基因组医学与个性化医疗时代.ppt

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1、Genomic medicine and Personalized MedicineFrancis S.Collins,M.D.,Ph.D.National Human Genome Research InstitutePAEA Annual MeetingOctober 27,2007完全健康完全健康完全健康完全健康绝对绝对绝对绝对死亡死亡死亡死亡健康健康,亚临亚临床床,疾病与疾病与损伤损伤,濒濒死死中危中危险险状状态态低危低危险险状状态态出出现临现临床症状（疾病）床症状（疾病）高危高危险险状状态态（早期病理改（早期病理改变变）相对健康/一般小病慢性病严重疾病1%19%80%卫生资源70%3

2、0%医疗卫生事业发展面临的问题医疗卫生事业发展面临的问题诊断治疗系统耗费了大量卫生费用，而效益低下诊断治疗没有个性化，导致过度治疗，事倍功半我国十一五科学发展规划有关人口与健康部分的指导方针重点前移将医学研究的重点从“诊断治疗”前移到“预测预防”重心下移政府重点投入社区医疗、基层医疗Collins et al.,Nature 4/24/03Collins et al.,Nature 4/24/03A SMALL SAMPLING OF COOL THINGS ABOUT THE GENOMEHumans have fewer protein-coding genes than expected

3、 only about 20,000Only about 1.5%of the human genome is involved in coding for protein,but there are numerous complex critical functions encoded in the rest of the DNA instruction bookWe are all 99.9%the same at the DNA levelCystic fibrosisAdult onset diabetesAIDS SNP A SNP BSearching for genetic ca

4、uses ofdisease in the pre-genome era“Genome Wide Association”Approach to Common Disease:The View from 2002Identify all 10 million common SNPsCollect 1000 cases and 1000 controlsGenotype all DNAs for all SNPsThat adds up to 20 billion genotypesAt 50 cents a genotype,thats$10 billion for each disease

5、completely out of the questionGenome Wide Association Approach to Common Disease:The View from 2007Identify an optimum set of 300,000 tag SNPsCollect 1000 cases and 1000 controlsGenotype all DNAs for all SNPsThat adds up to 600 million genotypesGenotyping just dropped to$0.0012,so thats$800,000 for

6、each diseaseSearching for genetic causes ofdisease in the genome eraConfirmed genetic contributors to common human diseases(April 2007)2000200620072001CF3GCKRFTOCDKN2A8q24#28q24#38q24#48q24#58q24#6 ATG16L1IRGM5p133p2110q21NKX2PTPN2IL12BCDKN2AIGF2BP2CDKAL1HHEXSLC30A8CholesterolObesityCoronary DzKCNJ1

7、120022003 20042005PPAR Type 2 DiabetesIBD5NOD2Crohns DiseaseCFHAge Related Macular DegenerationCFB/C2LOC3877158q24IL23RTCF7L2Prostate cancerCholesterolObesityCoronary DiseaseQT intervalAtrial FibrillationType 2 Diabetes Prostate cancerBreast cancerColon cancerKCNJ1120032000PPAR 2001IBD5NOD2200520062

8、002CTLA42004PTPN22Age Related Macular DegenerationCrohns DiseaseType 1 DiabetesSystemic Lupus ErythematosusAsthmaRestless leg syndromeGallstone diseaseCD25IRF5PCSK9CFHNOS1APIFIH1PCSK9CFB/C2LOC3877158q24IL23RTCF7L22007CDKN2A8q24#28q24#38q24#48q24#58q24#6ATG16L15p1310q21IRGMNKX2-3IL12B3p211q24PTPN2TCF

9、2CDKN2AIGF2BP2CDKAL1HHEXSLC30A8MEIS1LBXCOR1BTBD9C38q24ORMDL34q25TCF2GCKRFTOC12orf30ERBB3KIAA0350CD22616p13PTPN2SH2B3FGFR2TNRC9MAP3K1LSP18q24Confirmed genetic contributors to common human diseases(August 2007)CholesterolObesityCoronary DiseaseQT intervalAtrial FibrillationType 2 Diabetes Prostate can

10、cerBreast cancerColon cancerKCNJ1120032000PPAR2001IBD5NOD2200520062002CTLA42004PTPN22Age Related Macular DegenerationCrohns DiseaseType 1 DiabetesSystemic Lupus ErythematosusAsthmaRestless leg syndromeGallstone diseaseMultiple sclerosisRheumatoid arthritisGlaucomaCD25IRF5PCSK9CFH2007NOS1APIFIH1PCSK9

