theme-based research scheme (trs) - med.hku.hk · lks faculty of medicine mr and mrs oliver wong...
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Theme-based Research Scheme (TRS) on Personalized Medicine for Cardiovascular Disease :
From Genomic Testing and Biomarkers to Human Pluripotent Stem Cell Platform
Prof TSE Hung-fat William MW Mong Professor in Cardiology, Professor of Medicine, Cardiology Division, Department of Medicine
Prof LAM Siu Ling, Karen Rosie TT Young Professor in Endocrinology and Metabolism Chair Professor and Head of Department of Medicine
Prof SHAM Pak Chung Director, Centre for Genomic Sciences Chair Professor in Psychiatric Genomics, Department of Psychiatry
Dr TANG Sze Man, Clara Research Assistant Professor, Department of Surgery
Coronary Artery Disease (CAD)
Department of Health (http://www.healthyhk.gov.hk/)
2013: - 3rd killer in Hong Kong - Account for 9.2% death in Hong Kong (total 4,007) - 11 persons died of CAD per day
CAD pathogenesis
Normal inner
vessel wall
CAD inner vessel wall
References : National Heart, Lung and Blood Institute (NHLBI), National Institute of Health (NIH)
Modifiable risk factors of CAD
HKTB, Chest and Heart Association
Abnormal blood lipid levels is the major risk factor of CAD
TC: ↑1mmol/L =↑ risk of CAD death 35%
Total cholesterol (TC, <5.2)
Low-Density Lipoprotein cholesterol (LDL,<3.4; Optimal :<2.6)
High-Density Lipoprotein cholesterol
(HDL >1.0; Optimal :>1.6)
Triglycerides (TG, <1.7) LDL
HDL
• A large proportion of blood lipids in the human body is
manufactured by the liver
• A small proportion is directly derived from diet (10-15%)
• Variation of blood lipid levels depends on
– Genetics (50-70%)
Genetic variations
inherited from parents
– Environment (<50%)
Diet (saturated fat,
trans fat, and cholesterol)
Exercise
Lifestyle
Factors affecting blood lipids levels
• Frequencies of genetic variations vary across populations
Background of this study
Adapted from 1000 Genomes Project Consortium. Nature 526, 68–74. doi:10.1038/nature15393
• Contribution of genetic factors affecting blood lipid levels also varies across populations
• Most genetic studies on blood lipids focus on Europeans
• Genetic factors influencing blood lipid levels on Chinese remain largely unknown
• Evaluate if genetic factors influencing blood lipid levels in Europeans also have similar influences on Chinese
• Identify genetic factors specifically affecting blood lipid levels in Chinese population
• Identify genetic factors contributing to the risk of CAD in Chinese population
Aims of this study
Theme-based Research Scheme (TRS) on Personalized Medicine for Cardiovascular Disease :
From Genomic Testing and Biomarkers to Human Pluripotent Stem Cell Platform
8,621 Northern Chinese(Beijing) • 1,682 CAD patients • 6,939 non-CAD controls
PUUMA-MI
Study subjects
6,048 Southern Chinese (HK) • 2,372 CAD patients • 3,388 non-CAD controls
HKUTRS
6,048 Southern Chinese (HK) • 2,372 CAD patients • 3,388 non-CAD controls
HKUTRS
Study subjects
• Started in 2004-2005 in Queen Mary Hospital • On-going prospective cohort study on the risk factors and clinical
outcomes in Chinese patients with established CAD
Hong Kong Chinese CAD Cohort
Hong Kong Cardiovascular Risk Factors Prevalence Study (CRISPS) • On-going population-based prospective study of cardiovascular
risk factors in Hong Kong, which was started in 1995
Hong Kong West Diabetes Registry (HKWDR) • commenced in 2008 at medical specialist clinics of the Hong Kong West Cluster • Prospective study on control of diabetes and related cardiovascular risk factors,
and development of diabetic complications in type 2 diabetes patients
Sample preparation
4054 CAD cases
10327 Non-CAD controls
Blood lipid levels
DNA
LDL TG
HDL
TC
14,669 Northern + Southern Chinese
Theme-based Research Scheme (TRS) on Personalized Medicine for Cardiovascular Disease :
