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1、Genomic medicine and Personalized Medicine,Francis 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,Genomic medicine and Personali,完全健康,绝对死亡,健康,亚临床,疾病与损伤,濒死,中危险状态,低危险状态,出现临床症状（疾病）,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%,3
2、0%,基因组医学与个性化医疗时代,2,完全健康绝对死亡健康,亚临床,疾病与损伤,濒死中危险状态低危,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,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,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,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,面对目前医疗卫生改革的难题除了政策层面的体制改革，在
3、技术层面我们能够做什么？,基因组医学能给我们带来什么？根据易感基因，预测疾病发生的概率，做到个性化预防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，做到个性化治疗以导致疾病的相关基因作为靶点，开发新的治疗药物。,基因组医学与个性化医疗时代,5,面对目前医疗卫生改革的难题除了政策层面的体制改革，在技术层,基因组医学与个性化医疗时代,6,基因组医学与个性化医疗时代6,Collins et al., Nature 4/24/03,基因组医学与个性化医疗时代,7,Collins et al., Nature 4/24/03,Collins et al., Nature 4/24/03,基因组医学
4、与个性化医疗时代,8,Collins et al., Nature 4/24/03,A SMALL SAMPLING OF COOL THINGS ABOUT THE GENOME,Humans have fewer protein-coding genes than expected 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 res
5、t of the DNA instruction bookWe are all 99.9% the same at the DNA level,基因组医学与个性化医疗时代,9,A SMALL SAMPLING OF COOL THING,Cystic fibrosis,Adult onset diabetes,AIDS,基因组医学与个性化医疗时代,10,Cystic fibrosisAdult onset dia,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11,基因组医学与个性化医疗时代,12,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
6、,13,SNP A SNP B基因组医学与个性化医疗时代1,Searching for genetic causes ofdisease in the pre-genome era,基因组医学与个性化医疗时代,14,Searching for genetic causes o,“Genome Wide Association” Approach to Common Disease:The View from 2002,Identify all 10 million common SNPsCollect 1000 cases and 1000 controlsGenotype all DNAs
7、for all SNPsThat adds up to 20 billion genotypesAt 50 cents a genotype, thats $10 billion for each disease completely out of the question,基因组医学与个性化医疗时代,15,“Genome Wide Association” Appr,基因组医学与个性化医疗时代,16,基因组医学与个性化医疗时代16,Genome Wide Association Approach to Common Disease:The View from 2007,Identify an
8、 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 each disease,基因组医学与个性化医疗时代,17,Genome Wide Association Approa,Searching for genetic causes ofdisease in the
9、genome era,基因组医学与个性化医疗时代,18,Searching for genetic causes o,Confirmed genetic contributors to common human diseases (April 2007),2000,2006,2007,2001,KCNJ11,2002,2003,2004,2005,基因组医学与个性化医疗时代,19,Confirmed genetic contributors,CholesterolObesityCoronary DiseaseQT intervalAtrial FibrillationType 2 Diabet
10、es Prostate cancerBreast cancerColon cancer,2005,2006,Age Related Macular DegenerationCrohns DiseaseType 1 DiabetesSystemic Lupus ErythematosusAsthmaRestless leg syndromeGallstone disease,CD25IRF5PCSK9CFH,NOS1APIFIH1PCSK9CFB/C2LOC3877158q24IL23RTCF7L2,2007,CDKN2A8q24 #28q24 #38q24 #48q24 #58q24 #6AT
11、G16L15p1310q21IRGMNKX2-3IL12B3p211q24PTPN2TCF2CDKN2AIGF2BP2CDKAL1HHEXSLC30A8,MEIS1LBXCOR1BTBD9C38q24ORMDL34q25TCF2GCKRFTOC12orf30ERBB3KIAA0350CD22616p13PTPN2SH2B3FGFR2TNRC9MAP3K1LSP18q24,Confirmed genetic contributors to common human diseases (August 2007),基因组医学与个性化医疗时代,20,CholesterolKCNJ1120032000P
12、PAR,CholesterolObesityCoronary DiseaseQT intervalAtrial FibrillationType 2 Diabetes Prostate cancerBreast cancerColon cancer,2005,2006,Age Related Macular DegenerationCrohns DiseaseType 1 DiabetesSystemic Lupus ErythematosusAsthmaRestless leg syndromeGallstone diseaseMultiple sclerosisRheumatoid art
13、hritisGlaucoma,CD25IRF5PCSK9CFH,2007,NOS1APIFIH1PCSK9CFB/C2LOC3877158q24IL23RTCF7L2,CDKN2A8q24 #28q24 #38q24 #48q24 #58q24 #6ATG16L15p1310q21IRGMNKX2-3IL12B3p211q24PTPN2TCF2CDKN2B/AIGF2BP2CDKAL1HHEXSLC30A8,MEIS1LBXCOR1BTBD9C38q24ORMDL34q25TCF2GCKRFTOC12orf0ERBB3KIAA030CD22616p13PTPN2SH2B3FGFR2TNRC9M