11、CFB/C2LOC3877158q24IL23RTCF7L2CDKN2A8q24#28q24#38q24#48q24#58q24#6ATG16L15p1310q21IRGMNKX2-3IL12B3p211q24PTPN2TCF2CDKN2B/AIGF2BP2CDKAL1HHEXSLC30A8MEIS1LBXCOR1BTBD9C38q24ORMDL34q25TCF2GCKRFTOC12orf0ERBB3KIAA030CD22616p13PTPN2SH2B3FGFR2TNRC9MAP3K1LSP18q24LOXL1IL7RTRAF1STAT4ABCG8GALNT2PSRC1NCANTBL2TRIB

12、1KCTD10ANGLPT3GRIN3AConfirmed genetic contributors to common human diseases(Sept 2007)We wouldnt think of buying shoes in a single sizeSo why should we be satisfied with one-size-fits-all medicine?DiagnosticsPreventive MedicineDisease with Genetic ComponentTimeAccelerated by HumanGenome Projectand H

13、apMapIdentify Genetic Defect(s)Taking a good family history will be supplemented,not supplanted,by genetic testing-95%confidence interval curves Recurrence score for individual patientsSource:Paik,et al.,N Engl J Med,December 2004Genomics Is Not Just About Heredity:Using Gene Expression To Predict C

14、ancer RecurrenceMultigene assay predicts recurrence of tamoxifen-treated,node-negative breast cancerGene expression analysis was combined with an algorithm for calculating risk for distant recurrenceDiagnosticsPreventive MedicineDisease with Genetic ComponentTimeAccelerated by HumanGenome Projectand

15、 HapMapIdentify Genetic Defect(s)PharmacogenomicsM.Wortman Technology Review,Feb.2001药物的反应与副作用Analysis of VKORC1 and CYP2C9 reveal variable warfarin dose responseNeedslow-doseNeedshigh-doseSlow P450metabolizersVariants at these two genes account for 60%of variability in therapeutic doseProspective t

16、rials now underwayFDA has added information about genetics to labelRieder,M.et al.NEJM 352:2285-2293,2005Diagnostics TherapeuticDevelopments Gene Therapy Drug TherapyPreventive MedicineDisease with Genetic ComponentTimeAccelerated by HumanGenome Projectand HapMapIdentify Genetic Defect(s)Pharmacogen

17、omicsImatinib(Gleevec)Specifically TargetsAn Abnormal Protein,Blocking Its Ability To Cause Chronic Myeloid LeukemiaChromosome 9;22 translocationCMLBcr-Abl fusion proteinGleevecBcr-Abl fusion protein NormalPrediction:Physician Assistants Will Play a Lead Role in the Personalized Medicine RevolutionA

18、nd lots of resources are being developed to assist you“81%of programs expressedthe need to enhance thequality and extent of geneticand molecular medicine in their curricula”Top 10 Topics For PA Education In Genetics/Genomics1.“Genetics 101”basic concepts in genetic and genomic science2.The family hi

19、story3.Preconception and prenatal genetics4.Newborn screening and pediatric genetics5.Adult genetics6.Cancer genetics7.The genetics of common disease8.Pharmacogenetics9.Ethical,legal,and social aspects of genetics10.Genetic counseling and genetic referralsPersonalized Medicine:A future dream Bettys

20、story in 2015Betty completes the Surgeon Generals family history tool at age 25,learns of uncles with early heart disease.She consults her PA,who works in a practice that has made an effort to stay informed about genomic medicine.She suggests complete genome sequencing for$1000.Betty inquires about

21、the risk of genetic discrimination,but effective legislation has outlawed this.She is found to have three gene variants that have been shown conclusively in well validated studies to increase her risk of early heart attack 4-fold.She and her PA design a program of prevention based on diet,exercise,a

22、nd medication precisely targeted to her genetic situation.Bettys story continuesBetty does well until age 75.She develops left arm pain that she assumes is due to gardening,but her care providers know her higher risk and diagnose an acute MI.Referring to her genome sequence,the PA and MD choose the

23、drugs that will work best to treat her.She survives and is alive and well in the 22nd century.Personalized Medicine:Could the dream become a nightmare?Bettys story gone wrongBetty never learns about her family history,educational efforts for the public and health care providers were defunded,communi

24、ty efforts never got off the ground,and Bettys PA and MD thought genetics was irrelevant to practice.Betty hears about genome sequencing,but after seeing her brother lose his health insurance from this information,she decides not to.Betty eats an unhealthy diet,gains weight,and develops high blood p

25、ressure.While tests to predict which drug would be most effective for Betty have been proposed,they have never been validated,and are not reimbursed.Bettys story gone wrong,continuedBettys hypertension is treated with a drug that causes a hypersensitivity reaction,so she stops treatment.After 10 yea