From Genomic Testing and Biomarkers to Human Pluripotent Stem Cell Platform
Asian Exome-chip
Asian custom panel
59,317 variants
HumanExome BeadChip
242,901 variants
HKU custom panel 1,501 variants
Asian Exome-chip 303,719 variants
Exome-wide association analysis
• Blood lipids • CAD
3,834 CAD cases
9,371 Non-CAD controls
12,685 Chinese subjects passing quality controls
No association
Positive association
Negative association
Adapted from Mathew. (2008) Nat Rev Genet 9(1), 9–14
Theme-based Research Scheme (TRS) on Personalized Medicine for Cardiovascular Disease :
From Genomic Testing and Biomarkers to Human Pluripotent Stem Cell Platform
TG
HDL
LDL
TC
PNPLA3
PKD1L3
Lipid-associated genes not
reported before
LDL
TG
TC
Results of exome-wide association analysis
TG
HDL
LDL
TC
PNPLA3 TEAD2
PKD1L3
Lipid-associated genes not
reported before
LDL
TG
HDL
TC
TEAD2
Results of exome-wide association analysis
Novel lipid-associated genes not reported before
Blood lipid level CAD
Gene Lipid type Frequency (%) Effect P risk P
PNPLA3 (I148M) TG 36.7 -3% 4x10-8
7% 0.011
PKD1L3 (T429S) LDL 74.0 +3% 5x10-8 5% 0.11
TEAD2 HDL 0.09 +37% 2x10-7 - -
Novel lipid-associated genes
DOCK7 GCKR MLXIPL
APOA5
TM6SF2
LPL
CETP
ABCA1
LIPC
PCSK9
CELSR -2
APOB
LDLR
APOE
Novel lipid-associated genes
PKD1L3 PNPLA3 TEAD2
TG HDL
LDL TC
Results of exome-wide association analysis
DOCK7 GCKR MLXIPL
APOA5
TM6SF2
LPL
CETP
ABCA1
LIPC
PCSK9
CELSR -2
APOB
LDLR
APOE
Known lipid-associated genes TG HDL
LDL TC
Results of exome-wide association analysis
DOCK7 GCKR MLXIPL
APOA5
TM6SF2
LPL
CETP
ABCA1
LIPC
PCSK9
CELSR -2
APOB
LDLR
APOE
Known lipid-associated genes TG HDL
LDL TC
Results of exome-wide association analysis
Asian-specific association
Blood lipid level CAD
Gene Lipid type Frequency (%) Effect P risk P
PCSK9 (R93C) LDL 1.3 -24% 8x10-32 52% 4x10-7
CETP (D459G) HDL 2.7 +17% 3x10-29 3% 0.73
LDLR (R257W) LDL 0.1 +32% 3x10-8 366% 1x10-4
Known lipid-associated genes
Novel association with blood lipids from this study
Blood lipid level CAD
Gene Lipid type Frequency (%) Effect P risk P
PCSK9 (R93C) LDL 1.3 -24% 8x10-32 52% 4x10-7
CETP (D459G) HDL 2.7 +17% 3x10-29 3% 0.73
LDLR (R257W) LDL 0.1 +32% 3x10-8 366% 1x10-4
Known lipid-associated genes
Blood lipid level CAD
Gene Lipid type Frequency (%) Effect P risk P
PNPLA3 (I148M) TG 36.7 -3% 4x10-8
7% 0.011
PKD1L3 (T429S) LDL 74.0 +3% 5x10-8 5% 0.11
TEAD2 HDL 0.09 +37% 2x10-7 - -
Novel lipid-associated genes
Summary
• Exome-wide association analysis of 12,685 Chinese on blood lipid levels identified association of DNA variations in three genes not previously reported
to be associated with lipids (PNPLA3, PKD1L3 and TEAD2)
three Asian-specific protein-altering variants in genes (CETP, LDLR and PCSK9) known to affect blood lipid levels
• Some of these Asian-specific lipid-associated variants also
influence risk of CAD
Tonight, I'm launching a new Precision Medicine Initiative to bring us closer to curing diseases like cancer and diabetes – and to give all of us access to the personalized information we need to keep ourselves and our families healthier
— President Barack Obama, State of the Union Address January 20, 2015
http://www.nih.gov/precisionmedicine/
Precision Medicine
The Promise of Precision Medicine
Conventional Approach Precision Medicine Approach
Gene-chip
Clinical risk factor assessment
High risk
Low risk
Clinical risk factor assessment
+
Low risk
High risk
Acknowledgements
Theme-based Research Scheme (T12-705/11),
Research Grants Council of Hong Kong
Center for Genomic Sciences,
LKS Faculty of Medicine
Mr and Mrs Oliver Wong for their generous donation
in support of the core genotyping facility
Theme-based Research Scheme (TRS) on Personalized Medicine for Cardiovascular Disease :
From Genomic Testing and Biomarkers to Human Pluripotent Stem Cell Platform