Atherosclerosis is the major cause of myocardial infarction and stroke, and is responsible for half of all deaths in Sweden and other Western countries. Complications of atherosclerosis are rapidly increasing as a major cause of death also in developing countries; the World Health Organisation has predicted that this will become the number one killer by 2010.

‚ÄúIt has been an exciting research project, which has gone on for nearly seven years, involving many different disciplines from thoracic surgeons to mathematicians‚ÄĚ, says team leader Dr. Johan Bj√∂rkegren at Karolinska Institutet in Stockholm. ‚ÄúI believe that this kind of clinical study will follow in the aftermath of the large number of ongoing genome-wide association studies.‚ÄĚ

Rather than individual genes or individual DNA variants, the discovery encompasses a group of 128 functionally related genes in a ‚Äėmodule‚Äô or ‚Äėnetwork‚Äô, which explains their mutual interactions. The involvement of most of these genes in CAD has not previously been known, but it has been known that they are involved in endothelial function and angiogenesis.

Through the collaboration with Dr. Eric Schadt’s team at Washington University, Seattle, the researchers were also able to take advantage of previously published genome-wide association studies (GWAS) of CAD to show that the gene module they have discovered is enriched for inherited risk of developing myocardial infarction.

‚ÄúThe GWAS are genetic epidemiology studies often involving tens of thousands of patients and controls, originally designed to link isolated DNA locus to the risk of developing complex common disorders, such as atherosclerosis‚ÄĚ, says Dr Bj√∂rkegren. ‚ÄúThese studies now need to be complemented with clinical studies where the patients also are screened for intermediate molecular phenotypes in disease-relevant organs. The computational capacities and expertise required to address simultaneously all molecular activities and their relative risk-enrichment are available, all that remains is to start recruiting this kind of cohorts.‚ÄĚ

The findings suggest that the severity of atherosclerosis depends on the rate of the migration of white blood cells from the blood into the atherosclerotic plaques. Although this pathway is already known to play a role in atherosclerosis, the Swedish findings suggest that it is the rate limiting step for disease progression. However, Dr Björkegren admits that the exact roles of all 128 genes in atherogenesis remain unexplained. Future studies will focus on understanding the details of how these genes actually contribute to atherosclerosis in cell cultures and animal model systems.

Publication: ‚ÄėMulti-Organ Expression Profiling Uncovers a Gene Module in Coronary Artery Disease Involving Transendothelial Migration of Leukocytes and LIM Domain Binding 2; The Stockholm Atherosclerosis Gene Expression (STAGE) Study‚Äô, Sara H√§gg, Josefin Skogsberg, Jesper Lundstr√∂m, Peri Noori, Roland Nilsson, Hua Zhong, Shohreh Maleki, Ming-Mei Shang, Bj√∂rn Brinne, Maria Bradshaw, Vladimir B. Bajic, Ann Samneg√•rd, Angela Silveira, Lee M. Kaplan, Bruna Gigante, Karin Leander, Ulf de Faire, Stefan Rosfors, Ulf Lockowandt, Jan Liska, Peter Konrad, Rabbe Takolander, Anders Franco-Cereceda, Eric E. Schadt, Torbj√∂rn Ivert, Anders Hamsten, Jesper Tegn√©r, and Johan Bj√∂rkegren. PLoS Genetics, online publication, 3 December 2009, doi: 10.1371/journal.pgen.1000754.

For further information, please contact:

Associate Professor Johan Björkegren, MD, PhD
Department of Medicine, Solna
Center for Molecular Medicine
Tel: +46 (0)8-5177 0314 or +46 (0)73-356 8181 (mobile)
Email: johan.bjorkegren@ki.se

Press Officer Katarina Sternudd
Tel: +46 (0)8-5248 3895
Email: katarina.sternudd@ki.se

Karolinska Institutet is one of the leading medical universities in Europe. Through research and education, Karolinska Institutet contributes to improving human health. Each year, the Nobel Assembly at Karolinska Institutet awards the Nobel Prize in Physiology or Medicine. For more information, visit ki.se.