myocardial infarction in chinese population -...

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.


Background of MI Project


Genotypic variation is the cause of many diseases

Complex diseases

Common genetic disorders

UMHS‐PUHSC JOINT INSTITUTEFord Museum

Technology Innovations and International Collaborations Providing Us New Opportunities


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Predicted impact of results

Pred

icted cost of study

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Genome‐wide association

scan

Whole genome

sequencing

Exome ChipGenotyping

MetabochipGenotyping

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Cutting‐edge genomics technology


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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What have we learned about MI using genome‐wide

approaches in European samples?

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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• 59 of these loci were new• Follow‐up in additional 102,000 individuals identified 89 novel loci (unpublished)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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• 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


Mouse model of GALNT2

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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


Different Characteristic of Atherosclerosis between China and U.S.A

Arterioscler Thromb Vasc Biol. 2005;25:611-616


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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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.


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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Progress Report ‐‐MI Project


Got Training Certificates


Working Together on Protocol


This project has been approved


PUMI Project is lunching now…

• PUHSC‐UMMS investigation of MI


• 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


Database Setup


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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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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Three things in life, once gone, never come backWe are in the race against time!

Time

Opportunity

Words


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…

myocardial infarction in chinese population -...

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