Volume 1, Number 4, December 2000

Genetic basis of cardiovascular disease – the renin-angiotensin-aldosterone system as a paradigm
Neal Padmanabhan, Sandosh Padmanabhan, John MC Connell

There is considerable evidence that genetic variation in the renin-angiotensin-aldosterone system (RAAS) may influence cardiovascular structure and risk. However, the strength of the associations remain uncertain and it is likely that their importance (and particularly that of the angiotensin-converting enzyme [ACE] inhibitor insertion/deletion [I/D] polymorphism) has been over-stated. The existence of numerous contradictory studies engenders scepticism, which is compounded by lack of evidence of an intermediate phenotype to link genotype and phenotype. In addition, mechanisms by which polymorphisms in non-coding regions of these genes can influence their expression have not been identified. Authors have consistently suggested that the ACE I/D and AT₁-receptor A1166C polymorphisms, for example, may be in linkage disequilibrium with regulatory elements, but these have yet to be identified or characterised at a molecular level. It is equally possible that they are also in linkage disequilibrium with other loci. Of the available evidence, the most persuasive comes from data on aldosterone synthase. This locus is implicated in animal models of raised blood pressure, rare monogenic syndromes and may also be involved in patients with essential hypertension. Finally, further work is clearly required to determine whether specific polymorphisms, or combinations of polymorphisms, will be useful in quantifying cardiovascular risk or guiding treatment. Future studies will need to consider other candidate genes, both within the RAAS and distinct from it. Other studies are already being performed which do not depend on the knowledge of a candidate gene, but instead use the tools of population genetics to identify useful markers. In this regard, the possibility of gene-gene and gene-environment interactions adds another layer of complexity to an already confusing subject.

JRAAS 2000;1:316-324.

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