遗传学英文课件：Phmarcogenetics

1、Learning Objectives,What is pharmacogenetics? What is the ultimate goal of pharmacogenetics? What is pharmacogenomics ? What is the ultimate goal of pharmacogenomics?,Patient Response to Medicine Varies,“One size fits all ?!”,“I have hypertension which is not being controlled. My doctor prescribes a

2、 drug for hypertension, we wait 3-4 months to find its not working and then try another one.,In 18 months, Ive tried 6 new medications and Im fast losing confidence in this hit or miss approach and in my physician”.,Pharmacogenetics,Pharmacogenetics is the study of interindividual variations in DNA

3、sequence related to drug response. An ultimate goal of pharmacogenetics is to understand how someones genetic make-up determines how well a medicine works in his or her body, as well as what side effects are likely to occur.,In 1902, British physician Sir Garrod A. suggested that genetic factors dir

4、ect chemical transformations in humans and underlie individual variability.,In 1957, Motulsky A. demonstrated the relationship between adverse drug reactions and genetically determined variation.,Gurwitz D, Motulsky AG. “Drug reactions, enzymes, and biochemical genetics”: 50 years later.Pharmacogeno

5、mics. 2007;8(11):1479-84.,Vogel F. coined the term pharmacogenetics in 1959,Kalow W.(1962) showed that an abnormal form of serum cholinesterase血清胆碱酯酶 leads to catastrophic adverse reactions to succinylcholine琥珀胆碱 (Anectine, Quelicin), and he wrote the first systematic account of pharmacogenetics.,Ph

6、armacogenomics,Pharmacogenomics is the study of the variability of the expression of individual genes relevant to disease susceptibility as well as drug response at cellular, tissue, individual or population level. The term is broadly applicable to drug design, discovery, and clinical development. T

7、he ultimate goal of pharmacogenomics A. Better, Safer Drugs the First Time B. More Accurate Methods of Determining Appropriate Drug Dosages C. Advanced Screening for Disease,Pharmacogenetic “Targets”,Drug absorption Drug distribution Drug-receptor interaction Drug metabolism Drug excretion,Conservat

8、ion vs. Variation,99.9% similar between individuals,0.1% differences has functional consequences,SNP: A change in which a single base in the DNA differs from the usual base at that position. Millions of SNPs have been cataloged in the human genome. Some SNPs such that which causes sickle cell are re

9、sponsible for disease. Other SNPs are normal variations in the genome.,Pharmacogenetics,Genetic Polymorphism: common variation in DNA sequence (i.e. in 1% of population) Most are SNPs Also deletions, insertions, variable number of tandem repeats (VNTRs) Deletion: glutathione S-transferase GSTM1 Pote

10、ntial Target Genes are those that encode: Drug-metabolizing enzymes Transporters Drug targets,Malignant hyperthermia (MH。恶性高热) OMIM:145600. 1q13.1,Genetics of MH,AD Incidence: rare, 1/5 000 65 000 anesthetics, depending on drugs, populations, any ages, any races Male 2.4 x female The basic defect is

11、 the increase of intracellular Ca of skeletal muscle Spontaneous, animal models for MH were discovered in pigs and dogs,MHS Gene Loci,G-6-PD deficiency-favism,Worldwide XR Xq28,Succinylcholine琥珀胆碱 OR suxamehonium sensitivity：butyrylcholinesterase丁酰胆碱酯酶, BChE (OMIM: 177400. 3q26.1-q26.2),Family Blame

12、s Soldiers Suicide on Anti-Malaria Drug. Washington Post, Oct. 12, 2008,CHICAGO - Juan Torres didnt believe that his son, Army Reservist Juan John M. Torres, had killed himself in Afghanistan just weeks before he was to return home in July 2004Now, he is convinced that his son did indeed kill himsel

13、f. But he blames Lariam(mefloquine), a drug taken by tourists, Peace Corps volunteers and troops to prevent malaria. An Army psychiatrists report also suggests the medication was a factor in Torress suicide.,Cytochrome P450（细胞色素P450） CYP2D6: debrisoquine hydroxylase异喹胍羟化酶,Strongly expressed in liver

14、 22q13.1 many drugs are substrates for CYP2D6: amitriptyline, clozapine, haloperidol, propanolol, amiodarone, flecainide highly polymorphic with 50 allelic variants identified,CYP2D6 polymorphic variants,Relatively common gene inactivating mutations: CYP2D6*4 splice site variants (GA transition at i

15、ntron 3/exon 4) CYP2D6*3 bp deletion in exon 5 CYP2D6*5 gene deletion homozygotes for these (and other rarer) mutant alleles are PM (poor metabolisers) and comprise about 10% of European populations,Guengerich F. AAPS J, 2006;8:E101 /P450lect.html,What are the anticipated ben

16、efits of pharmacogenomics?,1. More Powerful Medicines Pharmaceutical companies will be able to create drugs based on the proteins, enzymes, and RNA molecules associated with genes and diseases.,2. Better, Safer Drugs the First Time Instead of the standard trial-and-error method of matching patients

17、with the right drugs, doctors will be able to analyze a patients genetic profile and prescribe the best available drug therapy from the beginning.,3. More Accurate Methods of Determining Appropriate Drug Dosages Current methods of basing dosages on weight and age will be replaced with dosages based

18、on a persons genetics -how well the body processes the medicine and the time it takes to metabolize it. This will maximize the therapys value and decrease the likelihood of overdose.,4. Advanced Screening for Disease Knowing ones genetic code will allow a person to make adequate lifestyle and environment at early age so as to avoid or lessen the severity of a genetic disease.,Gene Chips:Genotyping基因分型,: curates information that establishes knowledge about the relationships among drugs, diseases and genes, incl