Download Commentaries on Viewpoint: Epigenetic regulation of the ACE gene

J Appl Physiol 112: 1084 –1085, 2012;
doi:10.1152/japplphysiol.00065.2012.
Letters To The Editor
Commentaries on Viewpoint: Epigenetic regulation of the ACE gene
might be more relevant to endurance physiology than the I/D
polymorphism
EPIGENETIC REGULATION ON TOP OF THE ACE I/D
POLYMORPHISM: CAN IT EXPLAIN THE INCONSISTENCIES
REGARDING THE ASSOCIATION OF THIS POLYMORPHISM
WITH ENDURANCE PHYSIOLOGY?
A. H. Jan Danser,
Professor of Pharmacology
Erasmus MC, Rotterdam
The Netherlands
TO THE EDITOR:
REFERENCES
1 Alexiou T, Boon WM, Denton DA, Nicolantonio RD, Walker LL,
McKinley MJ, Campbell DJ. Angiotensinogen and angiotensin-converting
enzyme gene copy number and angiotensin and bradykinin peptide levels in
mice. J Hypertens 23: 945–954, 2005.
2. Danser AHJ, Batenburg WW, van den Meiracker AH, Danilov SM.
ACE phenotyping as a first step toward personalized medicine for ACE
inhibitors. Why does ACE genotyping not predict the therapeutic efficacy
of ACE inhibition? Pharmacol Ther 113: 607–618, 2007.
3. Danser AHJ, Derkx FHM, Hense HW, Jeunemaitre X, Riegger GA,
Schunkert H. Angiotensinogen (M235T) and angiotensin-converting enzyme (I/D) polymorphisms in association with plasma renin and prorenin
levels. J Hypertens 16: 1879 –1883, 1998.
4. Raleigh SM. Viewpoint: Epigenetic regulation of the ACE gene might be
more relevant to endurance physiology than the I/D polymorphism. J Appl
Physiol; doi:10.1152/japplphysiol.00828.2011.
5. Van Esch JHM, van Gool JMG, de Bruin RJA, Payne JR, Montgomery
HE, Hectors M, Deinum J, Dive V, Danser AHJ. Different contributions
1084
EPIGENETIC FACTORS AND ACE GENE I/D POLYMORPHISM
IN ENDURANCE PHYSIOLOGY
TO THE EDITOR:
Endurance physiology is a complex phenomenon controlled by many factors such as cardiovascular endurance, type of muscle fiber, total body hemoglobin, body composition, lung capacity, superior myosin-ATPase activity, calcium carrier mechanics, etc. Physical endurance is not only an
integrated outcome among cardiovascular and muscular components but also neurological. They function cooperatively to
transfer the energy efficiently from aerobic and anaerobic ATP
turnover into velocity and power.
More than 90 genes or gene variations have been identified to account for the varying levels of endurance and
strength performance and health-related fitness phenotypes
(2). Important among them is ACE, which not only controls
the circulatory system by degrading vasodilator kinins, but
also converts angiotensin I (ANG I) to the vasoconstrictor
angiotensin II (ANG II). It is also an important determinant
of muscle function (1). Nucleotide polymorphisms of local
growth factors such as neurotrophic factors and interleukin-6 genotypes are known to influence muscle strength (4,
5). Also there is ample evidence that epigenetic factors tune
gene expression and regulate their function. Pending an
exhaustive and deterministic mapping of genotypes with
associated phenotypes and predictive markers, it is sensible
to suspect an epigenetic role. Neurological factors peripherally determine motor unit recruitment. But to gain a more
profound insight into the complexities of endurance physiology, one cannot evade the epigenetic factors because they
may affect different sites and molecules, whereas the DNA
sequence might remain the same, thus altering the expected
phenotype. Raleigh (3) is reasonable in pointing to the
importance of epigenetic factors.
REFERENCES
1. Jones A, Woods DR. Skeletal muscle RAS and exercise performance. Int
J Biochem Cell Biol 35: 855–866, 2003.
2. Perusse L, Rankinen T, Rauramaa R, Rivera MA, Wolfarth B,
Bouchard C. The human gene map for performance and health-related
fitness phenotypes: the 2002 update. Med Sci Sports Exerc 35: 1248 –1264,
2003.
