Analysis of gene-environment interactions by "stressing-the-genotype" studies: the angiotensin converting enzyme and...

The human angiotensin converting enzyme (ACE) gene contains a length polymorphism consisting of the presence (insertion, I) or absence (deletion, D) of a 287 base pair "Alu" repeat sequence in intron 16, with the D allele being associated with higher ACE levels than the I allele in plasma and in tissues. We have carried out several studies to examine the relationship between this polymorphism and cardiovascular health, and have examined the hypothesis that if renin-angiotensin systems regulate left ventricular (LV) growth, individuals of DD genotype might show a greater hypertrophic response than those of II genotype. A strategy was used involving screening over 1200 male military recruits to select only subjects homozygous for the I or D allele for the expensive and time-consuming but extremely accurate method of LV mass determination by magnetic resonance imaging. LV dimensions and mass were compared at the start and end of a 10-week physical training period. LV mass increased with training by 8.4 g overall (p < 0.0001), but with DD men showing roughly 3 fold greater growth than II men (p < 0.001). When indexed to lean body mass, LV growth in II subjects was essentially negligible whilst remaining significant in DD subjects (-0.022 vs +0.131 g/kg respectively, p = 0.0009). Although the precise molecular mechanism of this effect remains to be elucidated it clearly demonstrates the importance of the ACE-renin-angiotensin system in determining LV dimensions in situations of high cardiac demand, which may also be important in pathology such as hypertension and heart failure. The use of these "stress-the-genotype" approaches to explore gene-environment interactions are likely to be the key to understanding the causes determining both coronary artery disease and other multi-factorial disorders.