In the news

For about eight years there has been controversy about whether a common polymorphism in the angiotensin converting enzyme (ACE) confers an increased risk of heart disease. Numerous small studies (fewer than 200 cases) reported risk ratios for cases versus controls ranging from about 1.4 to 1.8, but a meta-analysis of larger studies yielded a risk ratio of 0.99. Keavney et al have now reported the results of the largest case-control study to date, comparing around 5000 cases and 6000 controls [Keavney, B. et al. (2000) Lancet 355, 434-442]. Assuming a recessive genetic model for the association between the D polymorphism and myocardial infarction (that is, the risk applies only to people who have two copies of the D allele) they find a risk ratio of 1.10, with a 95% confidence interval of 1.00-1.21. Their calculation incorporated a correction for the effects of including, as controls, some healthy first-degree relatives of cases.

Comment: The results of this study emphasise the importance of large numbers of subjects in case-control studies to investigate disease associations with candidate genes. Keavney et al suggest that studies with at least 10000 cases and 10000 controls are likely to be needed in order to obtain reliable relative risk figures for common genetic variants that have only weak or moderate effects. The authors point out that weak associations might still be important from the point of view of elucidating mechanisms of disease. However, factors associated with an increased risk of less than 10% are clearly not - at least on their own - going to be useful to those who might contemplate genetic testing for predisposition to a disease. There might still turn out to be some subgroups of people for whom ACE genotype is a significant risk factor, but Keavney et al found no evidence that this was the case for any of the subgroups they investigated.