the 5th symposium ii: bioscience for health invited lecture ...the 5th science council of asia (sca)...
TRANSCRIPT
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The 5th Science Council of Asia (SCA) Conference (Hanoi, Vietnam, 2005)Symposium II: Bioscience for Health Invited Lecture 2 (May 12, 14:45-15:15)
Healthcare in the Eraof Genomic Medicine
Department of Medical GeneticsTohoku University School of Medicine, Sendai, Japan
Yoichi Matsubara, M.D.
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Human Genome Project
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Watson & Crick, May 1953
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KEIO
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Human Genome Project■ identify all genes (~30,000) in human
DNA ■ determine the sequences of the 3
billion base pairs that make up human DNA
■ store this information in databases ■ use genomic information for Genome
Science and Genomic Medicine■ address the ethical, legal, and social
issues (ELSI) that may arise from the project
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Human Genome Project has generatedcomplete parts list of human body
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Genetic VariationSingle Nucleotide Polymorphism (SNP)
A
CG
T
AC
G
T
A
G
T
AC
G
1 in 1,000 nucleotides between individuals
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Anticipated Benefits of Genome Research on Healthcare● improve diagnosis and treatment
of disease- Mendelian disorders
● detect genetic predispositions to disease
- Common diseases● design custom drugs based on
individual genetic profiles - pharmacogenomics
● use gene therapy and control systems as drugs
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Phenylketonuria (PKU)
Phenylalanine hydroxylase
TyrosinePhenylalanineBH4
Low-Phenylalanine Diet
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Low-Phenylalanine Diet
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Phenylketonuria (PKU)
PhenylalanineBH4
BH4
TyrosinePhenylalanine hydroxylase
BH4-responsivephenylalanine hydroxylase deficiency
(Kure S, et al. J Pediatr. 135:375-8, 1999)
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BH4 BH4
30-50% of PKU patients 4 therapy
Phenylalanine
responded to BH
(Trefz & Blau, Pediatrics 112:1566-9, 2003)
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Anticipated Benefits of Genome Research on Healthcare● improve diagnosis and treatment
of disease- Mendelian disorders
● detect genetic predispositions to disease
- Common diseases● design custom drugs based on
individual genetic profiles - pharmacogenomics
● use gene therapy and control systems as drugs
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Genes associated with bronchial asthma in Japanese populationGene LocusIL1RN Interleukin-1 receptor antagonist protein 2q14CTLA4 Cytotoxic T-lymphocyte protein 4 2q33PGDS Prostaglandin-H2 D-isomerase 4q21-22IRF1 Interferon regulatory factor 1 5q31IL4 Interleukin-4 5q31IL13 Interleukin-13 5q31UGRP1 Uteroglobin-related protein 1 5q31-34IL12B Interleukin-12B 5q31-33ADRB2 Adrenergic receptor, beta 2 5q32-34LTC4S Leukotriene C4 synthetase 5q35TNF Tumor necrosis factor alpha 6p21PAFAH Platelet activating factor acetylhydrolase 6p21EOTAXIN1 Eotaxin-1 7q11C5 Complement 5 9q33IKAP IKK complex-associated protein 9q34FCER1B High affinity IgE receptor beta chain 11q13AICDA Activation induced cytidine deaminase 12p13C3AR1 Complement 3a receptor 12p13STAT6 Signal transducer and activator of transcription 6 12q13IFNG Interferon-gamma 12q21NOS1 Nitric oxide synthetase 1 12q24FLAP Five-lipoxygenase activating protein 13q12CYSLTR2 Cysteinyl leukotriene receptor 2 13q14IL4RA Interleukin-4 receptor alpha 16p12NOS2A Nitric oxide synthetase 2 17cen-q11RANTES Regulated upon activation, and normal T-cell expressed
and presumably secreted 17q11-q12TBX21 T-box 21 17q21TBXA2R Thromboxane A2 receptor 19p13C3 Complement 3 19p13C5R1 Complement 5a receptor 19q13
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Prediction of risk for childhood asthmausing logistic regression analysis
(Japanese children)
Num
ber o
f cas
es
1 2 3 4 5 6 7 8 9 10
0
10
20
30
40
50
60
low
highRisk groups
affectednot affected
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Paradigm shift ?
Single-genedisorders
Commondiseases
AsthmaDiabetes mellitusHypertensionRheumatoid arthritis
PhenylketonuriaThalassemiaGaucher diseaseMuscular dystrophyHemophilia
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Genetic factors
Non-genetic factors
Single-genedisorders
Commondiseases
Single-gene and common diseases represent points on a continuum
Pharmaco-genomics
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What is Pharmacogenetics?(Pharmacogenomics)
The use of genetic analysis to predict drug response
- Efficacy: how well a medicine works in a patient
- Safety: whether there are any adverse side effects
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A pedigree of deafness
79y 76y
53y44y
11y
Otitis media in infancy was treated with streptomycin
At age 5, appendicitis was treated with streptomycin
At age 2, “common cold” was treated with streptomycin
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(Nature Genetics 4:289-94, 1993)
Aminoglycoside antibiotics*cause hearing loss to
individuals witha mitochondrial 1555A>G
mutation
*Streptomycin, Gentamicin, Amikacin, Tobramycin etc.
