Martin J, Humphries SE, Montgomery HE. The ACE gene and muscle ... John Moxham ... ries S, Montgomery H. Elite swimmers and the D allele of the ACE I/D.
Correspondence ACE Gene Polymorphism in COPD
References
To the Editor:
1. Hopkinson NS, Nickol AH, Payne J, Hawe E, Man WD, Moxham J, Montgomery H, Polkey MI. Angiotensin converting enzyme genotype and strength in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004;170:395–399. 2. Williams AG, Rayson MP, Jubb M, World M, Woods DR, Hayward M, Martin J, Humphries SE, Montgomery HE. The ACE gene and muscle performance. Nature 2000;403:614. 3. van Suylen RJ, Wouters EF, Pennings HJ, Cheriex EC, van Pol PE, Ambergen AW, Vermelis AM, Daemen MJ. The DD genotype of the angiotensin converting enzyme gene is negatively associated with right ventricular hypertrophy in male patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999;159:1791–1795. 4. Zhang B, Tanaka H, Shono N, Miura S, Kiyonaga A, Shindo M, Saku K. The I allele of the angiotensin-converting enzyme gene is associated with an increased percentage of slow-twitch type I fibers in human skeletal muscle. Clin Genet 2003;63:139–144. 5. Kanazawa H, Otsuka T, Hirata K, Yoshikawa J. Association between the angiotensin-converting enzyme gene polymorphisms and tissue oxygenation during exercise in patients with COPD. Chest 2002;121:697–701.
The study of Hopkinson and colleagues (1) showed that in patients with chronic obstructive pulmonary disease (COPD) the deletion allele (D) of the ACE polymorphism was associated with greater quadriceps strength compared with the insertion allele (I), and the authors suggested that this may also apply for exercise capacity. This is remarkable, because in healthy subjects it has consistently been reported that I, but not D, is positively associated with enhanced exercise and muscle performance (2). We have evaluated the ACE gene polymorphism, determined by polymerase chain reaction (3), in 95 patients with COPD (65 males and 30 females, aged 65 years, FEV1 39% of predicted) submitted to an 8-week pulmonary rehabilitation program comprising five exercise training sessions per week. ACE genotype distribution was comparable with that described by Hopkinson and colleagues (DD 32%; ID 50%; II 19%). Exercise capacity, measured by means of the maximal work load achieved during exhaustive incremental cycle ergometry (Wmax), was similar for all ACE genotypes at baseline (DD 57.5 W; II/ID 52.3 W), but I, and not D, was associated with an enhanced response to physical training (DD 6.0 ⫾ 9.8 W; II/ID 14.4 ⫾ 12 W; mean ⫾ SD; p ⫽ 0.04). It thus seems that exercise capacity, in contrast to muscle strength, is not associated with D in COPD. One could speculate that I is associated with enhanced improvement and/or preservation of endurance and D with better improvement and/or preservation of muscle strength. Unfortunately, in our study quadriceps strength was not measured. As in the study by Hopkinson and coworkers, no baseline association between ACE genotype and fat-free mass was found. However, this does not exclude the possibility that muscular properties other than variations in muscle mass are responsible for differences in muscle function. For example, I has been associated with increased proportions of fatigue-resistant slow-twitch fibers—and thus with decreased fast-twitch fiber proportions—in healthy subjects (4). In addition, impaired peripheral tissue oxygenation has been associated with D in COPD (5). It can therefore be hypothesized that a higher proportion of fast-twitch fibers underlies the D allele–associated preservation of muscle strength in the study by Hopkinson and colleagues, whereas in our study the I allele–associated increase in Wmax might be due to a higher proportion of slow-twitch fibers and/or better muscle oxygenation. To resolve this hypothesis, it is important that in future studies assessment of both muscle strength and endurance are included, in combination with muscle biopsy analysis of fiber types. Conflict of Interest Statement : H.R.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this letter; H.-J.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this letter; A.M.W.J.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this letter.
