1、Genomic medicine and Personalized MedicineFrancis S.Collins,M.D.,Ph.D.National Human Genome Research InstitutePAEA Annual MeetingOctober 27,2007基因组医学与个性化医疗时代1健康健康,亚临床亚临床,疾病与损伤疾病与损伤,濒死濒死中危险状态中危险状态低危险状态低危险状态出现临床症状（疾病）出现临床症状（疾病）高危险状态（早期病理改变）高危险状态（早期病理改变）相对健康/一般小病慢性病严重疾病1%19%80%卫生资源70%30%基因组医学与个性化医疗时代2医
2、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，事倍功半基因组医学与个性化医疗时代3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、基层医疗基因组医学与个性化医疗时代4基因组医学能给我们带来基因组医学能给我们带来什么？什么？根据易感基因，预测疾病发生的概率，做根据易感基因，预测疾病发生的概率，做到个性化预防到个性化预防 根据同一种疾病对对同一种药物的不同反根据同一种疾病对对同一种药物的不同反应进行基因分型，做到个性化治疗应进行
3、基因分型，做到个性化治疗 以导致疾病的相关基因作以导致疾病的相关基因作为靶点，开发新为靶点，开发新的治疗药物。的治疗药物。基因组医学与个性化医疗时代5基因组医学与个性化医疗时代6Collins et al.,Nature 4/24/03基因组医学与个性化医疗时代7Collins et al.,Nature 4/24/03基因组医学与个性化医疗时代8A SMALL SAMPLING OF COOL A SMALL SAMPLING OF COOL THINGS ABOUT THE GENOMETHINGS ABOUT THE GENOME Humans have fewer protein-co
4、ding genes than expected only about 20,000 Only 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 book We are all 99.9%the same at the DNA level基因组医学与个性化医疗时代9Cystic fibrosisAdult onset diabetes
5、AIDS基因组医学与个性化医疗时代10基因组医学与个性化医疗时代11基因组医学与个性化医疗时代12 SNP A SNP B基因组医学与个性化医疗时代13Searching for genetic causes ofdisease in the pre-genome era基因组医学与个性化医疗时代14“Genome Wide Association”Approach to Common Disease:The View from 2002 Identify all 10 million common SNPs Collect 1000 cases and 1000 controls Genot
6、ype all DNAs for all SNPs That adds up to 20 billion genotypes基因组医学与个性化医疗时代15基因组医学与个性化医疗时代16Genome Wide Association Approach to Common Disease:The View from 2007 Identify an optimum set of 300,000 tag SNPs Collect 1000 cases and 1000 controls Genotype all DNAs for all SNPs That adds up to 600 millio
7、n genotypes基因组医学与个性化医疗时代17Searching for genetic causes ofdisease in the genome era基因组医学与个性化医疗时代18Confirmed genetic contributors to common human diseases(April 2007)2000200620072001CF3GCKRFTOCDKN2A8q24#28q24#38q24#48q24#58q24#6 ATG16L1IRGM5p133p2110q21NKX2PTPN2IL12BCDKN2AIGF2BP2CDKAL1HHEXSLC30A8Chole
8、sterolObesityCoronary DzKCNJ112002200320042005PPAR Type 2 DiabetesIBD5NOD2Crohns DiseaseCFHAge Related Macular DegenerationCFB/C2LOC3877158q24IL23RTCF7L2Prostate cancer基因组医学与个性化医疗时代19CholesterolObesityCoronary DiseaseQT intervalAtrial FibrillationType 2 Diabetes Prostate cancerBreast cancerColon can
9、cerKCNJ1120032000PPAR 2001IBD5NOD2200520062002CTLA42004PTPN22Age Related Macular DegenerationCrohns DiseaseType 1 DiabetesSystemic Lupus ErythematosusAsthmaRestless leg syndromeGallstone diseaseCD25IRF5PCSK9CFHNOS1APIFIH1PCSK9CFB/C2LOC3877158q24IL23RTCF7L22007CDKN2A8q24#28q24#38q24#48q24#58q24#6ATG1
10、6L15p1310q21IRGMNKX2-3IL12B3p211q24PTPN2TCF2CDKN2AIGF2BP2CDKAL1HHEXSLC30A8MEIS1LBXCOR1BTBD9C38q24ORMDL34q25TCF2GCKRFTOC12orf30ERBB3KIAA0350CD22616p13PTPN2SH2B3FGFR2TNRC9MAP3K1LSP18q24Confirmed genetic contributors to common human diseases(August 2007)基因组医学与个性化医疗时代20CholesterolObesityCoronary Disease
11、QT intervalAtrial FibrillationType 2 Diabetes Prostate cancerBreast cancerColon cancerKCNJ1120032000PPAR2001IBD5NOD2200520062002CTLA42004PTPN22Age Related Macular DegenerationCrohns DiseaseType 1 DiabetesSystemic Lupus ErythematosusAsthmaRestless leg syndromeGallstone diseaseMultiple sclerosisRheuma
12、toid arthritisGlaucomaCD25IRF5PCSK9CFH2007NOS1APIFIH1PCSK9CFB/C2LOC3877158q24IL23RTCF7L2CDKN2A8q24#28q24#38q24#48q24#58q24#6ATG16L15p1310q21IRGMNKX2-3IL12B3p211q24PTPN2TCF2CDKN2B/AIGF2BP2CDKAL1HHEXSLC30A8MEIS1LBXCOR1BTBD9C38q24ORMDL34q25TCF2GCKRFTOC12orf0ERBB3KIAA030CD22616p13PTPN2SH2B3FGFR2TNRC9MAP