3. Raleigh SM. Viewpoint: Epigenetic regulation of the ACE gene might be
more relevant to endurance physiology than the I/D polymorphism. J Appl
Physiol; doi:10.1152/japplphysiol.00828.2011.
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The ACE I/D polymorphism has been inconsistently associated with many cardiovascular disorders, the
underlying concept being that the D allele associates with
higher ACE levels, thereby resulting, via enhanced angiotensin I-II conversion, in elevated angiotensin II levels. This
concept ignores the many feedback mechanisms within the
renin-angiotensin system, allowing increased angiotensin II
levels to be corrected immediately by a renin reduction (1,
3). In addition, although the DD genotype does result in a
50 – 60% rise in ACE, in both plasma and tissue, this did not
lead to increased angiotensin I-II conversion or changes in
renin (2). This implies that such conversion, which depends
entirely on tissue ACE, occurs in a highly efficient manner,
so that 50 – 60% increases in ACE have no functional
consequences. Alternatively, not all ACE may actually
“see” angiotensin I. Stuart Raleigh (4) now suggests that
epigenetic regulation of the ACE gene may explain the
inconsistencies with regard to the role of the I/D polymorphism in endurance physiology. Temporarily methylation of
the ACE gene would annihilate the D allele-related rise in
tissue ACE, without affecting circulating ACE. Because
circulating ACE is entirely derived from ACE-expressing
cells, a discrepancy between tissue and circulating ACE
levels is unlikely, if not impossible. Moreover, I/D-related
changes in ACE levels run in parallel in plasma and tissue
in all studies. Nevertheless, epigenetics should be considered in future studies, especially since the I/D polymorphism accounts for ⬍20% of ACE variability. Furthermore,
it is important to realize that ACE has two active domains
(the N- and the C-domain) capable of angiotensin I-II
conversion, which both display activity in IIs but not
DDs (5).
of the angiotensin-converting enzyme C-domain and N-domain in subjects
with the angiotensin-converting enzyme II and DD genotype. J Hypertens
26: 706 –713, 2008.
Letters To The Editor
1085
LETERS TO THE EDITOR
4. Roth SM, Schrager MA, Ferrell RE, Riechman SE, Metter EJ, Lynch
NA, Lindle RS, Hurley BF. CNTF genotype is associated with muscular
strength and quality in humans across the adult age span. J Appl Physiol 90:
1205–1210, 2001.
5. Roth SM, Schrager MA, Lee MR, Metter EJ, Hurley BF, Ferrell RE.
Interleukin-6 (IL6) genotype is associated with fat-free mass in men but
not women. J Geront A Biol Sci Med Sci 58: B1085–B1088, 2003.
Mary C. Vagula,
Assistant Professor
Robert Rawding
Gannon University
INTENSE PHYSICAL ACTIVITY AND EPIGENETIC
REGULATION OF THE ACE GENE
REFERENCES
1. Amir O, Amir R, Yamin C, Attias E, Eynon N, Sagiv M, Meckel Y. The
ACE deletion allele is associated with Israeli elite endurance athletes. Exp
Physiol 92: 881–886, 2007.
2. Calvanese V, Fernandez AF, Urdinguio RG, Suarez-Alvarez B, Mangas
C, Perez-Garcia V, Bueno C, Montes R, Ramos-Mejia V, MartinezCamblor P, Ferrero C, Assenov Y, Bock C, Menendez P, Carrera AC,
Lopez-Larrea C, Fraga MF. A promoter DNA demethylation landscape
of human hematopoietic differentiation. Nucleic Acids Res 40: 116 –131,
2011.
3. Feil R, Fraga MF. Epigenetics and the environment: emerging patterns and
implications. Nat Rev Genet 13: 97–109, 2012.
4. Puthucheary Z, Skipworth JR, Rawal J, Loosemore M, Van Someren
K, Montgomery HE. The ACE gene and human performance: 12 years on.
Sports Med 41: 433–448, 2011.
Mario F. Fraga,
Group Leader
Agustin F. Fernandez
IUOPA and CNB-CSIC
TO THE EDITOR: Several studies have suggested that the I-allele
of the human angiotensin I-converting enzyme (ACE) gene
polymorphism may be associated with endurance performance
(3). Such studies are prone to difficulties in comparison,
because the definition of the “elite athlete” and the heterogeneity of the elite athlete phenotype may be variable. It is not
clear how the ACE I/D polymorphism contributes to the
enzyme level, nevertheless, in some cases it is known that the
D allele mRNA is more abundant that the I allele mRNA (5).
