Coronary artery disease and its sequelae myocardial infarction are among the leading causes of death worldwide. In addition to an unhealthy lifestyle, it is known for a long time that familial or inherited factors contribute to the development of these diseases. Now, an international team of 42 researchers from 36 institutions and 7 countries – led by the University of Lübeck and Deutsches Herzzentrum München – unravelled a novel cause of myocardial infarction in an extraordinary large German family comprising more than 23 affected family members.
Next-generation sequencing made it feasible to pinpoint disease-causing mutations. PD Dr. Tim Strom und Prof. Dr. Thomas Meitinger from the Institute of Human Genetics (IHG) at the Helmholtz Zentrum München contributed essentially to these anlayses.
The surprising finding was that two mutations affecting the same enzyme came together in a family with an extraordinary high myocardial infarction risk. The researchers identified two private mutations in the functionally related genes, GUCY1A3 and CCT7. Extensive follow-up studies revealed that these genes encode proteins that work together to mediate effects following nitric oxide stimulation which, among other actions, inhibit platelet activation.
Moreover, the team shows that this pathway is not only relevant in rare families but plays also a role in the general population.
Overall, these data suggest a link between impaired nitric oxide signalling and myocardial infarction risk. Furthermore, it comes clear that it is important not only to search for one disease-causing mutation in families, but to look for two, or even three potentially interacting mutations to explain clustering of a disease in families.
Erdmann, J. et al. (2013). Dysfunctional nitric oxide signalling increases risk of myocardial infarction, Nature, doi: 10.1038/nature12722.
The family was identified as part of the German Myocardial Infarction Family Study (GerMIFS). The aim of the GerMIFS was to analyse MI families to unravel the genetic components of this life-threatening disease.
Funding was provided by the BMBF in the context of the NGFN-plus (Atherogenomics) and DZHK (Deutsches Zentrum für Herz-Kreislauf-Forschung e. V.)
Helmholtz Zentrum München, as German Research Center for Environmental Health, pursues the goal of developing personalized medical approaches for the diagnosis, treatment and prevention of major widespread diseases such as diabetes mellitus and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The head office of the Center is located in Neuherberg in the north of Munich. Helmholtz Zentrum München has a staff of about 2,000 people and is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 34,000 staff members. www.helmholtz-muenchen.de
Dr. Tim Strom, Helmholtz Zentrum München – German Research Center for Environmental Health (GmbH), Institute of Human Genetics, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany – Phone: +49 89-3187-3297