A DNA Variant at the Angiotensin-Converting Enzyme Gene Locus Associates With Coronary Artery Disease in the Caerphilly Heart Study

Background We analyzed an insertion/deletion (I/D) polymorphism of the angiotensin I–converting enzyme (ACE) gene in 1226 subjects from the Caerphilly Prospective Heart Disease Study. Amplification of genomic DNA using the polymerase chain reaction yielded the genotypes II, ID, and DD. Distribution of the polymorphism was analyzed among the whole group and within subgroups (specified following multiple risk factor analysis) for coronary artery disease (CAD) and against multiple risk factors. Methods and Results Allele frequencies were I=0.413 and D=0.587. No association was observed between the polymorphism and CAD in the whole group. Among subjects defined at lower risk of CAD by total cholesterol/HDL cholesterol (TC/HDL) ratios, we found significant associations of the DD genotype with CAD ( P <.0053, n=586 for TC/HDL <5.654 [median] and P <.009, n=385 for TC/HDL <5.0 [clinical threshold]). On further exclusion of subjects with blood pressures ≥140/90 or on hypotensive medications, the DD genotype still associated with CAD ( P <.07, n=210, TC/HDL <5.654 and P <.016, n=135, TC/HDL <5.0). Further stratification of risk incorporating other risk factors, except body mass index, did not alter or enhance this association. Although similar association was observed when risk was specified by using HDL and apo B levels instead of TC/HDL, this association was lost when body mass index was included in the low-risk stratification. Conclusions The DD genotype is a linkage marker for an etiologic mutation at or near the ACE gene that may confer risk of CAD detectable in subjects previously unidentifiable with “classic” risk factors. However, this risk may be quantitatively small among the general male population.