One of the ways that I/D polymorphism can affect the ACE
gene’s expression is if one or both of its alleles are in genetic
linkage with promoter sequence variants that render the respective promoter amenable to methylation, which can also be cell
specific. In such case, the I/D polymorphism and the epigenetics in the ACE gene are complementary genetic entities that, in
concert, can affect ACE expression. In two studies in neonates,
a population naive to after-birth epigenetic mechanisms, an
association of I/I ACE genotype with respiratory muscle performance (1) and an association of the D-allele of ACE
genotype with increased circulating ACE activity (2) was
revealed. In conclusion, I personally agree with Dr Raleigh’s
(4) view that the effect of epigenetic regulation of the ACE
gene on modifying human endurance should be investigated;
however, until this issue is clarified, I think that the right title
of this Viewpoint should be “The relevance of the ACE gene
epigenetic regulation to endurance physiology.”
REFERENCES
1. Dimitriou G, Papakonstantinou D, Stavrou EF, Tzifas S, Vervenioti A,
Athanassiadou A, Mantagos S. Angiotensin-converting enzyme gene
polymorphism and respiratory muscle function in infants. Pediatr Pulmonol
45: 1233–1239, 2010.
2. Dimitriou G, Papakonstantinou D, Stavrou EF, Tzifas S, Vervenioti A,
Onufriou A, Athanassiadou A, Mantagos S. Association of circulating
angiotensin converting enzyme activity with respiratory muscle function in
infants. Respir Res 11: 57, 2010.
3. Puthucheary Z, Skipworth JR, Rawal J, Loosemore M, Van Someren
K, Montgomery HE. The ACE gene and human performance: 12 years on.
Sports Med 41: 433–448, 2011.
4. Raleigh SM. Viewpoint: Epigenetic regulation of the ACE gene might be
more relevant to endurance physiology than the I/D polymorphism. J Appl
Physiol; doi:10.1152/japplphysiol.00828.2011.
5. Suehiro T, Morita T, Inoue M, Kumon Y, Ikeda Y, Hashimoto K.
Increased amount of the angiotensin-converting enzyme (ACE) mRNA
originating from the ACE allele with deletion. Hum Genet 115: 91–96,
2004.
Gabriel Dimitriou,
Professor in Pediatrics & Neonatology
University of Patras
School of Medicine
Patras, Greece
J Appl Physiol • doi:10.1152/japplphysiol.00065.2012 • www.jappl.org
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TO THE EDITOR: In general, the factors involved in extreme
exercise capacity are still poorly understood. It has been
proposed that polymorphism at the angiotensin converting
enzyme (ACE) might play an important role (4). However,
the relationship between ACE genetic variants and endurance is variable (1), and the underlying molecular mechanisms are still poorly understood (5). In this issue of Journal
of Applied Physiology, Stuart M. Raleigh (5) proposes that
THE epigenetic factors could explain this variable relationship. Because the environmental conditions can affect epigenetics (3), the ACE gene could represent a fascinating
opportunity to study the relative contribution of intrinsic
(genetic) and extrinsic factors in modeling the organismal
phenotype. We agree that it is very interesting to determine
whether epigenetic regulation of the ACE gene is specifically involved in modifying human endurance. However, we
believe that establishing the epigenetic status of the ACE
gene in participants involved in endurance is not trivial. As
stated by Raleigh, tissue-specific methylation of the ACE
gene would make it necessary to analyze different tissues
(2), some of which are not available from healthy individuals. In addition, the analysis of other epigenetic marks such
as histone modifications requires types of samples that are
not possible to obtain in this type of study. Thus we propose
that, in addition to studies in humans, animal models must
be used to determine the role of epigenetic factors in the
regulation of the ACE gene in endurance.
5. Raleigh SM. Viewpoint: Epigenetic regulation of the ACE gene might be
more relevant to endurance physiology than the I/D polymorphism. J Appl
Physiol; doi:10.1152/japplphysiol.00828.2011.