Sports Medicine

, Volume 41, Issue 6, pp 433–448

The ACE Gene and Human Performance

12 Years On
  • Zudin Puthucheary
  • James R. A. Skipworth
  • Jai Rawal
  • Mike Loosemore
  • Ken Van Someren
  • Hugh E. Montgomery
Review Article

Abstract

Some 12 years ago, a polymorphism of the angiotensin I-converting enzyme (ACE) gene became the first genetic element shown to impact substantially on human physical performance. The renin-angiotensin system (RAS) exists not just as an endocrine regulator, but also within local tissue and cells, where it serves a variety of functions. Functional genetic polymorphic variants have been identified for most components of RAS, of which the best known and studied is a polymorphism of the ACE gene. The ACE insertion/deletion (I/D) polymorphism has been associated with improvements in performance and exercise duration in a variety of populations. The I allele has been consistently demonstrated to be associated with endurance-orientated events, notably, in triathlons. Meanwhile, the D allele is associated with strength- and power-orientated performance, and has been found in significant excess among elite swimmers. Exceptions to these associations do exist, and are discussed.

In theory, associations with ACE genotype may be due to functional variants in nearby loci, and/or related genetic polymorphism such as the angiotensin receptor, growth hormone and bradykinin genes. Studies of growth hormone gene variants have not shown significant associations with performance in studies involving both triathletes and military recruits. The angiotensin type-1 receptor has two functional polymorphisms that have not been shown to be associated with performance, although studies of hypoxic ascent have yielded conflicting results. ACE genotype influences bradykinin levels, and a common gene variant in the bradykinin 2 receptor exists. The high kinin activity haplotye has been associated with increased endurance performance at an Olympic level, and similar results of metabolic efficiency have been demonstrated in triathletes.

Whilst the ACE genotype is associated with overall performance ability, at a single organ level, the ACE genotype and related polymorphism have significant associations. In cardiac muscle, ACE genotype has associations with left ventricular mass changes in response to stimulus, in both the health and diseased states. The D allele is associated with an exaggerated response to training, and the I allele with the lowest cardiac growth response. In light of the I-allele association with endurance performance, it seems likely that other regulatory mechanisms exist. Similarly in skeletal muscle, the D allele is associated with greater strength gains in response to training, in both healthy individuals and chronic disease states. As in overall performance, those genetic polymorphisms related to the ACE genotype, such as the bradykinin 2 gene, also influence skeletal muscle strength.

Finally, the ACE genotype may influence metabolic efficiency, and elite mountaineers have demonstrated an excess of I alleles and I/I genotype frequency in comparison to controls. Interestingly, this was not seen in amateur climbers. Corroboratory evidence exists among high-altitude settlements in both South America and India, where the I allele exists in greater frequency in those who migrated from the lowlands. Unfortunately, if the ACE genotype does influence metabolic efficiency, associations with peak maximal oxygen consumption have yet to be rigorously demonstrated.

The ACE genotype is an important but single factor in the determinant of sporting phenotype. Much of the mechanisms underlying this remain unexplored despite 12 years of research.

