Insertion/Deletion Polymorphism of the Angiotensin-Converting Enzyme Gene and Hypertension
To the Editor:
Recently, an analysis was performed using a prospective, longitudinal, population-based sample in which the insertion/deletion (I/D) polymorphism of the ACE gene was postulated as a sex-specific candidate gene for hypertension.1 A significant association between hypertension in males and the ACE DD genotype was observed after adjustment for all confounders (OR 1.59, P=0.02), whereas linkage between the DD genotype and diastolic blood pressure (DBP) in men was significant only when adjusted for age alone (P=0.03 and P=0.16 after and before adjustment for age alone, respectively).
In contrast, an independent prospective, population-based study found no association between the ACE I/D polymorphism and hypertension, nor was there any sex stratification with regard to allele or genotype.2 Adjustment for several potential confounders did not affect this result for isolated systolic hypertension (systolic blood pressure [SBP] ≥160 mm Hg, DBP ≤90 mm Hg) (II versus DD OR 1.06; I versus D OR 1.09) or systolic-diastolic hypertension (SBP ≥160 mm Hg, DBP ≥90 mm Hg) (II versus DD OR 1.19; I versus D OR 1.16).
O’Donnell et al1 used the Framingham cohort, which has a large sample size (n=3095/1044 sib pairs) and allowed use of both association analyses and pedigree-based linkage analyses, which provides considerable power to the study. The Dubbo cohort subset used by Johnson et al2 is smaller (n=33) but epidemiologically superior, with a sound geographical definition.3
The most obvious differences between these studies are the definition of high blood pressure and the criteria used to classify patients. O’Donnell and coworkers1 classified patients as having hypertension on the basis that they were using antihypertensive medication or that SBP was ≥140 mm Hg or DBP ≥90 mm Hg. Subjects administered antihypertensive medication were excluded altogether by Johnson et al2 to avoid misclassification and to minimize the introduction of serious flaws in the regression of genotype, whereas subjects with SBP ≤160 mm Hg would be classified as normotensive.
The mean age of the Framingham subjects studied was in the mid to late 50s, considerably younger than the Dubbo subset (late 60s). It remains a possibility that the Dubbo cohort signifies an older, progressive representation of the Framingham cohort that has suffered the removal (through premature death) of those subjects with a genetic predisposition to hypertension. The more stringent classification of high blood pressure in the Dubbo cohort, however, would tend to belie this possibility. Certainly, the concerns outlined above render any correlations between the ACE I/D variant and hypertension speculative at the present time.
- Copyright © 1999 by American Heart Association
O’Donnell CJ, Lindpaintner K, Larson MG, Rao VS, Ordovas JM, Schaefer EJ, Myers RH, Levy D. Evidence for association and genetic linkage of the angiotensin-converting enzyme locus with hypertension and blood pressure in men but not women in the Framingham Heart Study. Circulation. 1998;97:1766–1772.