Correspondence

Association between a Deletion Polymorphism of the Angiotensin-Converting-Enzyme Gene and Left Ventricular Hypertrophy

N Engl J Med 1994; 331:1097-1098October 20, 1994

Article

To the Editor:

The report by Schunkert et al. (June 9 issue)1 was intriguing, but it did not elaborate on why the effect of the DD genotype of the angiotensin-converting-enzyme (ACE) gene on the development of left ventricular hypertrophy was stronger in normotensive subjects than in hypertensive patients. On this subject, we previously reported2 that the association between plasma ACE activity and the ACE genotypes is observed in normotensive subjects, but not in hypertensive patients, and that plasma ACE activity in hypertensive patients with the II, ID, and DD genotypes is similar to that in normotensive subjects with the DD genotype. Since angiotensin II is known to cause cardiac-cell hypertrophy, the strong effect of the DD genotype on left ventricular hypertrophy in normotensive subjects, but not in hypertensive patients, may result in the clear association between the DD genotype and plasma ACE activity without confounding by high blood pressure, which is a strong causative factor of left ventricular hypertrophy.

As Schunkert et al. stated, the geographical and racial background of the study subjects is an important factor qualifying the results of the association analysis. We have investigated the association between the ACE genotypes and left ventricular hypertrophy in the Japanese. We used echocardiography instead of electrocardiography to detect left ventricular hypertrophy, because electrocardiography is less sensitive in the detection of left ventricular hypertrophy, as Schunkert et al. point out. Furthermore, echocardiography is essential in order to exclude subjects with old myocardial infarction. This exclusion is very important because the DD genotype of ACE was identified as a powerful risk factor for myocardial infarction in both white3 and Japanese4 persons. Our study demonstrated that the left-ventricular-mass index of normotensive subjects was higher in those with the DD genotype than in those with the other genotypes (Table 1Table 1Association of the Left-Ventricular-Mass Index with the ACE Genotypes in Normotensive and Hypertensive Japanese Men.). These results strongly support the findings that the DD genotype is in close proximity to the critical gene responsible for left ventricular hypertrophy.

Mitsuru Ohishi, M.D.
Hiromi Rakugi, M.D.
Toshio Ogihara, M.D.
Osaka University Medical School, Osaka 565, Japan

4 References

1. 1

   Schunkert H, Hense H-W, Holmer SR, et al. Association between a deletion polymorphism of the angiotensin-converting-enzyme gene and left ventricular hypertrophy. N Engl J Med 1994;330:1634-1638
   Full Text | Web of Science | Medline

2. 2

   Higashimori K, Zhao Y, Higaki J, et al. Association analysis of a polymorphism of the angiotensin converting enzyme gene with essential hypertension in the Japanese population. Biochem Biophys Res Commun 1993;191:399-404
   CrossRef | Web of Science | Medline

3. 3

   Cambien F, Poirier O, Lecerf L, et al. Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature 1992;359:641-644
   CrossRef | Web of Science | Medline

4. 4

   Zhao Y, Higashimori K, Higaki J, et al. Significance of the deletion polymorphism of the angiotensin converting enzyme gene as a risk factor for myocardial infarction in Japanese. Hypertens Res 1994;17:55-57
   CrossRef

Author/Editor Response

The authors reply:

To the Editor: The interesting finding that only normotensive subjects homozygous for the deletion (D) allele of the ACE gene present with increased serum ACE activity1 may help in analyzing the role of the ACE DD genotype in cardiovascular disease. We agree with Ohishi et al. that echocardiography may extend the available information on the cardiac phenotype and thus enhance analyses of molecular genetic linkage or association. A word of caution needs to be added, however, given the small numbers of men in the study described in their letter and the surprising finding that normotensive subjects with the ACE DD genotype had even higher left-ventricular-mass indexes than hypertensive patients with that genotype.

