Discovery of novel genetic markers linked to increased risk of heart attack

An international team of researchers including scientists of Helmholtz Zentrum München has succeeded in identifying new gene variants associated with an increased risk for myocardial infarction (MI), or heart attack.

The identified genes and their underlying mechanisms provide new starting points for understanding genetic patterns in MI and for developing new treatment options. A key finding is that the MI risk is more than twice as great in individuals who carry not only one but several of the genetic markers. Three studies on genetic markers and MI risk have now been published in the current online issue of the renowned journal Nature Genetics.

In a large-scale study coordinated by the University of Lübeck, German, European and American researchers succeeded in identifying novel genetic markers associated with MI. Two institutes of Helmholtz Zentrum München - the Institute of Epidemiology (director: Prof. Dr. Dr. H. Erich Wichmann) and the Institute of Human Genetics (director: Prof. Dr. Thomas Meitinger) - were also involved in the study. The scientists performed a genome-wide scan of thousands of patients with hundreds of thousands of genetic markers. Included in the studies were MI patients from the KORA study (director: Dr. Christine Meisinger) as well as healthy control persons from the population.

"The future challenge for us will be to integrate the insights we have gained about genetic factors and lifestyle factors in order to provide effective preventive measures for the population," said Prof. Dr. Annette Peters, research group leader at Helmholtz Zentrum München.

The first of the three studies investigated a million genetic markers in 1,200 MI patients and the same number of healthy test persons. Subsequent control studies on an additional 25,000 patients and healthy persons confirmed the initial suspicion: Culprit genes for MI are located on chromosomes 3 and 12. Scientists suspect that one of these genes, the MRAS gene, plays an important role in cardiovascular biology. The second gene, the HNF1A gene, is closely associated with cholesterol metabolism.

What is special about the second study is that it not only investigated individual genetic markers as to their influence on the risk of myocardial infarction, but also investigated haplotypes, combinations of up to ten neighboring markers. With this method additional genetic information can be derived compared to individual genetic markers. Thus the scientists were able to identify another region, this time localized on chromosome 6, which is associated with MI risk. The LPA gene at this locus regulates the concentration of a specific lipoprotein (Lp(a)), a particle which transports lipids in the blood. This finding, too, may be useful in the future for developing new therapeutic interventions.

The third study, published in the name of the Myocardial Infarction Genetics Consortium (MIGen), was able to identify three further, previously unknown MI genes on chromosomes 2, 6 and 21. The study also shows that in individuals with not just one but several genetic markers, the MI risk is more than double. The higher the number of disease genes now identified, the higher the disease risk. This knowledge will aid in assessing the risk for myocardial infarction in order to develop preventive and early intervention strategies.

More than 750,000 people die of myocardial infarction in Europe every year. MI and the underlying coronary artery disease are among the most frequent causes of death in Germany. Besides traditional risk factors such as age, hypertension, disorders of the lipid metabolism, diabetes mellitus, smoking and overweight, genetic risk factors play a key role in the emergence of the disease.

These studies provide crucial pieces to the at present incomplete puzzle of myocardial infarction genetics. The findings indicate that there may be many mechanisms involved in myocardial infarction that are still to be discovered. New mechanisms also mean new approaches for MI prevention and treatment.