Harry R. Gosker Herman-Jan Pennings Annemie M. W. J. Schols Maastricht University Maastricht, The Netherlands
From the Authors:
We thank Gosker and colleagues for their interest in our article (1) and for presenting further data in this area. We assume that, as with our patients, ACE genotype was unrelated to disease severity as judged by lung function. We would make two comments: First, we agree entirely with the authors’ comment that “one could speculate that I is associated with enhanced improvement and/or preservation of endurance and D with better improvement and/or preservation of muscle strength”; indeed there is a wealth of data to support this view (2–6). Second, the data they present supports a role for the D allele in preserving muscle function: peak workload among I-allele carriers was lower than those of DD genotype (statistical significance possibly representing lack of power). The greater rise in peak workload with training thus seems to have yielded final status remarkably similar between genotype groups. Such data might suggest that I-allele carriers had become the most detrained and therefore had the greatest capacity to improve with pulmonary rehabilitation. Clearly, exercise limitation in patients with cardiorespiratory disease is a multifactorial process and renin–angiotensin systems may be involved at a number of potentially conflicting levels. We would certainly agree that further work in this area is required to clarify the mechanisms involved. Conflict of Interest Statement : N.S.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this letter. J.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this letter. E.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this letter. A.H.N. does not have a financial relationship with a commercial entity that has an interest in the subject of this letter. W.D.-C.M. has received assistance for travel to international conferences from Schering-Plough, GlaxoSmithKline, Allen & Hanbury’s, Boehringer-Ingelheim, and Bayer pharmaceutical companies. J.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this letter. H.M. is a named inventor on a patent concerning the role of RAS in metabolic efficiency, but passed this at no personal gain to a university-based company. He receives a stipend of approximately £10,000 per year from Ark Therapeutics Ltd for consultancy work relating to the use of RAS manipulation in cancer, together with stock options. His department has received unrestricted educational grants from Aventis Pharmaceuticals over the past three years. M.I.P. has received fees for lecturing from the following companies that total £2,674 (approximately US$3,700) between 2000 and 2003: Astra Zeneca, Glaxo Smith Kline, Nutricia, and Cephalon. He has also attended professional meetings (ERS, ATS, APSS) as a guest of various companies including Glaxo Wellcome, Astra Zeneca, Cephalon, 3M, and Ciba.
Correspondence
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Nicholas S. Hopkinson Annabel H. Nickol John Payne Emma Hawe William D.-C. Man John Moxham Hugh Montgomery Michael I. Polkey Royal Brompton Hospital London, United Kingdom References 1. Hopkinson NS, Nickol AH, Payne J, Hawe E, Man WD, Moxham J, Montgomery H, Polkey MI. Angiotensin converting enzyme genotype
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and strength in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004;170:395–399. Payne J, Montgomery H. The renin-angiotensin system and physical performance. Biochem Soc Trans 2003;31:1286–1289. Nazarov IB, Woods DR, Montgomery HE, Shneider OV, Kazakov VI, Tomilin NV, Rogozkin VA. The angiotensin converting enzyme I/D polymorphism in Russian athletes. Eur J Hum Genet 2001;9:797–801. Woods D, Hickman M, Jamshidi Y, Brull D, Vassiliou V, Jones A, Humphries S, Montgomery H. Elite swimmers and the D allele of the ACE I/D polymorphism. Hum Genet 2001;108:230–232. Folland J, Leach B, Little T, Hawker K, Myerson S, Montgomery H, Jones D. Angiotensin-converting enzyme genotype affects the response of human skeletal muscle to functional overload. Exp Physiol 2000;85:575– 579. Myerson S, Hemingway H, Budget R, Martin J, Humphries S, Montgomery H. Human angiotensin I-converting enzyme gene and endurance performance. J Appl Physiol 1999;87:1313–1316.