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Aminogycoside antibiotics are widely used to treat serious bacteral infection
They are commonly prescribed for newborns (such as gentamicin)to treat bacterial infections
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A pedigree of deafness
79y 76y
53y44y
11y
Mitochondrial 1555A>G
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(診察時、このカードを医師にお見せ下さい)
薬 剤 カ ー ド
お 名 前 ○ ○ ○ ○ 殿
生年月日 年 月 日
この方は、 アミノグリコシド系抗生物質 の投与により難聴をきたす可能性が高いため、診療時のご配慮をお願い致します。
東北大学病院遺伝科(TEL:022-717-8140)
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Medical Alert Name: Birth Date:
Do NOT administer aminoglycosideantibiotics to this person.It would cause irreversible hearing loss.
Department of Medical GeneticsTohoku University School of MedicineSendai, Japan(TEL: +81-22-717-8140)
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Aminoglycoside antibiotics- Amikacin- Gentamicin- Kanamycin- Neomycin- Netilmicin- Streptomycin- Tobramycin
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Stevens-Johnson syndrome
Life-threatening reactions of the skin to particular types of medication
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Genetic marker for Stevens-Johnson syndrome
caused by carbamazepine (CBZ)
HLA-B*1502 allele was detected in:- 100% of CBZ-SJS individuals- 3% of CBZ-tolerant individuals- 8.6% of normal individuals
(Han Chinese)
(Chung et al. Nature 428:486, 2004)
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One drug fits all
Personalized medication
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Guidance for IndustryPharmacogenomic Data
Submissions
DRAFT GUIDANCE
November 2003Procedural
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“Here’s my sequence …”
Nature Medicine6:487, 2000
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How do we detect pharmacogenomic SNPs?
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Requirements forPoint-of-Care Genetic TestingSimple
RapidReadily performed by non-expert
InexpensiveGenotyping on the spot
ReliableNo expensive instrumentation
No errors allowed
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CASSOHCompetitiveAllele-SpecificShortOligonucleotideHybridization
(Human Mutation, 22:166-172, 2003)
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CASSOHStep 1
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CASSOHStep 2
PCRReagent
Blood (or DNA)
(DNA amplification)
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CASSOH
Pipette 5 ul of PCR product
Anti-digoxigeninmonoclonal antibody conjugated to gold particles
Streptavidin
Anti-mouse polyclonal antibody
Step 3
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Chromatography
CASSOHCASSOH
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Stand at room temp. for 5 min.
CASSOH
Stand at room temp. for 5 min.
CASSOH
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CASSOHCASSOH
Diagnostic line
Control line
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CASSOH
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Control line
Diagnostic line
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Application of CASSOH to pharmacogenetic SNPs
PhenotypeGene SNPALDH2CYP2C19NAT2NAT2NAT2TPMTUGT1A1
Alcohol intolerancePoor metabolizer of omeprazole, diazepam
Poor metabolizer of isoniazid (INH)
Poor metabolizer of 6-MP and AZPPoor metabolizer of irinotecanHearing loss by aminoglycoside antibiotics
1459G>A 681G>A341T>C590G>A857G>A719A>G211G>A1555A>G Mitochondria
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Ethnic differencein drug metabolism
Frequency*Gene Mutation/allele Phenotype
Caucasians Orientals
N-acetyl transferase(NAT2)
Cytochrome P4502D6 (CYP2D6)
Cytochrome P4502C19 (CYP2C19)
>28%>5%
3%20%
2.5-6%
7%10-18%
50%<1%
15-23%
T341CC282T/G857A
C188T (P34S)*4
m1 and m2
Slow acetylatorRapid acetylator
Poor metabolizer (mild)Poor metabolizer
Poor metabolizer
*Numbers are for homozygous individuals.
(Nature Biotechnology 16 Supplement, 1998)
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International Federation ofHuman Genetics Societies (IFHGS)
European Societyof Human Genetics
American Societyof Human Genetics
Human Genetics Societyof Australasia
Latin American Networkof Human Genetics Societies
East Asian Unionof Human Genetics
Societies
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Genomic MedicineEthical, Legal, and Social Issues
- fairness in the use of genetic information- privacy and confidentiality- psychological impact and stigmatization- genetic testing- reproductive issues- education, standards, and quality control- commercialization- conceptual and philosophical implications
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Healthcare in the Eraof Genomic Medicine