The Pharmacogenomics Unit is the most recently developed Section of the Department whose mission is to endeavor to understand the role of genetic variation and exploit its potential for the purpose of establishing most appropriate therapeutic modalities in the management of cardiovascular diseases. In the present report period therefore, our efforts have been directed primarily at setting up the programme of the Unit.

It is now clear that the variability in drug responses among patients has a genetic basis, as a result of genetically determined differences in drug absorption, disposition, metabolism and excretion. These inter-individual differences in patient responses to drug therapy are a major clinical problem, and are responsible for several devastating side effects as well as certain types of drug interactions, which may be an underlying cause of death. The ability to predict or avoid such adverse events would allow drugs to be prescribed in a manner obviating the need to use alternative drugs, or to adjust the optimum dose empirically based on patient response. Therefore, detailed knowledge of the genetic basis of individual drug responses (Pharmacogenomics) is potentially of major clinical and economic importance, and could provide the basis for a rational approach to drug prescription. Pharmacogenomics is of particular importance in the treatment of cardiovascular disease in general, especially in combating those diseases such as coronary artery disease (CAD) that may have a genetic component as a risk factor, e.g. hypertension or diabetic disorders. Whatever the underlying basis for the differential patient response to drug therapy may be, it is becoming increasingly evident that a large number of these mechanisms are genetically determined. In particular, it has recently become evident that a mutation in a single nucleotide often leads to gene polymorphism(s) with grave functional consequences for the protein products.

The major focus of the Pharmacogenetics Unit is therefore directed at understanding the relevance of single nucleotide polymorphism in the therapeutic management of CAD and related risk factors, such as diabetes and hypertension in the Saudi population. It is known that the prevalence of individual SNPs varies among ethnic or population groups. Furthermore, the composition of interactive haplotypes depends on the prevalence of the individual SNPs in the population. Therefore, the impact of SNPs on therapy and manifestation of CAD may be determined by interactions of the same predisposing factors for hypertension, diabetes etc. It is therefore imperative to determine the characteristics of SNP distribution in the relevant genes in order to define their role in optimizing drug therapy of interest for any particular population. Determination of SNP polymorphisms will be based on direct sequencing of amplicons providing near-full coverage primarily of the coding regions for candidate genes. The screening for SNPs will be done in a small representative group of individuals in the general population. This will be followed by association studies involving several SNPs predicted to produce functional changes at the protein levels. The assessment of SNP frequency in disease/subgroup will then be performed in large populations. Characterization of these polymorphisms would lay basis for the criteria for defining the genetic basis for such inter-individual differences in CAD therapy in this population. As a long-term goal, we intend to perform population-based association studies on selected genes, in order to characterize influence of SNPs on responses to certain therapeutic agents, initiate polymorphism screening for genes of interest and identify common gene-based SNPs that can be used as markers for CAD.

There are other smaller projects also currently running primarily as PhD training programmes. These include evaluating the possibility of co-segregation of genetic loci with lack of blood pressure responses to losartan (angiotensin receptor blocker) and the relevance of the angiotensin receptor subtype ratios in the treatment of hypertension with receptor blockers. We hope to identify some suitable therapeutic modalities for selected agents such as losartan, which can be put to clinical translation, and trust that these studies will serve as a nucleus for potential national screening programs for CAD and hypertension.

In setting up the programme, we are working in close collaboration with other laboratories in the Research Centre, particularly Cell Biology and Genomics Units, several physicians from the Cardiovascular Diseases Department and Department of Medicine as well as the KSU College of Medicine and University of Brighton in the UK