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유전체 의학과 미래 의학
최형진
충북대학교 내분비내과
Genomics/
Biomarker
Big Data/
Medical Informatics
Smart Device/
Wearable
Genome Sequencing
Data Science
Quantified Self
He...
시대변화
Genomics/
Biomarker
Big Data/
Medical Informatics
Smart Device/
Wearable
Genome Sequencing
Data Science
Quantified Self
He...
Contents
1. Introduction
2. Genetic Variation and Expression
Analyses
3. Human Genome Project and Beyond
4. Personalized M...
1997
발전한다?
저의 유전자
분석 결과를
반영하여 진료
해주세요!! 헠?
Your
estimated
lifetime
risk
$2,000~$3,000
Personal Genome Service
$99
2013.01.29
헬스케어 3.0 시대의 변화 키워드
2011.11.23 헬스케어 3.0: '건강수명' 시대의 도래
주: 선의 굵기는 영향의 강도를 의미
2013.4.25. KBS 9시 뉴스
며칠 전 유전자 검사를 받은 40대 남성입니다.
혈액세포의 DNA 상태를 분석해 앞으로 암에 걸릴 위험이 있는지 여부를 판단할 수 있다
고 합니다.
2013.4.25. KBS 9시 뉴스
2013.4.25. KBS 9시 뉴스
60년전 DNA의 구조가 밝혀진 이래 2003년 인간 유전자 지도가 완성됐고, 현재는 어떤 유
전자가 어떤 질병을 일으키는지 분석도 80% 정도 끝난 상태입니다.
예를들어 13번 염...
개인별 유전체 분석을 통해 암 발병 예측
및 예방, 치료하는 ‘유전체 기반 맞춤치료’
는 전 세계적으로 가장 주목받고 있는 차
세대 치료 트랜드. 때문에 국내 주요 대학
병원들도 관심을 보이고 각기 ‘맞춤치료’
를 주요...
2011 Nature. Charting a course for genomic medicine from base pairs to bedside
Genomics and KOREA
Contents
1. Introduction
2. Genetic Variation and Expression
Analyses
3. Human Genome Project and Beyond
4. Personalized M...
DNA
mRNA
Protein
Metabolite
Epigenetics
Genetics Information and OMICs
Genomics
Epigenomics
Transcriptomics
Proteomics
Met...
외래/입원
진료
당뇨병으로
진단된 환자
임상정보 수집 혈액 샘플 수집
외래/입원
진료 및 투약
당뇨병 합병증
및 추적관찰 정보
합병증/치료효과 관련
유전체 연관 분석
유전체 분석
검체 수집
구 분 수집 목표 수집 현황 달성도 (%) 수집 예상 달성도 (%)
당뇨병 1400 건 1365 97.50% 1462 104.4
Food
Diabetes
Genetic
Predisposition
Environmental
Predisposition
Epigenetic change
Epigenetic change
Diabetic
Complicatio...
Metabolomics
2013 Metabolomics platforms for genome wide association studies—linking the genome to the metabolome
Metabolo...
Metabolomics - OGTT
2008 Metabolic profiling of the human response to a glucose challenge reveals distinct axes of insulin ...
2013 Diabetes. Metabolite profiles during oral glucose challenge
Metabolomics Profiling
• Quantification of 186 metabolites
– Acylcarnitines
– Amino Acids
– Biogenic Amines
– Hexoses (sum...
Next-Generation Sequencing (NGS)
Benchtop Genome Center (90min)
454/FLX (Roche), Solexa (Illumina), SOLiD (AB)
50ng DNA (S...
Contents
1. Introduction
2. Genetic Variation and Expression
Analyses
3. Human Genome Project and Beyond
4. Personalized M...
1000 Genomes Samples
Population
When cell li
ne avail. (ap
prox)
DNA seque
nced from b
lood
Offspring sa
mples from
trios ...
Wellcome Trust: 10,000 human genomes to uncover disease-causing variants
Korean Reference Genome
Comprehensive Catalogues of
Genomic Data
Variation in the human genome
Mendelian (monogenic) diseases
(N=21,862) as of 201...
Contents
1. Introduction
2. Genetic Variation and Expression
Analyses
3. Human Genome Project and Beyond
4. Personalized M...
Genome-wide Profiling Human Genome(DNA) Study
Microarray
Proteonomics
GWAS, Candidate gene study
Familial study
Linkage st...
Personalized Medicine
2012 European Heart Journal. Personalized medicine: hope or hype?
Contents
1. Introduction
2. Genetic Variation and Expression
Analyses
3. Human Genome Project and Beyond
4. Personalized M...
Common Disease Risk
1. Disease Genetic Susceptibility
2. Ethnic Difference
3. Complication Genetic Susceptibility
4. Envir...
Common Disease Risk
1. Disease Genetic Susceptibility
2. Ethnic Difference
3. Complication Genetic Susceptibility
4. Envir...
Influence of Genetics on Human Disease
For any condition the overall balance of g
enetic and environmental determinants ca...
2008 HMG Genome-based prediction of common diseases- advances and prospects
2008 HMG Genome-based prediction of common diseases- advances and prospects
Variants and Disease Susceptibility
2008 NRG Genome-wide association studies for complex traits- consensus, uncertainty an...
Promise of Human Genome Project
Estrada et al., Nature Genetics, 2012
+ novel targets
for bone biology
Recent largest GWAS
GEFOS consortium
Diabetes ≠ Genetic Disease?
• Familial aggregation
– Genetic influences?
