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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,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%,30%,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
2、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,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。,Collins et al.,Nature 4/24/03,Collins et al.,Nature 4/24/03,A SMALL SAMPLING OF CO
3、OL 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 rest of the DNA instruction bookWe are all 99.9%the same at the DNA l
4、evel,Cystic fibrosis,Adult onset diabetes,AIDS,SNP A,SNP B,Searching for genetic causes ofdisease in the pre-genome era,“Genome Wide Association”Approach to Common Disease:The View from 2002,Identify all 10 million common SNPsCollect 1000 cases and 1000 controlsGenotype all DNAs for all SNPsThat add
5、s up to 20 billion genotypesAt 50 cents a genotype,thats$10 billion for each disease completely out of the question,Genome Wide Association Approach to Common Disease:The View from 2007,Identify an optimum set of 300,000 tag SNPsCollect 1000 cases and 1000 controlsGenotype all DNAs for all SNPsThat
6、adds up to 600 million genotypesGenotyping just dropped to$0.0012,so thats$800,000 for each disease,Searching for genetic causes ofdisease in the genome era,Confirmed genetic contributors to common human diseases(April 2007),2000,2006,2007,2001,KCNJ11,2002,2003,2004,2005,CholesterolObesityCoronary D
7、iseaseQT intervalAtrial FibrillationType 2 Diabetes Prostate cancerBreast cancerColon cancer,2005,2006,Age Related Macular DegenerationCrohns DiseaseType 1 DiabetesSystemic Lupus ErythematosusAsthmaRestless leg syndromeGallstone disease,CD25IRF5PCSK9CFH,NOS1APIFIH1PCSK9CFB/C2LOC3877158q24IL23RTCF7L2
8、,2007,CDKN2A8q24#28q24#38q24#48q24#58q24#6ATG16L15p1310q21IRGMNKX2-3IL12B3p211q24PTPN2TCF2CDKN2AIGF2BP2CDKAL1HHEXSLC30A8,MEIS1LBXCOR1BTBD9C38q24ORMDL34q25TCF2GCKRFTOC12orf30ERBB3KIAA0350CD22616p13PTPN2SH2B3FGFR2TNRC9MAP3K1LSP18q24,Confirmed genetic contributors to common human diseases(August 2007),
9、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 arthrit
10、isGlaucoma,CD25IRF5PCSK9CFH,2007,NOS1APIFIH1PCSK9CFB/C2LOC3877158q24IL23RTCF7L2,CDKN2A8q24#28q24#38q24#48q24#58q24#6ATG16L15p1310q21IRGMNKX2-3IL12B3p211q24PTPN2TCF2CDKN2B/AIGF2BP2CDKAL1HHEXSLC30A8,MEIS1LBXCOR1BTBD9C38q24ORMDL34q25TCF2GCKRFTOC12orf0ERBB3KIAA030CD22616p13PTPN2SH2B3FGFR2TNRC9MAP3K1LSP1
11、8q24,LOXL1IL7RTRAF1STAT4ABCG8GALNT2PSRC1NCANTBL2TRIB1KCTD10ANGLPT3GRIN3A,Confirmed genetic contributors to common human diseases(Sept 2007),We wouldnt think of buying shoes in a single size,So why should we be satisfied with one-size-fits-all medicine?,Disease with Genetic Component,Taking a good fa
12、mily history will be supplemented,not supplanted,by genetic testing,-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 predicts re
13、currence of tamoxifen-treated,node-negative breast cancerGene expression analysis was combined with an algorithm for calculating risk for distant recurrence,Disease with Genetic Component,M.Wortman Technology Review,Feb.2001,药物的反应与副作用,Analysis of VKORC1 and CYP2C9 reveal variable warfarin dose respo
14、nse,Needslow-dose,Needshigh-dose,Slow P450metabolizers,Variants at these 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,Disease with Genetic Component,Imatinib(Gleevec)
15、Specifically TargetsAn Abnormal Protein,Blocking Its Ability To Cause Chronic Myeloid Leukemia,Prediction:Physician Assistants Will Play a Lead Role in the Personalized Medicine Revolution,And lots of resources are being developed to assist you,“81%of programs expressedthe need to enhance thequality
16、 and extent of geneticand molecular medicine in their curricula”,Top 10 Topics For PA Education In Genetics/Genomics,“Genetics 101”basic concepts in genetic and genomic scienceThe family historyPreconception and prenatal geneticsNewborn screening and pediatric geneticsAdult genetics,6.Cancer genetic
17、s7.The genetics of common disease8.Pharmacogenetics9.Ethical,legal,and social aspects of genetics10.Genetic counseling and genetic referrals,Personalized Medicine:A future dream,Bettys story in 2015,Betty completes the Surgeon Generals family history tool at age 25,learns of uncles with early heart
18、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 the risk of genetic discrimination,but effective legislation has outlawed this.She is found to have three gene var
19、iants 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,and medication precisely targeted to her genetic situation.,Bettys story continues,Betty does well until age 75.She
20、 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 drugs that will work best to treat her.She survives and is alive and well in the 22nd century.,Personalized Medi
21、cine:Could the dream become a nightmare?,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 PA and MD thought genetics was irrelevant to practice.Betty he
22、ars 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 would be most effective for Betty have been proposed,they have neve
23、r been validated,and are not reimbursed.,Bettys story gone wrong,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 assu
24、mes 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 of therapy.Betty dies in the ER.,Charge to all of us:,SAVE BETTY!,Personalized Medicine:The dream needs YOU!
25、,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:http:/,Percent of U.S.GDP,$4.1trillion,Translating Genomics
26、,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 around the corner!,Translating Genomics,Genomic discoveries relevant to common disease diagn
27、osis 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 Medicine from Curative to Preemptive,Preemptive,Personalized,Predictive,Era
28、 of Precision Medicine,Personalized Medicine The Future?,62,Heres my sequence.”New Yorker,Progress in Genotyping 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,Affymetr
29、ixMegAllele,2001,2005,Affymetrix10K,Courtesy S.Chanock,NCI,GWA 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GW
30、A的设计方案肾结石的GWAS（2009年7月1日NG发表）,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,GWA in Guangxi,2009年7月参加上海GWA WORK
31、SHOP，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,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,
