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UMHS‐PUHSC JOINT INSTITUTE
Finding Genetic Risk Factors for Myocardial Infarction in Chinese Population
Wei Gao, MD, PhD. Cristen J. Willer, Ph.D. Ming Xu, Ph.D. Weixian Xu, MD.
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UMHS‐PUHSC JOINT INSTITUTE
Background of MI Project
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UMHS‐PUHSC JOINT INSTITUTE
Genotypic variation is the cause of many diseases
Complex diseases
Common genetic disorders
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UMHS‐PUHSC JOINT INSTITUTEFord Museum
Technology Innovations and International Collaborations Providing Us New Opportunities
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UMHS‐PUHSC JOINT INSTITUTE
Low High
Predicted impact of results
Pred
icted cost of study
Low High
Genome‐wide association
scan
Whole genome
sequencing
Exome ChipGenotyping
MetabochipGenotyping
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Cutting‐edge genomics technology
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UMHS‐PUHSC JOINT INSTITUTE
Metabochip
• We created a custom‐designed Illumina iSelect chip with 200,000 SNP markers (designed at U of Michigan by HM Kang)
• Top 5,000 hits from each of CAD, LDL, HDL, TG GWAS in Europeans
• Also hits from BMI, Waist‐hip‐ratio, DBP, SBP, fat percent, Type 2 Diabetes, fasting insulin, fasting glucose, 2hr glucose, white blood cell count, QT interval
• Metabochip SNPs selected from all 3 HapMap populations for fine‐mapping in non‐caucasian populations (using HapMap Han Chinese from Beijing)
(94 CAD or lipid loci = ~49k SNPs)
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UMHS‐PUHSC JOINT INSTITUTE
What have we learned about MI using genome‐wide
approaches in European samples?
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UMHS‐PUHSC JOINT INSTITUTE
GWAS results
• GWAS of 100,000 Europeans• Identified 95 loci associated with lipid levels with p < 5x10‐8
• 59 of these loci were new• Follow‐up in additional 102,000 individuals identified 89 novel loci (unpublished)
• Untangling the biology and functional effect of genetic variants at the new loci will take some time
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UMHS‐PUHSC JOINT INSTITUTE
• Successfully identified new genetic loci associated with lipid levels which led to a new understanding of the underlying biology
• Even though naturally‐occurring genetic variation has small effect sizes, we can drastically impact lipid levels by disruption of the gene (mouse models or therapeutics)
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Potential Targets
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UMHS‐PUHSC JOINT INSTITUTE
Mouse model of GALNT2
-40%
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0 14 28
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AAV empty vector AAV-mGALNT2
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AAV empty vector AAV-shRNA-mGALNT2
Hepatic over‐expression of Galnt2
shRNA knockdown of endogenous Galnt2
37% increase in HDL (p < .0003)20% decrease in HDL
(p < .0001)
Teslovich et al., Nature, 201010
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UMHS‐PUHSC JOINT INSTITUTE
Different Characteristic of Atherosclerosis between China and U.S.A
Arterioscler Thromb Vasc Biol. 2005;25:611-616
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UMHS‐PUHSC JOINT INSTITUTE
Large‐scale genomic discovery efforts in Asian studies
• Genome‐wide association scan for blood pressure in 19,608 Asian samples published (Nature Genetics June 2011)
• GWAS for breast cancer genes in ~2,000 Asian cases and 2,000 controls (Wang Nat Genet Mar 2011) with follow‐up in ~34,000 samples
• Metabochip genotyped in >10,000 of Asian samples• Exome Chip not yet released (Asian sample consortium
in preliminary organization stages)
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UMHS‐PUHSC JOINT INSTITUTE
Current Status of MI in China• Cardiovascular Disease Accounted for 40.27% of the country's total death rate.
• 2 million people are suffering MI now, 0.5 million additional myocardial infarction each year
2008年《中国卫生事业发展情况统计公报》
Tang et al.
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UMHS‐PUHSC JOINT INSTITUTE
MI project
• Aim 1: To identify novel loci associated with myocardial infarction
• Aim 2: To determine which MI identified in Europeans are also associated in Chinese individuals
• Aim 3: Refine the association signal using a Chinese cohort for 94 lipid or MI‐associated regions initially identified in Europeans
• Continue ongoing collection of samples to increase the sample size of the experiment
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UMHS‐PUHSC JOINT INSTITUTE
Progress Report ‐‐MI Project
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UMHS‐PUHSC JOINT INSTITUTE
Got Training Certificates
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UMHS‐PUHSC JOINT INSTITUTE
Working Together on Protocol
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UMHS‐PUHSC JOINT INSTITUTE
This project has been approved
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UMHS‐PUHSC JOINT INSTITUTE
PUMI Project is lunching now…
• PUHSC‐UMMS investigation of MI
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UMHS‐PUHSC JOINT INSTITUTE
• Extraction of DNA from 6000~ samples from patients who had cardiac catheterization
• All necessary data are transforming from paper document to electronic database.
• Additional MI cases and control identified from other hospitals for next phase of project
Data and Sample Collection
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UMHS‐PUHSC JOINT INSTITUTE
Database Setup
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UMHS‐PUHSC JOINT INSTITUTE
Translational benefits of proposed studies
• Identification of genetic variants of large effect on risk may allow: – Prediction of individuals at risk for MI or CVD– Targeted treatment plans
• Identification of novel MI or lipid‐associated genes will:– Identify novel drug targets– Uncover biological basis and biological pathways related to MI or other cardiovascular disease
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UMHS‐PUHSC JOINT INSTITUTE
Maximizing success
• Have large follow‐up samples available for analysis of top hits (ongoing collection)
• Anticipate need to collaborate with others** Collect unusual cases for sequencing
– extreme phenotypes– many affected family members– very early onset
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UMHS‐PUHSC JOINT INSTITUTE
Three things in life, once gone, never come backWe are in the race against time!
Time
Opportunity
Words
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UMHS‐PUHSC JOINT INSTITUTE
Acknowledgements
• Dr. Eugene Chen (UM CVC)• Dr. David Pinsky (UM CVC)• Dr. Xian Wang (PKU CVC)
• All Joint Institute leaders and staffs: – Weigang Fang, Joseph C Kolars, Ruqun Shen,Youyi Zhang, Qiudan Sun, Yanfang Wang, Ping Ji, Amy Huang…
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UMHS‐PUHSC JOINT INSTITUTE