– Epigenetic influences
• Intrauterine environmen...
Per-allele effect of BMI-associated
loci on body weight
2012 Genetic determinants of common obesity and their value in pre...
2011 Hum Genet. Type 2 diabetes and obesity- genomics and the clinic
2014 DC Impact of Type 2 Diabetes Susceptibility Variants on Quantitative Glycemic Traits Reveals Mechanistic Heterogeneity
SNP N…………
…………
…………
…………
∑ = 1
Max = N x 2
∑ = 2
∑ = 4
SNP 1
0
1
2
SNP 2
0+0
1+1
2+1
Genetic Predisposition Score
2008 HMG Genome-based prediction of common diseases- advances and prospects
Single variant Single variant 20 variants
2010 AJCN Cumulative effects and predictive value of common obesity-susceptibility variants identified by genome-wide asso...
◇◆ ‘parental obesity’
as a test to predict obesity
in adult life
•Dark blue 1–2 yrs
•Green 3–5 yrs
•Red 6–9 yrs
•Light blu...
CONCLUSIONS:
In this study, adding genetic information to a
previously validated clinic + biological score does
not seem t...
“At the end of the era of common variant discovery for T2D,
polygenic scores can predict T2D in whites and blacks but do
n...
2014 DC Polygenic Type 2 Diabetes Prediction at the Limit of Common Variant Detection
2014 DC Polygenic Type 2 Diabetes Prediction at the Limit of Common Variant Detection
Predicting Complex Diseases
2013 NG Predicting the influence of common variants
“For most diseases, it should be possible ...
Rare Variants
with Large Effect Size?
• "These results indicate that the T2D landscape is not dominated by low-
frequency ...
2014 NG Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diab...
2014 NG Loss-of-function mutations in SLC30A8 protect against type 2 diabetes
Gene based approach
2014 NG Low copy number of the salivary amylase gene predisposes to obesity
Gene-centric CNV association study
(GCAS)
2014 NG Low copy number of the salivary amylase gene predisposes to obesity
Normal-weight controls
(BMI < 25 kg/m2)
Obese cases
(BMI ≥ 30 kg/m2)
2014 NG Low copy number of the salivary amylase gene ...
AMY1 copy numbers and Obesity
2014 NG Low copy number of the salivary amylase gene predisposes to obesity
Common Disease Risk
1. Disease Genetic Susceptibility
2. Ethnic Difference
3. Complication Genetic Susceptibility
4. Envir...
Trans-ethnic heterogeneity
2012 Ethnic differences in genetic predisposition to hypertension
Different linkage disequilibrium
patterns
2009 PLOS one. Transferability and Fine-Mapping of Genome-Wide Associated Loci f...
Trans-ethnic heterogeneity
EastAsianSouthAsian
2013 Comparing methods for performing trans-ethnic meta-analysis of genome-...
535 SNPs (59 GWS loci) Korea
Ansung
N=2729
In silico
Replication
European BMD GWAS
182 suggestive SNPs
276 SNPs (25 GWS lo...
FDA Halt 23andMe
2013.11.22.
Common Disease Risk
1. Disease Genetic Susceptibility
2. Ethnic Difference
3. Complication Genetic Susceptibility
4. Envir...
당뇨병 합병증 예측 유전형 연구
관찰기간 20년
합병증 발병
50%
20%
고위험 유전형 환자
저위험 유전형 환자
당뇨병
합병증
Diabetes Complication Prediction
2013 NEJM APOL1 Risk Variants, Race, and Progression of Chronic Kidney Disease
APOL1 geno...
2014 DC Genetic Risk Score Associations With Cardiovascular Disease and Mortality in the Diabetes Heart Study
Genetic Risk and
Cardiovascular Mortality
2014 DC Genetic Risk Score Associations With Cardiovascular Disease and Mortalit...
2014 DRCP Transcription factor 7-like 2 (TCF7L2) gene
polymorphism rs7903146 is associated with stroke in type 2
diabetes ...
Common Disease Risk
1. Disease Genetic Susceptibility
2. Ethnic Difference
3. Complication Genetic Susceptibility
4. Envir...
Gene-Environment Interaction
Gene Environment
Disease
Genetic Predisposition Score Sugar-Sweetened Beverages
2010 PLoS Med Physical activity attenuates the genetic predisposition to obesity in 20,000 men and women from EPIC-Norfolk...
High Sugar Intake
Low Sugar Intake
Genetic Predisposition Score
10 4020 30
BMI Slope = 2.43
Slope = 1.46
Slope = ΔBMI / Δ1...
Soda School
No-Soda School
Obese Family Lean Family
Common Disease Risk
1. Disease Genetic Susceptibility
2. Ethnic Difference
3. Complication Genetic Susceptibility
4. Envir...
당뇨병과 후성유전체 연구
Food
Diabetes
Genetic
Predisposition
Environmental
Predisposition
Epigenetic change
Epigenetic change
Diabet...
2012 The genetic and epigenetic basis of type 2 diabetes and obesity
Common Disease Risk
1. Disease Genetic Susceptibility
2. Ethnic Difference
3. Complication Genetic Susceptibility
4. Envir...
Pleiotropy
2012 NG Meta-analysis identifies multiple loci associated with kidney function-related traits in
east Asian pop...
Contents
1. Introduction
2. Genetic Variation and Expression
Analyses
3. Human Genome Project and Beyond
4. Personalized M...
2012 European Heart Journal. Personalized medicine: hope or hype?
Laboratory Director
강현석
Personal genomics: His daughter's DNA (2007)
Do-it-yourself science
Mutation provides clue to daughter’s undefined syndrom...
