6. 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
16. 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
17. 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.
18. 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
19. 2011 Nature. Charting a course for genomic medicine from base pairs to bedside
Genomics and KOREA
20. 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
32. 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
33.
34.
35. 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
38. 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
39. 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
40. 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
42. 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
45. 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
50. Estrada et al., Nature Genetics, 2012
+ novel targets
for bone biology
Recent largest GWAS
GEFOS consortium
51.
52. 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
53. Per-allele effect of BMI-associated
loci on body weight
2012 Genetic determinants of common obesity and their value in prediction
54. 2011 Hum Genet. Type 2 diabetes and obesity- genomics and the clinic
55. 2014 DC Impact of Type 2 Diabetes Susceptibility Variants on Quantitative Glycemic Traits Reveals Mechanistic Heterogeneity
56. 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
57. 2008 HMG Genome-based prediction of common diseases- advances and prospects
Single variant Single variant 20 variants
58. 2010 AJCN Cumulative effects and predictive value of common obesity-susceptibility variants identified by genome-wide association studies
59. ◇◆ ‘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
60. CONCLUSIONS:
In this study, adding genetic information to a
previously validated clinic + biological score does
not seem to improve the prediction of T2DM
61. “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.”
62. 2014 DC Polygenic Type 2 Diabetes Prediction at the Limit of Common Variant Detection
63. 2014 DC Polygenic Type 2 Diabetes Prediction at the Limit of Common Variant Detection
64.
65. 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?
66. 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?
67. 2014 NG Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes
Variant based approach
68. 2014 NG Loss-of-function mutations in SLC30A8 protect against type 2 diabetes
Gene based approach
69. 2014 NG Low copy number of the salivary amylase gene predisposes to obesity
70.
71. Gene-centric CNV association study
(GCAS)
2014 NG Low copy number of the salivary amylase gene predisposes to obesity
72. 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
73. AMY1 copy numbers and Obesity
2014 NG Low copy number of the salivary amylase gene predisposes to obesity
78. 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
86. 당뇨병 합병증 예측 유전형 연구
관찰기간 20년
합병증 발병
50%
20%
고위험 유전형 환자
저위험 유전형 환자
당뇨병
합병증
87. Diabetes Complication Prediction
2013 NEJM APOL1 Risk Variants, Race, and Progression of Chronic Kidney Disease
APOL1 genotype predicts kidney function decline
88. 2014 DC Genetic Risk Score Associations With Cardiovascular Disease and Mortality in the Diabetes Heart Study
89. Genetic Risk and
Cardiovascular Mortality
2014 DC Genetic Risk Score Associations With Cardiovascular Disease and Mortality in the Diabetes Heart Study
90.
91. 2014 DRCP Transcription factor 7-like 2 (TCF7L2) gene
polymorphism rs7903146 is associated with stroke in type 2
diabetes patients with long disease duration
94. 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
101. 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.
102. 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
105. Personal genomics: His daughter's DNA (2007)
Do-it-yourself science
Mutation provides clue to daughter’s undefined syndrome
2013.6.26.
106. 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
116. Large Effect Size Variant?
Disease susceptibility variant Pharmacogenetic variant
Environmental
Exposure
Drug
Exposure
117. Variants and Disease Susceptibility
2008 NRG Genome-wide association studies for complex traits- consensus, uncertainty and challenges
Natural selection
Pharmacogenetics
118. 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
126. 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?
131. 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
132. 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
133. 2012 Individualized therapy for type 2 diabetes- clinical implications of pharmacogenetic data
List of SNPs Associated with Diabetes Drug Response
143. 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
