血壓是一種嚴(yán)重的慢性疾病，也是世界范圍內(nèi)的公共健康問(wèn)題 藥物治療是控制高血壓的主要手段，然而個(gè)體差異性導(dǎo)致了藥物的療效有所不同。Calcium channel blockersAngiotensin II receptor blockers (ARBs)Beta-blockersAngiotensin-converting enzyme inhibitors (ACEI) Diuretics Drugs to Treat High Blood P

8、ressureCommon antihypertension drugs:2022/9/1324Common Antihypertension DrugsLife Cycle of Drug in Human BodyLiver: Cytochrome P450represents a major set of drug metabolising enzymesDoseDestroyed in gutNotabsorbed Destroyed by gut wallDestroyedby livertosystemiccirculationPharmacokineticsProportion

9、of drug metabolized by P450 Enzyme SystemDrug Safety Gene TestCYPs are the major enzymes involved in drug metabolism and bioactivation.Individual Difference of Drug ResponseThe genetic variations of drug related proteins including drug metabolism enzymes, drug transport proteins, and drug active rec

10、eptors and/or targets are basic factors resulting in individual and ethnic differences in drug response.DNARNAProteinEnzyme Individual difference caused by genetic variations of P450 genes.poor metabolizer normal metabolizer2022/9/1328Possible designs:heritability estimates genome wide scanscandidat

11、e gene studiesTypes of studies:sib pairsfamily studiesassociation studiesResearch Designs for Human Genetic StudiesSelected genes affecting hypertension drug metabolism: Candidate Gene Selection CYP2C9*3 CYP2C19*2/*3 CYP2D6*10與中國(guó)疾控中心及武漢市衛(wèi)生局合作， 我們?cè)谖錆h五個(gè)社區(qū)醫(yī)療中心挑選了350個(gè)原發(fā)性高血壓患者，并確定了這些患者的P450基因的基因型，隨后我們對(duì)基因

12、型與降壓藥物的反應(yīng)做了關(guān)聯(lián)分析。Patient SelectionAge: 37-71 years oldGender: men and women, half and halfSample collection: bloodProcessesgenotypingDNA preparationSample collectionbioinformatics analysis reports GenotypeFrequency Genotype ResultsFrequency Allele RESULT GeneGenotypePhenotypeCYP2C9*3AANormal Metaboli

13、zerCYP2D6 *10TTPoor MetabolizerCYP2C19*2GGNormal MetabolizerCYP2C19*3GGNormal MetabolizerCase 1Drug SafetyNormal MetabolizerPoor MetabolizerPoor metaboliser - these subjects have little or no metabolism function Intermediate metabolizers - these subjects metabolize drugs at a rate somewhere between

14、the poor and normal metabolizers Normal/extensive metaboliser - these subjects have normal function Case 1Poor metaboliser - these subjects have little or no metabolism function Intermediate metabolizers - these subjects metabolize drugs at a rate somewhere between the poor and normal metabolizers N

15、ormal/extensive metaboliser - these subjects have normal function Case 2GeneGenotypePhenotypeCYP2C9*3AANormal MetabolizerCYP2D6*10CTNormal MetabolizerCYP2C19*2AGNormal MetabolizerCYP2C19*3GGNormal MetabolizerDrug SafetyCase 2Poor metaboliser - these subjects have little or no metabolism function Int

16、ermediate metabolizers - these subjects metabolize drugs at a rate somewhere between the poor and normal metabolizers Normal/extensive metaboliser - these subjects have normal function 我們能為減少高血壓患者對(duì)降壓藥產(chǎn)生的不良反應(yīng)提供有效的方法。 初步研究顯示：不同的藥物代謝基因的基因型不同，導(dǎo)致了對(duì)藥物的不同反應(yīng)，這種基因型的不同也幫助解釋了降壓藥對(duì)不同個(gè)體的療效和副作用都會(huì)存在差異。 如果社區(qū)醫(yī)療中心將這種基

17、因的差異性能夠劃在考慮范圍之內(nèi)，就能夠有效地減少降壓藥對(duì)高血壓患者的不良反應(yīng)。 Summary基因指導(dǎo)兒童安全用藥藥物基因檢測(cè)將成為新生兒接受的一個(gè)常規(guī)程序, 人們將像知道自己的血型一樣，很容易知道自己哪些藥物應(yīng)該謹(jǐn)慎使用。一個(gè)簡(jiǎn)單明了的個(gè)體化醫(yī)療的流程是：病人就醫(yī)時(shí)隨身帶上一張智能卡，上面除了姓名、性別、年齡、生活史等常規(guī)資料外，還存儲(chǔ)著與藥物代謝和藥物效應(yīng)有關(guān)的各種基因型資料?！皞€(gè)體化醫(yī)療”個(gè)體化醫(yī)療在未來(lái)將具備以下四大特征: 預(yù)測(cè)性，預(yù)防性，個(gè)體化，和參與性 (P4 Medicine: predictive, preventative, personalized and participatory)。 預(yù)測(cè)性：基于個(gè)人特異性DNA序列與蛋白水平上的健康預(yù)測(cè)。預(yù)防性：在疾病未發(fā)病時(shí)，即對(duì)個(gè)人有可能獲得的疾病進(jìn)行預(yù)防性治療，阻止疾病的發(fā)生或最大限度的降低疾病造成的損害。個(gè)體化：根據(jù)每個(gè)人獨(dú)特的基因組對(duì)疾病進(jìn)行有針對(duì)性的治療，對(duì)預(yù)測(cè)、預(yù)防進(jìn)行補(bǔ)充。參與性：患者積極參與治療的全過(guò)程，與醫(yī)生一起制定治療方案。2022/9/13Dr. Jiang XiaWuhan Centers for