Contents
1. Introduction
2. Genetic Variation and Expression Analyses
3. Human Genome Project and Beyond
4. Personalized M...
Variable Drug Responses
2012 European Heart Journal. Personalized medicine: hope or hype?
Herceptin
Glivec
November 19, 2013
Cancer genomics
Pharmacogenomics
From 2012 MGR of Pf. Hye-Suk Han
Targeted TherapyGenetic TestCancer
Genomics in Oncology
JCO-2013-Dienstmann-1874-84
JCO-2013-Garraway-1806-14
10 oncogenic drivers testing
2014 JAMA Using Multiplexed Assays of Oncogenic Drivers in Lung Cancers to Select Targeted Dr...
Personalized Medicine
Pharmacogenomics
Nutrigenomics
IRS1 SNP GA/AA
High fat/
Low carb
IRS1 SNP GG
Standard
Higher
effect
...
Large Effect Size Variant?
Disease susceptibility variant Pharmacogenetic variant
Environmental
Exposure
Drug
Exposure
Variants and Disease Susceptibility
2008 NRG Genome-wide association studies for complex traits- consensus, uncertainty an...
GWAS
Effect Size vs. Sample Size
genotype relative
risks (GRR)
Small effect size
Large
effect size
2007 BMC Genetics. Powe...
November 19, 2013
November 19, 2013
2013 NEJM A Randomized Trial of
Genotype-Guided Dosing of Warfarin
2013 NEJM A
Randomized Trial of
Genotype-Guided Dosing
of Warfarin
Median
21 days
Median
29 days
Median
44 days
Median
59 ...
Case/Control=39/833
SNP chip
Chr 6
Discover
Validate
2013/10/24 China
Discovery Patients (N=294)
SNP chip
Chr 3
2013/12/25
Discover
Validate
Replication Patients (N=100)
Taiwan Bipolar Consort...
Anti-thyroid drug related agranulocytosis
Hyperthyroidism Anti-thyroid drug Fatal side effect
Agranulocytosis
Hyperthyroid...
2013.11.14.
141 drugs
158 labels
60 indications/contraindications
Atorvastatin, Azathioprine, Carbamazepine, Carvediolol, ...
CPIC Pharmacogenetic Tests: 최형진
No
Drug
(N= 10)
Gene
(6 genes=8 bioma
rkers)
Target SNPs
(N=12)
#5
(HJC)
Genotype Interpre...
Point-of-care
Genotyping
HyBeacon Probes
Pharmacogenomics
• Treatment Response
– GGPS1 SNP ↔ Bisphosphonate response
Choi et. al. Yonsei Med J. 2010
Metformin Transporters
AA
AC
CC
MATE1
OCT1
GG GA AA
2011 Nature. Drugs, diabetes and cancer
2013 The Role of Pharmacogenet...
Expected Metformin response
Other drug Metformin usual dose Metformin low dose (S/E)
0% -1% -2%-1.5% -2.5% -3%+0.5%
HbA1c ...
2012 Individualized therapy for type 2 diabetes- clinical implications of pharmacogenetic data
List of SNPs Associated wit...
2012 Individualized therapy for
type 2 diabetes- clinical
implications of pharmacogenetic
data
Genotype Guided Personalized Treatment
Baseline
Genotyping
- Drug metabolism
- DM etiology
- DM complication
1 week 3 mont...
2010 Lancet Clinical assessment incorporating a personal genome
Whole Genome
Sequencing
Heliscope Genome sequencer
Pharmacogenomic variants
2010 Lancet Clinical assessment incorporating a personal genome
2010 Lancet Clinical assessment incorporating a personal genome
Common
Disease Risk
Prediction
2010 Lancet Clinical assessment incorporating a
personal genome
Common
Disease Risk
Prediction
Rare variants
2010 Lancet Clinical assessment incorporating a personal genome
2010 Lancet Clinical assessment incorporating a personal genome
A Genotype-First Approach to Defining
the Subtypes of a Complex Disease
2014.2.27.
Genome-wide Profiling Human Genome(DNA) Study
Microarray
Proteonomics
GWAS, Candidate gene study
Familial study
Linkage st...
Genome Surgery
Future of Genomic Medicine?
Test when neededWithout information Know your type
Blood
type
Geno
type
Here is my
sequence
유전체의학과 미래의학 1 유전체의학_공개용
유전체의학과 미래의학 1 유전체의학_공개용
유전체의학과 미래의학 1 유전체의학_공개용
유전체의학과 미래의학 1 유전체의학_공개용
유전체의학과 미래의학 1 유전체의학_공개용
유전체의학과 미래의학 1 유전체의학_공개용
유전체의학과 미래의학 1 유전체의학_공개용
유전체의학과 미래의학 1 유전체의학_공개용
유전체의학과 미래의학 1 유전체의학_공개용
유전체의학과 미래의학 1 유전체의학_공개용
유전체의학과 미래의학 1 유전체의학_공개용
유전체의학과 미래의학 1 유전체의학_공개용
유전체의학과 미래의학 1 유전체의학_공개용
유전체의학과 미래의학 1 유전체의학_공개용
유전체의학과 미래의학 1 유전체의학_공개용
유전체의학과 미래의학 1 유전체의학_공개용
유전체의학과 미래의학 1 유전체의학_공개용
유전체의학과 미래의학 1 유전체의학_공개용
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Transcript of "유전체의학과 미래의학 1 유전체의학_공개용"

  1. 1. 유전체 의학과 미래 의학 최형진 충북대학교 내분비내과
  2. 2. Genomics/ Biomarker Big Data/ Medical Informatics Smart Device/ Wearable Genome Sequencing Data Science Quantified Self Health Avatar Mobile Health Machine Learning 미래의학 유전체, 빅데이터, 스마트 의료 최형진
  3. 3. 시대변화
  4. 4. Genomics/ Biomarker Big Data/ Medical Informatics Smart Device/ Wearable Genome Sequencing Data Science Quantified Self Health Avatar Mobile Health Machine Learning
  5. 5. Contents 1. Introduction 2. Genetic Variation and Expression Analyses 3. Human Genome Project and Beyond 4. Personalized Medicine in Endocrinology ① Common Disease Risk ② Rare Disease Risk ③ Pharmacogenomics
  6. 6. 1997
  7. 7. 발전한다?