13、3K1LSP18q24LOXL1IL7RTRAF1STAT4ABCG8GALNT2PSRC1NCANTBL2TRIB1KCTD10ANGLPT3GRIN3AConfirmed genetic contributors to common human diseases(Sept 2007)基因组医学与个性化医疗时代21基因组医学与个性化医疗时代22We wouldnt think of buying shoes in a single sizeSo why should we be satisfied with one-size-fits-all medicine?基因组医学与个性化医疗时代23
14、DiagnosticsPreventive MedicineDisease with Genetic ComponentTimeAccelerated by HumanGenome Projectand HapMapIdentify Genetic Defect(s)基因组医学与个性化医疗时代24Taking a good family history will be supplemented,not supplanted,by genetic testing 基因组医学与个性化医疗时代25-95%confidence interval curves Recurrence score for
15、individual patientsSource:Paik,et al.,N Engl J Med,December 2004Genomics Is Not Just About Heredity:Using Gene Expression To Predict Cancer RecurrenceMultigene assay predicts recurrence of tamoxifen-treated,node-negative breast cancerGene expression analysis was combined with an algorithm for calcul
16、ating risk for distant recurrence基因组医学与个性化医疗时代26DiagnosticsPreventive MedicineDisease with Genetic ComponentTimeAccelerated by HumanGenome Projectand HapMapIdentify Genetic Defect(s)Pharmacogenomics基因组医学与个性化医疗时代27M.Wortman Technology Review,Feb.2001药物的反应与副作用基因组医学与个性化医疗时代28Analysis of VKORC1 and CYP2
17、C9 reveal variable warfarin dose responseNeedslow-doseNeedshigh-doseSlow P450metabolizers Variants at these two genes account for 60%of variability in therapeutic dose Prospective trials now underway FDA has added information about genetics to labelRieder,M.et al.NEJM 352:2285-2293,2005基因组医学与个性化医疗时代
18、29Diagnostics TherapeuticDevelopments Gene Therapy Drug TherapyPreventive MedicineDisease with Genetic ComponentTimeAccelerated by HumanGenome Projectand HapMapIdentify Genetic Defect(s)Pharmacogenomics基因组医学与个性化医疗时代30Imatinib(Gleevec)Specifically TargetsImatinib(Gleevec)Specifically TargetsAn Abnorm
19、al Protein,Blocking An Abnormal Protein,Blocking Its Ability To Cause Chronic Myeloid LeukemiaIts Ability To Cause Chronic Myeloid LeukemiaChromosome 9;22 Chromosome 9;22 translocationtranslocationCMLCMLBcrBcr-AblAbl fusion proteinfusion proteinGleevecGleevecBcrBcr-AblAbl fusion proteinfusion protei
20、n Normal Normal基因组医学与个性化医疗时代31基因组医学与个性化医疗时代32基因组医学与个性化医疗时代33基因组医学与个性化医疗时代34Prediction:Physician Assistants Will Play a Lead Role in the Personalized Medicine RevolutionAnd lots of resources are being developed to assist you基因组医学与个性化医疗时代35基因组医学与个性化医疗时代36“81%of programs expressedthe need to enhance th
21、equality and extent of geneticand molecular medicine in their curricula”基因组医学与个性化医疗时代37基因组医学与个性化医疗时代38基因组医学与个性化医疗时代39基因组医学与个性化医疗时代40基因组医学与个性化医疗时代41基因组医学与个性化医疗时代42基因组医学与个性化医疗时代43基因组医学与个性化医疗时代44基因组医学与个性化医疗时代45Top 10 Topics For PA Education In Genetics/Genomics1.“Genetics 101”basic concepts in genetic
22、and genomic science2.The family history3.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 referrals基因组医学与个性化医
23、疗时代46Personalized Medicine:A future dream 基因组医学与个性化医疗时代47Bettys story in 2015 Betty 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 s
24、uggests complete genome sequencing for$1000.Betty inquires about 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 a
25、nd her PA design a program of prevention based on diet,exercise,and medication precisely targeted to her genetic situation.基因组医学与个性化医疗时代48Bettys story continues Betty 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 an
26、d diagnose an acute MI.Referring to her genome sequence,the PA and MD choose the drugs that will work best to treat her.She survives and is alive and well in the 22nd century.基因组医学与个性化医疗时代49Personalized Medicine:Could the dream become a nightmare?基因组医学与个性化医疗时代50Bettys story gone wrong Betty never le
