L10	Cardiovascular genomics and oxidative stress.
Chr.Delles, A.F.Dominiczak
BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, GB.

Genetic factors, environmental factors and modifiable risk factors interact in the pathogenesis of cardiovascular disease (CVD). Despite considerable progress in the treatment of risk factors such as hypertension and hypercholesterolaemia the burden of cardiovascular morbidity and mortality remains high. This has led to the recognition that genetic disposition plays a pivotal role in the pathogenesis of CVD. There are a number of strategies to identify genes underlying CVD. The progress of genetic studies designed as nonhypothesis-driven such as genome-wide scans has been relatively slow. On the other hand, several new candidate pathways have been identified from hypothesis-driven research. One of the most promising pathways involved in the pathogenesis of CVD is the oxidative stress pathway. Oxidative stress is an imbalance between the production of and the defences against reactive oxygen species. Superoxide anion is the most important of reactive oxygen species in the vasculature. Scavenging of endothelium-derived nitric oxide by superoxide leads to endothelial dysfunction which is an early step in the development of CVD. Many of the genes and proteins within the oxidative stress pathway have proven contributions to cardiovascular disease. Among the most frequently studied genes are CYBA encoding p22phox subunit of NADPH synthase and ENOS encoding endothelial nitric oxide synthase both of which are involved in the production of superoxide. From our studies of rat chromosome 2 congenic strains we have identified another candidate gene involved in the defences against oxidative stress: glutathione S-transferase mu type 1 (Gstm1). We have demonstrated reduced Gstm1 expression in stroke-prone spontaneously hypertensive rats (SHRSP) as compared to normotensive Wistar Kyoto rats and a chromosome 2 congenic strain. Underexpression of Gstm1 was paralleled by increased vascular superoxide levels, endothelial dysfunction and hypertension. We are convinced that careful examination of new candidate genes for human cardiovascular disease includes (1) detailed analysis of gene function both in rodent and human models; (2) sequencing of the gene and detection of gene variants; (3) analysis of linkage disequilibrium and haplotype reconstruction across the gene or gene family; (4) large-scale association studies using both single locus and haplotype data supported by smaller studies looking at specific phenotypes such as markers of oxidative stress and endothelial function; and (5) confirmation of results in an independent population. For example, detailed analysis of conserved synteny across the genomes showed that Gstm1 has 5 human orthologues, GSTM1 to 5. We are currently examining associations between human GSTM variants and human cardiovascular disease. Although the availability of sequence data of human, rat and mouse genome facilitates detection of new candidate genes and further research, some considerations have to be carefully addressed. These include the importance of high-fidelity phenotyping, the development of new statistical methods and the necessity of quick and exact genotyping of large numbers of genetic variants within a certain pathway. The clinical dividend will certainly be detection of patients at particular high risk for CVD leading to targeted prevention and treatment in these subjects.

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