  8. 8. 저의 유전자 분석 결과를 반영하여 진료 해주세요!! 헠?
  9. 9. Your estimated lifetime risk $2,000~$3,000
  10. 10. Personal Genome Service $99
  11. 11. 2013.01.29
  12. 12. 헬스케어 3.0 시대의 변화 키워드 2011.11.23 헬스케어 3.0: '건강수명' 시대의 도래 주: 선의 굵기는 영향의 강도를 의미
  13. 13. 2013.4.25. KBS 9시 뉴스
  14. 14. 며칠 전 유전자 검사를 받은 40대 남성입니다. 혈액세포의 DNA 상태를 분석해 앞으로 암에 걸릴 위험이 있는지 여부를 판단할 수 있다 고 합니다. 2013.4.25. KBS 9시 뉴스
  15. 15. 2013.4.25. KBS 9시 뉴스 60년전 DNA의 구조가 밝혀진 이래 2003년 인간 유전자 지도가 완성됐고, 현재는 어떤 유 전자가 어떤 질병을 일으키는지 분석도 80% 정도 끝난 상태입니다. 예를들어 13번 염색체의 BRCA2 유전자에 이상이 생기면 유방암에 걸릴 확률이 높습니 다. 또 17번 염색체 유전자는 난소암, 7번 염색체 유전자는 비만을 일으킵니다.
  16. 16. 개인별 유전체 분석을 통해 암 발병 예측 및 예방, 치료하는 ‘유전체 기반 맞춤치료’ 는 전 세계적으로 가장 주목받고 있는 차 세대 치료 트랜드. 때문에 국내 주요 대학 병원들도 관심을 보이고 각기 ‘맞춤치료’ 를 주요 전략으로 내세우고 있지만, 삼성 서울병원처럼 구체적으로 언제부터 시작 하겠다고 공언한 곳은 없다. 송 원장은 또 "미국 보스턴에 하버드의대와 MIT대가 공동으로 설립한 세계 최고 유전체 연구소인 브로드(Broad) 연구소의 최신 기 법을 공동 활용하는 협약도 맺었다"고 말했 다. 브로드 연구소는 암이나 당뇨병을 일으 키는 원인 유전자를 찾아내어 이를 교정하 는 방식의 개인 맞춤형 치료를 연구하는 기 관이다. 2013.04.04 “유전체를 기반으로 한 맞춤형 항암치료를 5년 내 시작하겠다” “5년 안에 모든 암환자 맞춤치료 실현하겠다” 2013.06.24
  17. 17. 2011 Nature. Charting a course for genomic medicine from base pairs to bedside Genomics and KOREA
  18. 18. Contents 1. Introduction 2. Genetic Variation and Expression Analyses 3. Human Genome Project and Beyond 4. Personalized Medicine in Endocrinology ① Common Disease Risk ② Rare Disease Risk ③ Pharmacogenomics
  19. 19. DNA mRNA Protein Metabolite Epigenetics Genetics Information and OMICs Genomics Epigenomics Transcriptomics Proteomics Metabolomics
  20. 20. 외래/입원 진료 당뇨병으로 진단된 환자 임상정보 수집 혈액 샘플 수집 외래/입원 진료 및 투약 당뇨병 합병증 및 추적관찰 정보 합병증/치료효과 관련 유전체 연관 분석 유전체 분석
  21. 21. 검체 수집 구 분 수집 목표 수집 현황 달성도 (%) 수집 예상 달성도 (%) 당뇨병 1400 건 1365 97.50% 1462 104.4
  22. 22. Food Diabetes Genetic Predisposition Environmental Predisposition Epigenetic change Epigenetic change Diabetic Complications 1. Diabetes Susceptibility 2. Diabetes Complication Pathogenesis
  23. 23. Metabolomics 2013 Metabolomics platforms for genome wide association studies—linking the genome to the metabolome Metabolomics
  24. 24. Metabolomics - OGTT 2008 Metabolic profiling of the human response to a glucose challenge reveals distinct axes of insulin sensitivity
  25. 25. 2013 Diabetes. Metabolite profiles during oral glucose challenge
  26. 26. Metabolomics Profiling • Quantification of 186 metabolites – Acylcarnitines – Amino Acids – Biogenic Amines – Hexoses (sum of Hexoses) – Phospho and Sphingolipids • Phosphatidylcholines • LysoPhosphatidylcholines • Sphingomyelin Metabolomics
  27. 27. Next-Generation Sequencing (NGS) Benchtop Genome Center (90min) 454/FLX (Roche), Solexa (Illumina), SOLiD (AB) 50ng DNA (Sanger=1 ug)
  28. 28. Contents 1. Introduction 2. Genetic Variation and Expression Analyses 3. Human Genome Project and Beyond 4. Personalized Medicine in Endocrinology ① Common Disease Risk ② Rare Disease Risk ③ Pharmacogenomics