26、rs of uncontrolled hypertension,Betty develops left arm pain at age 50.Unaware of her high risk,her PA assumes this is musculoskeletal and prescribes rest.Betty returns to the ER a few hours later in cardiogenic shock.The absence of her genome sequence information prevents immediate optimum choice o

27、f therapy.Betty dies in the ER.Charge to all of us:SAVE BETTY!Personalized Medicine:The dream needs YOU!Challenge of Rising U.S.Health ExpendituresBiomedical Research Must Deliver8%10%12%14%16%18%20%201520122009200620032000199719941991198819851982National Health Expenditures as a Percent of GDP1980A

28、ctualProjectedSource:http:/Percent of U.S.GDP$4.1trillionTranslating GenomicsGenomic discoveries relevant to common disease diagnosis and management are coming at an increasing rate.Basic discoveries are leading to the development of clinical applications.Ergo,improved healthcare is around the corne

29、r!Translating GenomicsGenomic discoveries relevant to common disease diagnosis and management are coming at an increasing rate.Basic discoveries are leading to the development of clinical applications.Mind the gap!Ergo,improved healthcare is around the corner!The Future Paradigm:The 4 PsTransform Me

30、dicine from Curative to PreemptivePreemptivePersonalizedPredictiveParticipatoryEra of Precision MedicinePersonalized Medicine The Future?62Heres my sequence.”New YorkerProgress in Genotyping Technology1 1101010102 210103 310104 410105 510106 6Nb of Nb of SNPsSNPsCost per genotype(Cents,USD)Cost per

31、genotype(Cents,USD)10101 110102 2ABIABITaqManTaqManABIABISNPlexSNPlexIlluminaIlluminaGolden GateGolden Gate IlluminaIlluminaInfinium/SentrixInfinium/Sentrix AffymetrixAffymetrix100K/500K100K/500K Perlegen Perlegen AffymetrixAffymetrixMegAlleleMegAllele 2001200120052005AffymetrixAffymetrix10K10KCourt

32、esy S.Chanock,NCICourtesy S.Chanock,NCIGWA in Guangxi2007年9月，彭涛建议我在广西做前列腺癌相关SNP的验证研究，没有引起我的重视。2007年12月，Science把GWA列为总结10大科学进展，使我联想到彭涛提供那些相关的SNP正是来源于一个大型的GWA，由此点燃我对GWA的强烈兴趣2008年寒假，组织循证医学班在单个基因（病因）meta分析的基础上开展全基因组（GWA）的meta分析，开始理论准备2008年4月6月，到彭涛所在的NCI实验室，考察在中国，在广西开展GWA的可行性，产生第一个GWA的设计方案肾结石的GWAS（2009年7

33、月1日NG发表）GWA in Guangxi2008年7月，赴上海参加GWA学习班，同时参观国家基因组南方中心，与 illumina 和Aff展开价格谈判拉锯战2008年9月底，为了省钱同时提高投入产出效率，决定先从QTL的GWA开始研究2008年10月形成QTL的GWA初步研究方案并向卫生厅、财政厅提出申请2009年1月参加AFF在三亚召开的GWA设计研讨会，安徽张学军GWA在NG发表2009年5月参加杭州4P与个性化医学学习班2009年6月组建QTL-GWA研究小组，确定分工GWA in Guangxi2009年7月参加上海GWA WORKSHOP，认识美国徐剑锋教授，双方很快达成合作协议

34、，使每个样本的GWA研究成本从3200元降到2000元（不包括表型指标检测）2009年7月下旬，拜访国家人类遗传资源管理办公室，解决DNA样本出境问题2009年8月8日开始收集标本男性激素及其相关指标的GWAS研究目的：发现调控男性激素及其相关指标的基因位点（SNP）研究内容：各种QTL，包括男性激素及其相关指标，代谢类，炎症因子，细胞因子研究方法：全基因组扫描的关联研究技术路线预期结果GWA 研究论文普通指标论文LUTS：下尿路症状MS：代谢综合征ADAM：老年男性 雄激素缺乏症BPH：前列腺增生CP：慢性前列腺炎ED：勃起功能障碍男性激素及其相关指标可以撰写的论文研究小组成员分工学术组研究方案调整，各种报表的填写，各组之间协调，论文撰写投稿组长：彭涛 杨晓波 秘书：张士军成员：高勇，谭爱花，秦志明流行病学任务：宣传发动，知情同意，问卷调查，资料汇总组长：张海英，杨晓波成员：宣传，体检文秘宣传，对外联络，组织体检组长：王芃，米华成员：蒋书算，标本，实验任务：收集样本，phenotype检测，DNA及血清（浆）分离和保存组长：秦雪，莫林键成员：生物信息学分析资料汇总，生物信息学分析，统计图表制作组长：胡艳玲成员：高勇，谭爱花