Gene Variant Influencing Cholesterol and Myocardial Risk Discovered Interview with:
Cristen J. Willer, PhD
Assistant Professor
Division of Cardiovascular Medicine, Dept of Internal Medicine
Dept of Human GeneticsDept of Computational Medicine and Bioinformatics
University of Michigan Ann Arbor, MI 48109-5618 What are the main findings of the study?

Dr. Willer: We wanted to find new genes related to heart disease, so we examined the DNA of approximately 10,000 Norwegian individuals and found 10 genes that are important regulators of blood cholesterol levels. Nine of these were well known to be related to lipids, but one gene was new.  It turned out to be in a region we’d previously noticed to be related to cholesterol, but it was a big region and we hadn’t been able to pinpoint the gene yet.  Using this new approach, focusing on DNA differences that result in slightly different proteins in people, we zeroed in on the gene.  We then altered this gene in mice, and saw the predicted changes in cholesterol levels in mice. Were any of the findings unexpected?

Dr. Willer: We were not sure if we would find any new genes with this approach and a modest sample size (only 10,000 individuals) and were excited when we did. What should clinicians and patients take away from your report?

Dr. Willer: The major scientific advance is that TM6SF2 is a gene that plays an important role in blood lipid levels, risk of heart attack, and risk of fatty liver disease.  More research will be needed to understand exactly how this gene and its protein alter disease risk.  Another important concept is that none of these discoveries would be possible without people being generous and donating DNA samples to genetics research. What recommendations do you have for future research as a result of this study?

Dr. Willer: I think continuing on genetic discovery experiments to understand the secrets of disease susceptibility hiding in our DNA is really important.  Also, further exploration of the role of this gene in heart disease, liver disease and other metabolic diseases will help us understand if this gene will be a good drug target.  We owe the success of this experiment to collaborative science where different people work together, in this case the Norwegians who donated their samples, clinicians and epidemiologists from the Norwegian University of Science and Technology, and statistical geneticists and molecular biologists from the University of Michigan.


Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk

Oddgeir L Holmen, He Zhang, Yanbo Fan, Daniel H Hovelson, Ellen M Schmidt, Wei Zhou, Yanhong Guo, Ji Zhang, Arnulf Langhammer, Maja-Lisa Løchen, Santhi K Ganesh, Lars Vatten, Frank Skorpen, Håvard Dalen, Jifeng Zhang, Subramaniam Pennathur, Jin Chen, Carl Platou, Ellisiv B Mathiesen, Tom Wilsgaard, Inger Njølstad, Michael Boehnke, Y Eugene Chen, Gonçalo R Abecasis, Kristian Hveem & Cristen J Willer

Nature Genetics Published online: 16 March 2014 | doi:10.1038/ng.2926