27、arns about her family history,educational efforts for the public and health care providers were defunded,community 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 insura
28、nce from this information,she decides not to.Betty eats an unhealthy diet,gains weight,and develops high blood pressure.While tests to predict which drug would be most effective for Betty have been proposed,they have never been validated,and are not reimbursed.基因组医学与个性化医疗时代51Bettys story gone wrong,
29、continued Bettys hypertension is treated with a drug that causes a hypersensitivity reaction,so she stops treatment.After 10 years 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
30、the ER a few hours later in cardiogenic shock.The absence of her genome sequence information prevents immediate optimum choice of therapy.Betty dies in the ER.基因组医学与个性化医疗时代52Charge to all of us:SAVE BETTY!基因组医学与个性化医疗时代53Personalized Medicine:The dream needs YOU!基因组医学与个性化医疗时代54基因组医学与个性化医疗时代55基因组医学与个性
31、化医疗时代56基因组医学与个性化医疗时代57Challenge of Rising U.S.Health ExpendituresBiomedical Research Must Deliver8%10%12%14%16%18%20%201520122009200620032000199719941991198819851982National Health Expenditures as a Percent of GDP1980ActualProjectedSource:http:/new.cms.hhs.gov/NationalHealthExpendData/downloads/nhep
32、rojections2004-2014.pdfPercent of U.S.GDP$4.1trillion基因组医学与个性化医疗时代58Translating Genomics Genomic 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 arou
33、nd the corner!基因组医学与个性化医疗时代59Translating 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!基因组医学与个性化医疗时代
34、60The Future Paradigm:The 4 PsTransform Medicine from Curative to PreemptivePreemptivePersonalizedPredictiveParticipatoryEra of Precision Medicine基因组医学与个性化医疗时代61Personalized Medicine The Future?Heres my sequence.”New Yorker基因组医学与个性化医疗时代62基因组医学与个性化医疗时代63基因组医学与个性化医疗时代64基因组医学与个性化医疗时代65Progress in Genot
35、yping Technology1 1101010102 210103 310104 410105 510106 6Nb of Nb of SNPsSNPsCost per genotype(Cents,USD)Cost per genotype(Cents,USD)10101 110102 2ABIABITaqManTaqManABIABISNPlexSNPlexIlluminaIlluminaGolden GateGolden Gate IlluminaIlluminaInfinium/SentrixInfinium/Sentrix AffymetrixAffymetrix100K/500
36、K100K/500K Perlegen Perlegen AffymetrixAffymetrixMegAlleleMegAllele 2001200120052005AffymetrixAffymetrix10K10KCourtesy S.Chanock,NCICourtesy S.Chanock,NCI基因组医学与个性化医疗时代66GWA in Guangxi 2007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
37、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月1日NG发表）基因组医学与个性化医疗时代67GWA in Guangxi 2008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
38、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，确定分工基因组医学与个性化医疗时代68GWA in Guangxi 2009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，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日开始收集标本基因组医学与个性化医疗时代69男性激素及其相关指标的GWAS 研究目的：发现调
39、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基因组医学与个性化医疗时代70技术路线基因组医学与个性化医疗时代71预期结果 GWA 研究论文 普通指标论文基因组医学与个性化医疗时代72LUTS：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基因组医学与个性化医疗时代73研究小组成员分工基因组医学与个性化医疗时代74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，秦志明基因组医学与个性化医疗时代75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：基因组医学与个性化医疗时代76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，基因组医学与个性化医疗时代77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：基因组医学与个性化医疗时代78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，谭爱花基因组医学与个性化医疗时代79
