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(Circulation. 1999;100:e85-e86.)
© 1999 American Heart Association, Inc.

Circulation Electronic Pages

Renin-Angiotensin System and Blood Pressure

A.H.J. Danser, PhD

Department of Pharmacology Erasmus University Rotterdam, Rotterdam, The Netherlands

H. Schunkert, MD, PhD

Klinik und Poliklinik für Innere Medizin II University of Regensburg, Regensburg, Germany

	Introduction

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To the Editor:

With great interest, we read the articles by O'Donnell et al¹ and Fornage et al² in the May 12, 1998, issue of Circulation. Their data suggest genetic linkage between the ACE gene and blood pressure in men but not in women. Likewise, we previously described associations of ACE with arterial blood pressure³ and with ECG evidence of left ventricular hypertrophy⁴ only in men. It may be worthwhile, therefore, to point to another apparent sexual dimorphism of the renin-angiotensin system. In men, renin and prorenin are 30% and 50% higher, respectively, than in women,⁵ a difference that may diminish during menopause. Renin is the second major enzyme of this system and is responsible for generation of angiotensin I (the substrate of ACE). It may thus be speculated that men with genetically elevated ACE levels (DD genotype) are confronted with higher angiotensin I levels and, thereby, may have a higher chance to present with complex phenotypes. The stoichiometry of ACE and renin was also probed by a recent transgenic rat model with high levels of human ACE transgene expression in the heart.⁶ Although this transgenic animal has almost no apparent phenotype under baseline conditions, abdominal aortic banding and subsequently high renin levels resulted in enhanced left ventricular hypertrophy. Similarly, Montgomery et al⁷ found a much more marked increase in left ventricular mass in response to intense physical training in males with the ACE D allele than in II homozygotes, whereas left ventricular mass was similar in the genotype groups before training.

Taken together, genetic polymorphisms should be placed in the context of the physiological system to which they relate. Given that these physiological systems may be subject to feedback or gender-specific regulation, interpretation of respective analyses should pay attention to these factors, as exemplified by O'Donnell, Fornage, and their coworkers.

	References

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1. 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.[Abstract/Free Full Text]

2. Fornage M, Amos CI, Kardia S, Sing CF, Turner ST, Boerwinkle E. Variation in the region of the angiotensin-converting enzyme gene influences interindividual differences in blood pressure levels in young white males. Circulation. 1998;97:1773–1779.[Abstract/Free Full Text]

3. Schunkert H, Hense H-W, Muscholl M, Luchner A, Riegger GAJ. Association of angiotensin converting enzyme activity and arterial blood pressure in a population-based sample. J Hypertens. 1996;14:571–575.[Medline] [Order article via Infotrieve]

4. Schunkert H, Hense H-W, Holmer SR, Stender K, Perz S, Keil U, Lorell BH, Riegger GAJ. Association between a deletion polymorphism of the angiotensin-converting enzyme gene and left ventricular hypertrophy. N Engl J Med. 1994;330:1634–1638.[Abstract/Free Full Text]

5. Danser AHJ, Derkx FHM, Schalekamp MADH, Hense H-W, Riegger GAJ, Schunkert H. Determinants of interindividual variation of renin and prorenin concentrations: evidence for a sexual dimorphism of (pro)renin levels in humans. J Hypertens. 1998;16:853–862.[Medline] [Order article via Infotrieve]

6. Pinto YM, Tian X, Costerousse O, Stula M, Franz WM, Paul M. Cardiac overexpression of angiotensin-converting enzyme in transgenic rats augments cardiac hypertrophy. Circulation. 1996;96(suppl I):I-629. Abstract.

7. Montgomery HE, Clarkson P, Dollery CM, Prasad K, Losi M-A, Hemingway H, Statters D, Jubb M, Girvain M, Varnava A, World M, Deanfield J, Talmud P, McEwan JR, McKenna WJ, Humphries S. Association of angiotensin-converting enzyme gene I/D polymorphism with change in left ventricular mass in response to physical training. Circulation. 1997;96:741–747.[Abstract/Free Full Text]

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