Nevertheless, the echocardiographic data obtained by Ohishi et al. in Japanese men support the hypotheses tested in our paper. First, left ventricular hypertrophy seems to be mediated in part by genetic predisposition; second, a locus close to the ACE gene may be involved in the development of this condition; and third, the effect of this gene on left ventricular hypertrophy is predominantly detectable in normotensive men. Currently, we are using echocardiography to study more than 3000 subjects in a population-based sample, as well as affected sibling pairs with left ventricular hypertrophy, to define further the role of genetics and in particular the role of the ACE genetic polymorphism in cardiac hypertrophy.

Heribert Schunkert, M.D.
University of Regensburg, D-93042 Regensburg, Germany

Hans-Werner Hense, M.D.
University of Munster, D-4400 Munster, Germany

Gunter A.J. Riegger, M.D.
University of Regensburg, D-93042 Regensburg, Germany

1 References

1. 1

   Higashimori K, Zhao Y, Higaki J, et al. Association analysis of a polymorphism of the angiotensin converting enzyme gene with essential hypertension in the Japanese population. Biochem Biophys Res Commun 1993;191:399-404
   CrossRef | Web of Science | Medline

Citing Articles (10)

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   Claudio Picariello, Chiara Lazzeri, Paola Attanà, Marco Chiostri, Gian Franco Gensini, Serafina Valente. (2011) The Impact of Hypertension on Patients with Acute Coronary Syndromes. International Journal of Hypertension 2011, 1-7
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   Y. B. Saab, P. R. Gard, A. D. J. Overall. (2007) The geographic distribution of the ACE II genotype: a novel finding. Genetical Research 89:04,
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   Jop H. van Berlo, Yigal M. Pinto. (2003) Polymorphisms in the RAS and cardiac function. The International Journal of Biochemistry & Cell Biology 35:6, 932-943
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   Tomohiro KATSUYA, Yoshio IWASHIMA, Ken SUGIMOTO, Motoharu MOTONE, Takashi ASAI, Masayuki FUKUDA, Yuxiao FU, Yasuko HATANAKA, Mitsuru OHISHI, Hiromi RAKUGI, Jitsuo HIGAKI, Toshio OGIHARA. (2001) Effects of Antihypertensive Drugs and Gene Variants in the Renin-Angiotensin System.. Hypertension Research 24:4, 463-467
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   Mitsuru Ohishi, Hiromi Rakugi, Tetsuro Miki, Tomohiro Katsuya, Atsunori Okamura, Kei Kamide, Yukiko Nakata, Seiju Takami, Hiroshi Ikegami, Yoshihiro Yanagitani, Yoshikatsu Tabuchi, Yuichi Kumahara, Jitsuo Higaki, Toshio Ogihara. (2000) Deletion Polymorphism Of Angiotensin-Converting Enzyme Gene Is Associated With Postprandial Hyperglycaemia In Individuals Undergoing General Check-Up. Clinical and Experimental Pharmacology and Physiology 27:7, 483-487
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   Daniele Cusi, Giuseppe Bianchi. (1998) A primer on the genetics of hypertension. Kidney International 54:2, 328-342
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   Jan A. Staessen, Ji G. Wang, Giuliana Ginocchio, Victor Petrov, Arturo P. Saavedra, Florent Soubrier, Robert Vlietinck, Robert Fagard. (1997) The deletion/insertion polymorphism of the angiotensin converting enzyme gene and cardiovascular-renal risk. Journal of Hypertension 15:12, 1579-1592
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   Shoji Tsutaya, Hitomi Kitaya, Yuka Saito, Shinichi Nakata, Hideetsu Takamatsu, Minoru Yasujima. (1997) Angiotensin Converting Enzyme Gene Polymorphism and Its Enzyme Activity in Serum in Young Japanese Females.. The Tohoku Journal of Experimental Medicine 182:2, 151-155
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9. 9

   Hiroaki Yoshida, Valentina Kon, Iekuni Ichikawa. (1996) Polymorphisms of the renin-angiotensin system genes in progressive renal diseases. Kidney International 50:3, 732-744
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10. 10

    S. R. Holmer, H. Schunkert. (1996) Adaptive and genetic alterations of the renin angiotensin system in cardiac hypertrophy and failure. Basic Research in Cardiology 91:S1, 65-71
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