14、AP3K1LSP18q24,LOXL1IL7RTRAF1STAT4ABCG8GALNT2PSRC1NCANTBL2TRIB1KCTD10ANGLPT3GRIN3A,Confirmed genetic contributors to common human diseases (Sept 2007),基因组医学与个性化医疗时代,21,CholesterolKCNJ1120032000PPAR,基因组医学与个性化医疗时代,22,基因组医学与个性化医疗时代22,We wouldnt think of buying shoes in a single size,So why should we be
15、satisfied with one-size-fits-all medicine?,基因组医学与个性化医疗时代,23,We wouldnt think of buying sh,Diagnostics,Preventive Medicine,Disease with Genetic Component,Time,Identify Genetic Defect(s),基因组医学与个性化医疗时代,24,DiagnosticsPreventive Disease,Taking a good family history will be supplemented, not supplanted, b
16、y genetic testing,基因组医学与个性化医疗时代,25,Taking a good family history w,- 95% confidence interval curves Recurrence score for individual patients,Source: Paik, et al., N Engl J Med, December 2004,Genomics Is Not Just About Heredity:Using Gene Expression To Predict Cancer Recurrence,Multigene assay predict
17、s recurrence of tamoxifen-treated, node-negative breast cancerGene expression analysis was combined with an algorithm for calculating risk for distant recurrence,基因组医学与个性化医疗时代,26,- 95% confidence interval c,Diagnostics,Preventive Medicine,Disease with Genetic Component,Time,Identify Genetic Defect(s
18、),Pharmacogenomics,基因组医学与个性化医疗时代,27,DiagnosticsPreventive Disease,M. 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,28,M. Wortman Technology Review,Analysis of VKORC1 and CYP2C9 reveal variable warfarin dose response,Needslow-dose,Needshigh-dose,Slow P450metabolizers,Variants at these
19、two genes account for 60% of variability in therapeutic doseProspective trials now underwayFDA has added information about genetics to label,Rieder, M. et al. NEJM 352: 2285-2293, 2005,基因组医学与个性化医疗时代,29,Analysis of VKORC1 and CYP2C9,Diagnostics,TherapeuticDevelopments Gene Therapy Drug Therapy,Preven
20、tive Medicine,Disease with Genetic Component,Time,Identify Genetic Defect(s),Pharmacogenomics,基因组医学与个性化医疗时代,30,Diagnostics TherapeuticPreven,Imatinib (Gleevec) Specifically TargetsAn Abnormal Protein, Blocking Its Ability To Cause Chronic Myeloid Leukemia,CML,Normal,基因组医学与个性化医疗时代,31,Imatinib (Gleeve
21、c) Specific,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33,基因组医学与个性化医疗时代,34,基因组医学与个性化医疗时代34,Prediction: Physician Assistants Will Play a Lead Role in the Personalized Medicine Revolution,And lots of resources are being developed to assist you,基因组医学与个性化医疗时代,35,Prediction: Physician
22、 Assistan,基因组医学与个性化医疗时代,36,基因组医学与个性化医疗时代36,“81% of programs expressedthe need to enhance thequality and extent of geneticand molecular medicine in their curricula”,基因组医学与个性化医疗时代,37,“81% of programs expressed基因组医,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39,基因组医学与个性化医疗时代,40,基因组医学
23、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44,基因组医学与个性化医疗时代,45,基因组医学与个性化医疗时代45,Top 10 Topics For PA Education In Genetics/Genomics,“Genetics 101” basic concepts in genetic and genomic scienceThe family h
24、istoryPreconception and prenatal geneticsNewborn screening and pediatric geneticsAdult genetics,6.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疗时代,46,Top 10 Topics For PA Educati
25、on,Personalized Medicine:A future dream,基因组医学与个性化医疗时代,47,Personalized Medicine:A futur,Bettys 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 infor
26、med about genomic medicine. She suggests 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
27、 of early heart attack 4-fold.She and 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,48,Bettys story in 2015Betty com,Bettys story continues,Betty does well until age 75.She develops left arm pain that she assu
28、mes 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 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,49,Bettys story continues基因组医学与个,Perso
