Brotherly love can be a comfort in times of trouble, sometimes serving to mend a broken heart, but could brothers and sisters also be the key to mending a truly broken heart—one affected by disease? PROCARDIS, an international research consortium, believes they can. The key lies in the genetic make-up of brothers, sisters, mothers and fathers, where at least two family members have suffered from a heart attack. As of January 2003, this research group has completed a whole genome scan (a large scale genetic analysis) in 2,000 volunteer sibling pairs, which represents the largest database of familial genetic samples in this disease area. By analyzing the DNA of all these relatives, researchers hope to identify genetic variations, which could lead to new drug targets for future cardiovascular therapies.

Half of the people who suffer from heart attacks do not experience the classical risk factors such as hypertension, high cholesterol or smoking. Thus, there is a great potential to find new ways to intervene in the progression of this disease. That is why the University of Oxford, the Karolinska Institutet (Sweden), Munster University (Germany), GISSI Group (Italy), Oxagen (UK) and AstraZeneca (Sweden), have come together to form a research consortium that will use the best resources from each organization to find new treatments for heart disease.

Methodology

PROCARDIS is looking at sibling pairs - they do not need to be twins - who have both had heart attacks before the age of 65. In addition, researchers are studying families where an individual has had a heart attack before the age of 65 and where both parents are also available to take part in the study.

A technique called whole genome-wide linkage mapping is being used, in which the entire genome is scanned with certain well-known genetic markers. Scientists look for "common denominators" in siblings that have had a heart attack and also look to see if they inherit the same copy of a gene (from one or both parents) more often than would be expected by chance.

Once a linked genetic marker has been identified, scientists use a similar approach to find the individual genes within that genetic marker segment. By finding the gene/s, scientists can refer to specific proteins and thereby identify the mechanistic pathway involved in the disease. Within that pathway, the best targets for a new medicine are identified. Thus, the hope is that the systematic nature of the genetic approach will reveal entirely novel biological pathways in disease development. This type of large epidemiological study coupled with genetic/genomic research is a new area of research, and PROCARDIS is the largest of its kind in this disease area.

Next Steps

PROCARDIS has now completed the whole genome scan in approximately 2,000 affected sibling pairs, a number that is needed to increase the possibilities of identification of genetic susceptibility variants, which would lead to target identification for new drug candidates. The process of refined mapping to look for individual susceptibility genes is underway. Once a target is identified, scientists from AstraZeneca will start to screen for molecules that can be developed into new medicines. The consortium hopes that the first ideas around potential new susceptibility genes will appear in 2003-2005, with work aimed at exploring pathways and targets thereafter.