  29. 29. 1000 Genomes Samples Population When cell li ne avail. (ap prox) DNA seque nced from b lood Offspring sa mples from trios avail. First set Second set Third set Total Utah residents (CEPH) with Northern and Western Eu ropean ancestry (CEU) Available no yes 100 100 Toscani in Italia (TSI) Available no no 100 100 British from England and Scotland (GBR) Available no no 96 4 100 Finnish from Finland (FIN) Available no no 100 100 Iberian populations in Spain (IBS) Available no yes 30 70 100 Total European ancestry 426 74 500 Han Chinese in Beijing, China (CHB) Available no no 100 100 Japanese in Toyko, Japan (JPT) Available no no 100 100 Han Chinese South (CHS) Available most yes 100 100 Chinese Dai in Xishuangbanna (CDX) Feb-12 some no 100 100 Kinh in Ho Chi Minh City, Vietnam (KHV) Available some some 100 100 Chinese in Denver, Colorado (CHD) (pilot 3 only) Available no no 0 TOTAL East Asian ancestry 300 200 500 Yoruba in Ibadan, Nigeria (YRI) Available no yes 100 100 Luhya in Webuye, Kenya (LWK) Available no no 100 100 Gambian in Western Division, The Gambia (GWD) Aug-12 no yes 100 100 Mende in Sierra Leono (MSL) Aug-12 no yes 100 100 Esan in Nigeria (ESN) Aug-12 no yes 100 100 TOTAL West African ancestry 200 300 500 African Ancestry in Southwest US (ASW) Available no some 61 1 62 African Caribbean in Barbados (ACB) Available yes yes 79 21 100 Mexican Ancestry in Los Angeles, CA (MXL) Available no yes 70 70 Puerto Rican in Puerto Rico (PUR) Available yes yes 70 20 90 Colombian in Medellin, Colombia (CLM) Available no yes 70 19 89 Peruvian in Lima, Peru (PEL) Available yes yes 70 19 89 TOTAL Americas 271 150 79 500 Gujarati Indian in Houston, TX (GIH) Available no no 100 100 Punjabi in Lahore, Pakistan (PJL) May-Aug 20 12 yes yes 100 100 Bengali in Bangladesh (BEB) Aug-12 no yes 100 100 Sri Lankan Tamil in the UK (STU) Aug-12 yes yes 100 100 Indian Telegu in the UK (ITU) Aug-12 yes yes 100 100 TOTAL South Asian ancestry 100 400 500 TOTAL 1197 524 779 2500
  30. 30. Wellcome Trust: 10,000 human genomes to uncover disease-causing variants
  31. 31. Korean Reference Genome
  32. 32. Comprehensive Catalogues of Genomic Data Variation in the human genome Mendelian (monogenic) diseases (N=21,862) as of 2013-06-28 Whole genome sequencing (N=1,000) Four ethnic groups (CEU, YRI, JPT, CHB, N=270) GWAS catalog Complex (multigenic) traits (1647 publications and 10953 SNPs) As of 2013-06-28 Disease-related variations Functional elements in the human genome ENCyclopedia Of DNA Elements
  33. 33. Contents 1. Introduction 2. Genetic Variation and Expression Analyses 3. Human Genome Project and Beyond 4. Personalized Medicine in Endocrinology ① Common Disease Risk ② Rare Disease Risk ③ Pharmacogenomics
  34. 34. Genome-wide Profiling Human Genome(DNA) Study Microarray Proteonomics GWAS, Candidate gene study Familial study Linkage study Genomic Study Genomic Medicine Novel Variant(SNP) DiscoveryNovel Target Discovery GENE for everyone VARIANT based individualization Non-responder of treatment Severe side effect Anti-oxidant Monoclonal antibody for osteoporosis Genetic counseling for rare diseases Sensitive urine test, DM subtype Mendelian disease diagnosis High risk of future osteoporosis High risk of DM complications Diagnosis Treatment Prevention Common Disease Risk Rare Disease Risk Therapeutic Option Novel Disease Target Personalized Medicine
  35. 35. Personalized Medicine 2012 European Heart Journal. Personalized medicine: hope or hype?
