New milestone in the gentics of heart disease

A new milestone in understanding the genetic background of atherosclerosis and heart attack was announced on Thursday by Professor Gerd Assmann, this year's winner of the prestigious Morgagni prize for biomedical research during the award ceremony in Padua, Italy.

Gerd Assmann and his colleague Monika Stoll at the Leibniz Institute of Arteriosclerosis Research in Muenster have been performing genetic analyses in the German Prospective Cardiovascular Muenster (PROCAM) study to identify the genetic factors underlying the predisposition to heart attack. This disease is known to over-proportionally affect certain families – a clear hint to genetics as a contributing factor. A first milestone has been reached now in this research: More than 800 patients who suffered from a myocardial infarction and 800 controls have been genetically profiled. The results have revealed defined genetic traits predisposing an individual to a myocardial infarction. These findings are now awaiting their confirmation in a prospective clinical trail involving 2250 individuals. This is also expected to provide information how the findings can be combined into clinical algorithms for future cardiovascular risk management of patients. The recruitment of the new trial has already started

“This study, partly funded by the Diagnostics Division of Bayer HealthCare LLC (Tarrytown, NY, USA) takes genetic research in PROCAM to the next level”, said Assmann. “Using the most advanced technology available we have been able to obtain exciting new information on the genetic basis of atherosclerosis in general and heart attack in particular.”

Since 1978, the PROCAM study has been studying the causes of heart attack, stroke and atherosclerosis among the citizens of the northern German University City of Muenster and environs. The study at present includes more than 46.000 individuals in long-term follow-up for cardiovascular disease. The largest investigation of its kind in Europe, PROCAM has played a key role in identifying asymptomatic high risk individuals for heart attack, which remains the most frequent cause of death in the developed world – and increasingly also in many countries of Asia and South America. A simple risk score developed in PROCAM is now very widely used by many family doctors, cardiologists and other practitioners of preventive medicine throughout Europe and is making a major contribution towards reducing heart attack rates.

“This unique chance to learn about genetic heart attack risk was made possible by the great generosity of many thousands of my fellow-citizens who donated their time and their blood samples to assist our research”, notes Assmann. “We are grateful that the participants in PROCAM gave informed consent for genetic research and we have taken special care to protect the confidentiality of the data from participants and their families”, he adds. The project was reviewed and approved by an ethical oversight committee. An external oversight committee also regularly reviews the results of PROCAM.

Studies such as that reported by Assmann benefit from the wealth of information derived from the Human Genome Project, which published the complete human DNA code in 2000. Since then, great effort has been devoted to studying the genetic causes for the differences that make each individual person unique. Researchers have discovered that most of the inherited variation between people is due to the fact that about every five-hundredth letter of the genetic code is not fixed, but differs between different individuals. Now, Assmann and colleagues have investigated a half-million of these variable letters (single nucleotide polymorphisms or SNPs) in both MI patients and PROCAM controls and have narrowed down the search to only 400 SNPs that cluster in about 100 candidate genes. This is as if one narrowed down a search from all the books in the Library of Congress to a few hundred volumes on an even smaller number of shelves.

Advanced computer programs will now be used to match these candidates with various aspects of cell function in order to pinpoint those that make the biggest contribution to heart attack risk and to understand the detailed mechanism by which they increase risk.

A feature of this analysis that sets its apart from similar studies elsewhere is the fact that known risk factors for heart disease such as cholesterol, smoking and blood pressure were already accounted for, so that any genes found are likely to identify new disease mechanisms. This feature is of particular importance because even with the contribution made by PROCAM and other studies to risk prediction, about two-thirds of all heart attacks occur in men and women whose levels of conventional risk factors are not increased and who are therefore not currently regarded as being at high risk. “The main challenge for preventive research at the present time,” says Assmann, “is to improve our ability to identify more accurately those people who appear to be at low or medium risk, but who are actually likely to suffer a heart attack in the near to medium future.” Genetic research such as that presented by Assmann is likely to be one of the main ways in which such hidden high-risk can be found. This is not just an academic exercise, but is the key to intervention and risk reduction. For example, the target to which the cholesterol level should be lowered by diet or medication depends on a person's level of risk: persons with low risk are able to safely tolerate a high cholesterol level, while in those at high risk of heart attack, every effort must be made to lower cholesterol as far as possible.