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A critical assessment of the role of pharmacogenomics and pharmacogenetics approaches to cardiovascular diseases

The Pharmacogenomics Journal volume 1, pages 95–97 (2001)Cite this article

At the beginning of the 21st century, cardiovascular diseases represent the most frequent cause of death in the world with more than 11 million deaths per year, way ahead of other causes, including infectious diseases.1 Nevertheless, since the end of the 1970s, we have seen a significant fall in the death rate from coronary diseases below the age of 64 years. This reduction is due both to a decrease in the number of new cases and to an improvement in survival after acute cardiac illness.2 When the origin of these falls is examined, it can be seen that the variations in the classic determinants of risk (hypertension, cholesterol, smoking, obesity) explain about 20% of this fall, but that the major modifications in the treatment of the acute phase of the myocardial infarction (thrombolysis, beta-blockers, conversion enzyme inhibitors, aspirin or other anti-platelet drugs) explain more than 40%.3 In the context of clinical trials, the study of the effectiveness of these drugs shows, for each of them, a comparative 15–20% reduction of the risk of death for coronary patients. New treatments appear on the market regularly, reducing this vascular risk further. So in view of such progress, do we really need pharmacogenomics and pharmacogenetics in cardiology? In other words, what can we now expect from these new disciplines, born with the booming of genomics? Are they only new marketing concepts or useful tools for better therapeutic progress?

Numerous definitions exist, but one could characterise pharmacogenomics as the use of genomics for the discovery of new treatments. Most of the techniques involved in this discipline require methods of differential screening: comparison of a healthy tissue with a diseased one, of a normal cell with a diseased one, of a normal cell with a treated one, or of diseased cells at different phases in the progression of the disease.4 The ultimate objective of these comparisons is to discover the differentially expressed genes so as to deduce from them the specific pharmacological targets of the pathological process studied. This reasoning is directed by two key factors: the recent development in biotechnology, allowing the simultaneous characterisation of several hundreds, even several thousands of transcripts, and the postulate that the detection of a difference in expression may indicate the causality. This seductive and simplistic vision conflicts with the everyday reality of scientific research. Firstly, the definitions of cardiovascular diseases, which allow the distinction between normal and pathologic, are founded on very heterogeneous clinical and biological bases. Moreover, the multifactorial nature of cardiovascular diseases adds to the complexity of the underlying molecular mechanisms.5 Secondly, the high throughput transcription analysis techniques are not so well standardised and the studies of reproducibility or, more generally bench marks are rare, which limits the generalisation of the conclusions drawn. Thirdly, the differences observed are often multiple and lead to the isolation of several hundred transcribed sequences, more than half of which code for genes, the functions of which are still unknown.6 The initial characterisation of these transcripts is necessary for the definition of the newly expected therapeutic targets, and the genomics techniques cannot respond alone to this objective. If pharmacogenomics wants to reach the ambitious objectives it sets itself, it is therefore essential that it integrates techniques of the post-genome, firstly proteomics, and that it opens up swiftly towards physiology and functional exploration. Also, the times required to obtain specific, new, totally original, even revolutionary, molecules, that have been quoted by the start-up companies supported by some large pharmaceutical companies, will be difficult to adhere to.

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  1. INSERM U508, Institut Pasteur de Lille, Lille, France

    P Amouyel

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Amouyel, P. A critical assessment of the role of pharmacogenomics and pharmacogenetics approaches to cardiovascular diseases. Pharmacogenomics J 1, 95–97 (2001). https://doi.org/10.1038/sj.tpj.6500027

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