Large-scale test of hypothesised associations between the angiotensin-converting-enzyme insertion/deletion polymorphism and myocardial infarction in about 5000 cases and 6000 controls

Background The original report of a possible association between myocardial infarction and the insertion/deletion (VD) polymorphism of the gene for th e angiotensin-1-converting enzyme (ACE) indicated a risk ratio for myocardi al infarction with the DD genotype of 1.34 (95% CI 1.05-1.70), and the asso ciation was claimed to be particularly strong in a retrospectively defined low-risk subgroup (3.2 [95% CI 1.7-5.9). Subsequent investigations reached varying conclusions, but ail were small, and much larger studies were neede d. Methods 4629 myocardial infarction cases and 5934 controls were compared. C ases were UK men aged 30-54 years and women aged 30-64 years recruited on p resentation to hospital with confirmed myocardial infarction. Controls were aged 30-64 years with no history of cardiovascular disease, but were sibli ngs or children of myocardial infarction survivors, or spouses of such rela tives. All risk-ratio calculations allow for this relatedness of some of th e controls. An updated meta-analysis of previous studies was also conducted . Findings The ACE DD genotype was found in 1359 (29.4%) of the myocardial in farction cases and in 1637 (27.6%) of the controls (risk ratio 1.10 [95% CI 1.00-1.21]). The association between myocardial infarction and the DD geno type did not seem to be stronger in the subgroup defined as low risk by pre viously used criteria (234 [28%] of 836 cases and 911 [28%] of 3253 control s: risk ratio 1.04 [95% CI 0.87-1.24]), or in any other subgroup. Nor was t he ACE I/D genotype predictive of subsequent survival. Interpretation This study involved many more cases than any previously repo rted study of this question, but did not confirm the existence of any subst antial association. In an updated meta-analysis of these results with those of previously published studies, the risk ratio for myocardial infarction with the DD genotype seems to lie in the range 1.0 to about 1.1. Although a n increase in risk of up to about 10-15% cannot be ruled out, substantially more extreme risks can be. Moreover, there are not especially strong assoc iations in the subgroups previously selected for emphasis. These findings i llustrate the need for some studies of candidate genes to involve much larg er populations than is customary, without undue emphasis on retrospectively defined subgroups.