  36. 36. Contents 1. Introduction 2. Genetic Variation and Expression Analyses 3. Human Genome Project and Beyond 4. Personalized Medicine in Endocrinology ① Common Disease Risk ② Rare Disease Risk ③ Pharmacogenomics
  37. 37. Common Disease Risk 1. Disease Genetic Susceptibility 2. Ethnic Difference 3. Complication Genetic Susceptibility 4. Environmental Interaction 5. Epigenetics 6. Pleiotropy
  38. 38. Common Disease Risk 1. Disease Genetic Susceptibility 2. Ethnic Difference 3. Complication Genetic Susceptibility 4. Environmental Interaction 5. Epigenetics 6. Pleiotropy
  39. 39. Influence of Genetics on Human Disease For any condition the overall balance of g enetic and environmental determinants ca n be represented by a point somewhere w ithin the triangle. 45 Single Locus / Mendelian Multiple Loci or multi- chromosomal Environmental Cystic Fibrosis Hemophilia A Examples: Alzheimer’s Disease Type II Diabetes Cardiovascular Diseas Diet Carcinogens Infections Stress Radiation Lifestyle Gene = F8 Gene= CFTR F8 = Coagulation Factor VIII CFTR = Cystic Fibrosis Conductance Transmembrane Regulator Lung Cancer
  40. 40. 2008 HMG Genome-based prediction of common diseases- advances and prospects
  41. 41. 2008 HMG Genome-based prediction of common diseases- advances and prospects
  42. 42. Variants and Disease Susceptibility 2008 NRG Genome-wide association studies for complex traits- consensus, uncertainty and challenges
  43. 43. Promise of Human Genome Project
  44. 44. Estrada et al., Nature Genetics, 2012 + novel targets for bone biology Recent largest GWAS GEFOS consortium
  45. 45. Diabetes ≠ Genetic Disease? • Familial aggregation – Genetic influences? – Epigenetic influences • Intrauterine environment – Shared family environment? • Socioeconomic status • Dietary preferences • Food availability • Gut microbiome content • Overestimated heritability – Phantom heritability 2012. Drong AW, Lindgren CM, McCarthy MI. Clin Pharmacol Ther. The genetic and epigenetic basis of type 2 diabetes and obesity. 2012. PNAS The mystery of missing heritability- Genetic interactions create phantom heritability
  46. 46. Per-allele effect of BMI-associated loci on body weight 2012 Genetic determinants of common obesity and their value in prediction
  47. 47. 2011 Hum Genet. Type 2 diabetes and obesity- genomics and the clinic
  48. 48. 2014 DC Impact of Type 2 Diabetes Susceptibility Variants on Quantitative Glycemic Traits Reveals Mechanistic Heterogeneity
  49. 49. SNP N………… ………… ………… ………… ∑ = 1 Max = N x 2 ∑ = 2 ∑ = 4 SNP 1 0 1 2 SNP 2 0+0 1+1 2+1 Genetic Predisposition Score
  50. 50. 2008 HMG Genome-based prediction of common diseases- advances and prospects Single variant Single variant 20 variants
  51. 51. 2010 AJCN Cumulative effects and predictive value of common obesity-susceptibility variants identified by genome-wide association studies
  52. 52. ◇◆ ‘parental obesity’ as a test to predict obesity in adult life •Dark blue 1–2 yrs •Green 3–5 yrs •Red 6–9 yrs •Light blue 10–14 yrs •Grey , 15–17 yrs Genetic Prediction of Obesity Risk The predictive ability of the currently established BMI- associated loci is poor 2012 Genetic determinants of common obesity and their value in prediction
  53. 53. CONCLUSIONS: In this study, adding genetic information to a previously validated clinic + biological score does not seem to improve the prediction of T2DM
  54. 54. “At the end of the era of common variant discovery for T2D, polygenic scores can predict T2D in whites and blacks but do not outperform clinical models. Further optimization of polygenic prediction may require novel analytic methods, including less common as well as functional variants.”
  55. 55. 2014 DC Polygenic Type 2 Diabetes Prediction at the Limit of Common Variant Detection
  56. 56. 2014 DC Polygenic Type 2 Diabetes Prediction at the Limit of Common Variant Detection
  57. 57. Predicting Complex Diseases 2013 NG Predicting the influence of common variants “For most diseases, it should be possible to identify the individuals with the highest genetic risk. However, if the aim is to identify individuals with just twice the mean population risk, we cannot currently do that with SNPs” Mean population risk Highest genetic risk x2 DiseaseRisk Rare Variant?
  58. 58. Rare Variants with Large Effect Size? • "These results indicate that the T2D landscape is not dominated by low- frequency and rare coding variants of large effect." • "To conclude, either private loss of function variants may not have a phenotypic impact in diabetes-related traits or functional annotations need to be improved to separate SNPs with significant associations into meaningful categories." • "In 5,334 samples, no low-frequency or rare causal variants were identified using single marker or gene-level tests. " Rare Variant?
  59. 59. 2014 NG Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes Variant based approach
  60. 60. 2014 NG Loss-of-function mutations in SLC30A8 protect against type 2 diabetes Gene based approach
  61. 61. 2014 NG Low copy number of the salivary amylase gene predisposes to obesity
  62. 62. Gene-centric CNV association study (GCAS) 2014 NG Low copy number of the salivary amylase gene predisposes to obesity
  63. 63. Normal-weight controls (BMI < 25 kg/m2) Obese cases (BMI ≥ 30 kg/m2) 2014 NG Low copy number of the salivary amylase gene predisposes to obesity
  64. 64. AMY1 copy numbers and Obesity 2014 NG Low copy number of the salivary amylase gene predisposes to obesity
  65. 65. Common Disease Risk 1. Disease Genetic Susceptibility 2. Ethnic Difference 3. Complication Genetic Susceptibility 4. Environmental Interaction 5. Epigenetics 6. Pleiotropy
  66. 66. Trans-ethnic heterogeneity 2012 Ethnic differences in genetic predisposition to hypertension
  67. 67. Different linkage disequilibrium patterns 2009 PLOS one. Transferability and Fine-Mapping of Genome-Wide Associated Loci for Adult Height across Human Populations Replicate Not Replicate
  68. 68. Trans-ethnic heterogeneity EastAsianSouthAsian 2013 Comparing methods for performing trans-ethnic meta-analysis of genome-wide association studies
  69. 69. 535 SNPs (59 GWS loci) Korea Ansung N=2729 In silico Replication European BMD GWAS 182 suggestive SNPs 276 SNPs (25 GWS loci) 16 suggestive SNPs Replicated in Koreans Replication rate: 51.6% (276/535 SNPs)
  70. 70. FDA Halt 23andMe 2013.11.22.
