Global Collaboration on Myocardial Infarction Project

Myocardial Infarction (MI) is the leading cause of death in the United States and the 2nd leading cause of death in China. MI is heritable, particularly for those with a family history of early-onset MI.

Despite more than 2,300 Americans and 25,000 Chinese people dying of cardiovascular disease (CVD) every day, little is known about the etiology of MI, Moreover, it is predicted that CVD in China will increase by more than 50% between 2010 and 2030, due to aging and growth of the population.

Genome-wide association studies (GWAS) have proven successful at mapping genomic loci that influence human diseases and traits including MI, CAD, and lipid levels. However, for MI, the vast majority of the heritability remains unexplained. This is because there is no complete understanding of the causal variants and genes at known loci and also because many additional disease genes were likely not found by the GWAS approach.

Although many genetic discoveries have been made in individuals of European ancestry, few investigations into the genetic causes of high cholesterol and heart disease in Chinese have been published. Studying people with a different genetic history provides new insight into which genes and genetic changes are involved in heart disease and how they might be working. In 2011, the Joint Institute (JI) funded a research project “Finding genes for myocardial infarction and blood lipid levels in a Chinese sample from Beijing”, which aims to test whether the same variants and genes identified in Europeans will also be associated in Asian individuals. The project also aims to investigate the evidence for selection at lipid genes.

Project investigators from both institutional partners – the University of Michigan (UM) and Peking University Health Science Center (PUHSC) – met through the JI in 2010. According to Dr. Cristen Willer, co-principal investigator (PI) and scientific lead for the MI project at UM, “the JI provided a great platform for research collaboration. Thanks to the JI, I had the chance to work with collaborators from PUHSC and pioneered the use of the latest in genotyping technologies and resources for discovery genetics.”

Dr. Willer was able to access the samples from another JI project co-led by Dr. Santhi Ganesh (UM) and Dr. Yan Zhang (PUHSC). She explains, “The JI offers new opportunities for research synergies. We used samples collected by Dr. Yan Zhang’s group to confirm our findings, and were able to share the samples for different projects and optimally utilize the resources available for multiple projects.”

In order to validate the findings, the project also involves Hong Kong University (HKU). “When I
was studying for a PhD at Oxford University, I built collaborations with scientists at HKU,” Dr. Willer
shares. “By performing a meta-analysis with colleagues at HKU, we identified three novel genes associated with blood lipid levels and three novel Asian-specific variants in known genes. The collaborations from the three institutions work extremely well.” By leveraging existing collaborations with a research group in Norway, led by Kristian Hveem, the team was able to quickly compare findings in East Asian and European samples.

Dr. Xu Ming, Co-PI from PUHSC, indicates that this was a very successful collaboration which combines the resources together and sheds light on novel lipid biology and CAD. The project went very smoothly and the two teams work together to design the study, calculate power, and interpret findings using frequent telephone conferences and biannual face-to-face meetings either in Beijing or Michigan.

Through the global collaboration between Michigan, Hong Kong, Beijing, and Norway, scientists have published a manuscript on the discovery of several major new findings regarding blood cholesterol and heart disease:

  1. They discovered new genes involved in blood cholesterol levels, one of which has already been shown toincrease risk of fatty liver disease;
  2. In genes already known to cause heart disease, new genetic variants specific to Chinese individuals have been discovered. This suggests that in the same genes, different genetic changes in Chinese individual and European individuals developed over time that affected blood cholesterol levels; and
  3. Interestingly, all the Chinese-specific lipid variants identified were associated with heart disease, with the exception of HDL-increasing variants in CETP. CETP inhibitors have been developed to increase HDL cholesterol, thought previously to be the good cholesterol, but have not been able to prevent heartdisease. This study in Chinese people provides even more evidence that HDL cholesterol might not bethe good cholesterol after all, but instead may have no impact on heart disease risk;

Dr. Willer and Dr. Xu were delighted to work together to contribute new scientific findings that may one day result in more effective treatments and prevention for heart disease.