Theme-based Research Scheme (TRS) - med.hku.hk · LKS Faculty of Medicine Mr and Mrs Oliver Wong for their generous donation in support of the core genotyping facility Theme-based

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



6,048 Southern Chinese (HK) • 2,372 CAD patients • 3,388 non-CAD controls

HKUTRS

Study subjects

8,621 Northern Chinese(Beijing) • 1,682 CAD patients • 6,939 non-CAD controls

PUUMA-MI

Study subjects


HKUTRS


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



Exome

Protein

Exome

DNA variations in exome can change protein structure and function

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

Asian Exome-chip 303,719 variants

Assaying genetic variations

iScan microarray scanner

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



TG

HDL

LDL

TC

TEAD2

Results of exome-wide association analysis

TG

HDL

LDL

TC

PNPLA3

PKD1L3

Lipid-associated genes not

reported before

LDL

TG

TC


TG

HDL

LDL

TC

PNPLA3 TEAD2

PKD1L3

Lipid-associated genes not

reported before

LDL

TG

HDL

TC

TEAD2


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


PKD1L3 PNPLA3 TEAD2

TG HDL

LDL TC


DOCK7 GCKR MLXIPL

APOA5

TM6SF2

LPL

CETP

ABCA1

LIPC

PCSK9

CELSR -2

APOB

LDLR

APOE

Known lipid-associated genes TG HDL

LDL TC


DOCK7 GCKR MLXIPL

APOA5

TM6SF2

LPL

CETP

ABCA1

LIPC

PCSK9

CELSR -2

APOB

LDLR

APOE

Known lipid-associated genes TG HDL

LDL TC


Asian-specific association



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



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



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 - -


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

Individuals carrying more lipid-increasing allele tends to have higher blood lipid levels

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



The University of Hong Kong

LKS Faculty of Medicine

Acknowledgements

Documents

Theme-based Research Scheme (TRS) - med.hku.hk · LKS Faculty of Medicine Mr and Mrs Oliver Wong for their generous donation in support of the core genotyping facility Theme-based