29、nalized Medicine:Could the dream become a nightmare?,基因组医学与个性化医疗时代,50,Personalized Medicine:Could t,Bettys story gone wrong,Betty never learns about her family history, educational efforts for the public and health care providers were defunded, community efforts never got off the ground, and Bettys
30、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 pressure.While tests to predict which drug w
31、ould 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,51,Bettys story gone wrongBetty,Bettys story gone wrong, continued,Bettys hypertension is treated with a drug that causes a hypersensitivity reaction, so she stops treatment.Aft
32、er 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 the ER a few hours later in cardiogenic shock.The absence of her genome sequence information prevents immediate optim
33、um choice of therapy.Betty dies in the ER.,基因组医学与个性化医疗时代,52,Bettys story gone wrong, cont,Charge to all of us:,SAVE BETTY!,基因组医学与个性化医疗时代,53,Charge to all of us:SAVE BETTY,Personalized Medicine:The dream needs YOU!,基因组医学与个性化医疗时代,54,Personalized Medicine:The dre,基因组医学与个性化医疗时代,55,基因组医学与个性化医疗时代55,基因组医学与
34、个性化医疗时代,56,基因组医学与个性化医疗时代56,基因组医学与个性化医疗时代,57,基因组医学与个性化医疗时代57,Challenge of Rising U.S. Health ExpendituresBiomedical Research Must Deliver,8%,10%,12%,14%,16%,18%,20%,2015,2012,2009,2006,2003,2000,1997,1994,1991,1988,1985,1982,National Health Expenditures as a Percent of GDP,1980,ActualProjected,Source
35、: http:/new.cms.hhs.gov/NationalHealthExpendData/downloads/nheprojections2004-2014.pdf,Percent of U.S. GDP,$4.1trillion,基因组医学与个性化医疗时代,58,Challenge of Rising U.S. 8%10%,Translating Genomics,Genomic discoveries relevant to common disease diagnosis and management are coming at an increasing rate.Basic
36、discoveries are leading to the development of clinical applications.Ergo, improved healthcare is around the corner!,基因组医学与个性化医疗时代,59,Translating GenomicsGenomic d,Translating Genomics,Genomic discoveries relevant to common disease diagnosis and management are coming at an increasing rate.Basic disco
37、veries 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,60,Translating GenomicsGenomic d,The Future Paradigm: The 4 PsTransform Medicine from Curative to Preemptive,Preemptive,Personalized,Predictive,Participatory,Era
38、of Precision Medicine,基因组医学与个性化医疗时代,61,The Future Paradigm: The 4 Ps,Personalized Medicine The Future?,Heres my sequence.”New Yorker,基因组医学与个性化医疗时代,62,Personalized Medicine The Fu,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64,基因组医学与个性化医疗时代,65,基因组医学与个性化医疗时代65,Progress in Genotyping
39、 Technology,1,10,102,103,104,105,106,Nb of SNPs,Cost per genotype (Cents, USD),10,1,102,ABITaqMan,ABISNPlex,IlluminaGolden Gate,IlluminaInfinium/Sentrix,Affymetrix100K/500K,Perlegen,AffymetrixMegAllele,2001,2005,Affymetrix10K,Courtesy S. Chanock, NCI,基因组医学与个性化医疗时代,66,Progress in Genotyping Technol,G
40、WA 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,67,GWA in Guangx
41、i2007年9月，彭涛建议我在广西,GWA 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,68,GWA in Guangxi2008年7月，赴上海参加GW
42、A,GWA 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,GWA in Guangxi2009年7月参加上海GWA W,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,基
43、因组医学与个性化医疗时代,70,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,技术路线,基因组医学与个性化医疗时代,71,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,72,预期结果GWA 研究论文基因组医学与个性化医疗时代72,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,基因组医学与个性化医疗时代,73,LUTS：下尿路症状男性激素及其相关指标可以撰写的论文基因,研究小组成员分工,基因组医学与个性化医
44、疗时代,74,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,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,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,流行病学任务：宣传发动，知情同意，问卷调查，资料汇总基因组医,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,宣传，体检文秘宣传，对外联络，组织体检基因组医学与个性化医疗,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,标本，实验任务：收集样本，phenotype检测，DNA及血,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,生物信息学分析资料汇总，生物信息学分析，统计图表制作基因组医,