  71. 71. Common Disease Risk 1. Disease Genetic Susceptibility 2. Ethnic Difference 3. Complication Genetic Susceptibility 4. Environmental Interaction 5. Epigenetics 6. Pleiotropy
  72. 72. 당뇨병 합병증 예측 유전형 연구 관찰기간 20년 합병증 발병 50% 20% 고위험 유전형 환자 저위험 유전형 환자 당뇨병 합병증
  73. 73. Diabetes Complication Prediction 2013 NEJM APOL1 Risk Variants, Race, and Progression of Chronic Kidney Disease APOL1 genotype predicts kidney function decline
  74. 74. 2014 DC Genetic Risk Score Associations With Cardiovascular Disease and Mortality in the Diabetes Heart Study
  75. 75. Genetic Risk and Cardiovascular Mortality 2014 DC Genetic Risk Score Associations With Cardiovascular Disease and Mortality in the Diabetes Heart Study
  76. 76. 2014 DRCP Transcription factor 7-like 2 (TCF7L2) gene polymorphism rs7903146 is associated with stroke in type 2 diabetes patients with long disease duration
  77. 77. Common Disease Risk 1. Disease Genetic Susceptibility 2. Ethnic Difference 3. Complication Genetic Susceptibility 4. Environmental Interaction 5. Epigenetics 6. Pleiotropy
  78. 78. Gene-Environment Interaction Gene Environment Disease Genetic Predisposition Score Sugar-Sweetened Beverages
  79. 79. 2010 PLoS Med Physical activity attenuates the genetic predisposition to obesity in 20,000 men and women from EPIC-Norfolk prospective population study Gene-Environment Interaction Exercise X Genetic Predisposition
  80. 80. High Sugar Intake Low Sugar Intake Genetic Predisposition Score 10 4020 30 BMI Slope = 2.43 Slope = 1.46 Slope = ΔBMI / Δ10 allel 2012 NEJM Sugar-Sweetened Beverages and Genetic Risk of Obesity
  81. 81. Soda School No-Soda School Obese Family Lean Family
  82. 82. Common Disease Risk 1. Disease Genetic Susceptibility 2. Ethnic Difference 3. Complication Genetic Susceptibility 4. Environmental Interaction 5. Epigenetics 6. Pleiotropy
  83. 83. 당뇨병과 후성유전체 연구 Food Diabetes Genetic Predisposition Environmental Predisposition Epigenetic change Epigenetic change Diabetic Complications 1. Diabetes Susceptibility 2. Diabetes Complication Pathogenesis
  84. 84. 2012 The genetic and epigenetic basis of type 2 diabetes and obesity
  85. 85. Common Disease Risk 1. Disease Genetic Susceptibility 2. Ethnic Difference 3. Complication Genetic Susceptibility 4. Environmental Interaction 5. Epigenetics 6. Pleiotropy
  86. 86. Pleiotropy 2012 NG Meta-analysis identifies multiple loci associated with kidney function-related traits in east Asian populations 2011 NRG The pleiotropic structure of the genotype-phenotype map- the evolvability of complex organisms.
  87. 87. Contents 1. Introduction 2. Genetic Variation and Expression Analyses 3. Human Genome Project and Beyond 4. Personalized Medicine in Endocrinology ① Common Disease Risk ② Rare Disease Risk ③ Pharmacogenomics
  88. 88. 2012 European Heart Journal. Personalized medicine: hope or hype?
  89. 89. Laboratory Director 강현석
  90. 90. Personal genomics: His daughter's DNA (2007) Do-it-yourself science Mutation provides clue to daughter’s undefined syndrome 2013.6.26.
  91. 91. Contents 1. Introduction 2. Genetic Variation and Expression Analyses 3. Human Genome Project and Beyond 4. Personalized Medicine in Endocrinology ① Common Disease Risk ② Rare Disease Risk ③ Pharmacogenomics • Cancer • Non-cancer
  92. 92. Variable Drug Responses
  93. 93. 2012 European Heart Journal. Personalized medicine: hope or hype? Herceptin Glivec
  94. 94. November 19, 2013 Cancer genomics Pharmacogenomics
  95. 95. From 2012 MGR of Pf. Hye-Suk Han Targeted TherapyGenetic TestCancer
  96. 96. Genomics in Oncology JCO-2013-Dienstmann-1874-84
  97. 97. JCO-2013-Garraway-1806-14
  98. 98. 10 oncogenic drivers testing 2014 JAMA Using Multiplexed Assays of Oncogenic Drivers in Lung Cancers to Select Targeted Drugs
  99. 99. Personalized Medicine Pharmacogenomics Nutrigenomics IRS1 SNP GA/AA High fat/ Low carb IRS1 SNP GG Standard Higher effect Similar effect
  100. 100. Large Effect Size Variant? Disease susceptibility variant Pharmacogenetic variant Environmental Exposure Drug Exposure
  101. 101. Variants and Disease Susceptibility 2008 NRG Genome-wide association studies for complex traits- consensus, uncertainty and challenges Natural selection Pharmacogenetics
  102. 102. GWAS Effect Size vs. Sample Size genotype relative risks (GRR) Small effect size Large effect size 2007 BMC Genetics. Power analysis for genome-wide association studies Small sample size Large sample size
  103. 103. November 19, 2013
  104. 104. November 19, 2013
  105. 105. 2013 NEJM A Randomized Trial of Genotype-Guided Dosing of Warfarin
  106. 106. 2013 NEJM A Randomized Trial of Genotype-Guided Dosing of Warfarin Median 21 days Median 29 days Median 44 days Median 59 days P<0.001 P=0.003
  107. 107. Case/Control=39/833 SNP chip Chr 6 Discover Validate 2013/10/24 China
  108. 108. Discovery Patients (N=294) SNP chip Chr 3 2013/12/25 Discover Validate Replication Patients (N=100) Taiwan Bipolar Consortium
  109. 109. Anti-thyroid drug related agranulocytosis Hyperthyroidism Anti-thyroid drug Fatal side effect Agranulocytosis Hyperthyroidism: incidence 0.1~0.4 / 1000 / year (M<F) Rare side effect: 0.3~0.6% among treated Second exposure  Relapse HLA class II related?
  110. 110. 2013.11.14. 141 drugs 158 labels 60 indications/contraindications Atorvastatin, Azathioprine, Carbamazepine, Carvediolol, Clopidogrel, Codein, Diazepam…..
  111. 111. CPIC Pharmacogenetic Tests: 최형진 No Drug (N= 10) Gene (6 genes=8 bioma rkers) Target SNPs (N=12) #5 (HJC) Genotype Interpretation Clinical Interpretation 1 Clopidogrel CYP2C19 rs4244285 (G>A) GG *1/*1 (EM) Use standard dosers4986893 (G>A) GG rs12248560 (C>T) CC 2 Warfarin VKORC1 rs9923231 (C>T) TT Low dose (higher risk of bleeding) Warfarin dose=0.5~2 mg/day CYP2C9 rs1799853 (C>T) CC rs1057910 (A>C) AC 3 Simvastatin SLCO1B1 rs4149056 (T>C) TT Normal 4 Azathioprine (AP), MP, or TG TPMT rs1142345 (A>G) AA Normal 5 Carbamazepine or Phenytoin HLA-B*1502 rs2844682 (C>T) CT Normal rs3909184 (C>G) CC 6 Abacavir HLA-B*5701 rs2395029 (T>G) TT Normal 7 Allopurinol HLA-B*5801 rs9263726 (G>A) GG Normal Clopidogrel1) : UM/EM=standard dose, IM/PM= consider alternative antiplatelet agent (eg. prasugrel/ticagrelor) Warfarin2) : high dose=5~7 mg/day, medium dose=3~4 mg/day, low dose=0.5~2 mg/day $99 N>400,000
  112. 112. Point-of-care Genotyping HyBeacon Probes
  113. 113. Pharmacogenomics • Treatment Response – GGPS1 SNP ↔ Bisphosphonate response Choi et. al. Yonsei Med J. 2010
  114. 114. Metformin Transporters AA AC CC MATE1 OCT1 GG GA AA 2011 Nature. Drugs, diabetes and cancer 2013 The Role of Pharmacogenetics in Drug Disposition and Response of Oral Glucose-Lowering Drugs 2010 Interaction between polymorphisms in the OCT1 and MATE1 transporter and metformin response
  115. 115. Expected Metformin response Other drug Metformin usual dose Metformin low dose (S/E) 0% -1% -2%-1.5% -2.5% -3%+0.5% HbA1c change Good Response Genotype Poor Response Genotype
  116. 116. 2012 Individualized therapy for type 2 diabetes- clinical implications of pharmacogenetic data List of SNPs Associated with Diabetes Drug Response
  117. 117. 2012 Individualized therapy for type 2 diabetes- clinical implications of pharmacogenetic data
  118. 118. Genotype Guided Personalized Treatment Baseline Genotyping - Drug metabolism - DM etiology - DM complication 1 week 3 month Long term Genotype based treatment strategy - Drug choice - Drug dose - Lifestyle modification - Complication evaluation New T2DM
  119. 119. 2010 Lancet Clinical assessment incorporating a personal genome Whole Genome Sequencing Heliscope Genome sequencer
  120. 120. Pharmacogenomic variants 2010 Lancet Clinical assessment incorporating a personal genome
  121. 121. 2010 Lancet Clinical assessment incorporating a personal genome Common Disease Risk Prediction
  122. 122. 2010 Lancet Clinical assessment incorporating a personal genome Common Disease Risk Prediction
  123. 123. Rare variants 2010 Lancet Clinical assessment incorporating a personal genome
  124. 124. 2010 Lancet Clinical assessment incorporating a personal genome
  125. 125. A Genotype-First Approach to Defining the Subtypes of a Complex Disease 2014.2.27.
  126. 126. Genome-wide Profiling Human Genome(DNA) Study Microarray Proteonomics GWAS, Candidate gene study Familial study Linkage study Genomic Study Genomic Medicine Novel Variant(SNP) DiscoveryNovel Target Discovery GENE for everyone VARIANT based individualization Non-responder of treatment Severe side effect Anti-oxidant Monoclonal antibody for osteoporosis Genetic counseling for rare diseases Sensitive urine test, DM subtype Mendelian disease diagnosis High risk of future osteoporosis High risk of DM complications Diagnosis Treatment Prevention Common Disease Risk Rare Disease Risk Therapeutic Option Novel Disease Target Personalized Medicine
  127. 127. Genome Surgery
  128. 128. Future of Genomic Medicine? Test when neededWithout information Know your type Blood type Geno type Here is my sequence
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