References

  1. 1.
    Montgomery HE, Marshall R, Marshall R, et al. Human gene for physical performance. Nature 1998; 393 (6682): 221–2PubMedCrossRefGoogle Scholar
  2. 2.
    Timmermans PB, Smith RD. Angiotensin II receptor subtypes: selective antagonists and functional correlates. Eur Heart J 1994; 15 Suppl.D: 79–87PubMedCrossRefGoogle Scholar
  3. 3.
    Dendorfer A, Wolfrum S, Wolfrum S, et al. Pathways of bradykinin degradation in blood and plasma of normotensiveand hypertensive rats. Am J Physiol Heart Circ Physiol 2001; 280 (5): H2182–8Google Scholar
  4. 4.
    Regoli D, Nsa Allogho S, Rizzi A, et al. Bradykinin receptors and their antagonists. Eur J Pharmacol 1998; 348 (1): 1–10PubMedCrossRefGoogle Scholar
  5. 5.
    Brown NJ, Blais Jr C, Gandhi SK, et al. ACE insertion/ deletion genotype affects bradykinin metabolism. J Cardiovasc Pharmacol 1998; 32 (3): 373–7PubMedCrossRefGoogle Scholar
  6. 6.
    Murphey LJ, Gainer JV, Vaughan DE, et al. Angiotensinconverting enzyme insertion/deletion polymorphismmodulates the human in vivo metabolism of bradykinin. Circulation 2000; 102 (8): 829–32PubMedCrossRefGoogle Scholar
  7. 7.
    Kem DC, Brown RD. Renin: from beginning to end. N Engl J Med 1990; 323 (16): 1136–7PubMedCrossRefGoogle Scholar
  8. 8.
    Dzau VJ. Multiple pathways of angiotensin production in the blood vessel wall: evidence, possibilities and hypotheses. J Hypertens 1989; 7 (12): 933–6PubMedCrossRefGoogle Scholar
  9. 9.
    Nazarov IB, Woods DR, Montgomery HE, et al. The angiotensin converting enzyme I/D polymorphism inRussian athletes. Eur J Hum Genet 2001; 9 (10): 797–801PubMedCrossRefGoogle Scholar
  10. 10.
    Paul M, Poyan Mehr A, Kreutz R. Physiology of local renin-angiotensin systems. Physiol Rev 2006; 86 (3): 747–803PubMedCrossRefGoogle Scholar
  11. 11.
    Rigat B, Hubert C, Alhenc-Gelas F, et al. An insertion/deletion polymorphism in the angiotensin I-convertingenzyme gene accounting for half the variance of serumenzyme levels. J Clin Invest 1990; 86 (4): 1343–6PubMedCrossRefGoogle Scholar
  12. 12.
    Costerousse O, Allegrini J, Lopez M, et al. Angiotensin Iconverting enzyme in human circulating mononuclearcells: genetic polymorphism of expression in T-lymphocytes. Biochem J 1993; 290 (Pt1): 33–40PubMedGoogle Scholar
  13. 13.
    Danser AH, Schalekamp MA, Bax WA, et al. Angiotensinconverting enzyme in the human heart: effect of the deletion/insertion polymorphism. Circulation 1995; 92 (6): 1387–8PubMedCrossRefGoogle Scholar
  14. 14.
    Villard E, Tiret L, Visvikis S, et al. Identification of new polymorphisms of the angiotensin I-converting enzyme(ACE) gene, and study of their relationship to plasmaACE levels by two-QTL segregation-linkage analysis. AmJ Hum Genet 1996; 58 (6): 1268–78Google Scholar
  15. 15.
    Jeunemaitre X, Lifton RP, Hunt SC, et al. Absence of linkage between the angiotensin converting enzyme locusand human essential hypertension. Nat Genet 1992; 1 (1): 72–5PubMedCrossRefGoogle Scholar
  16. 16.
    Jeunemaitre X, Rigat B, Charru A, et al. Sib pair linkage analysis of renin gene haplotypes in human essential hypertension. Hum Genet 1992; 88 (3): 301–6PubMedCrossRefGoogle Scholar
  17. 17.
    Jeunemaitre X, Soubrier F, Kotelevtsev YV, et al. Molecular basis of human hypertension: role of angiotensinogen. Cell 1992; 71 (1): 169–80PubMedCrossRefGoogle Scholar
  18. 18.
    Ishigami T, Umemura S, Tamura K, et al. Essential hypertension and 50 upstream core promoter region of humanangiotensinogen gene. Hypertension 1997; 30 (6): 1325–30PubMedCrossRefGoogle Scholar
  19. 19.
    Sato N, Katsuya T, Rakugi H, et al. Association of variants in critical core promoter element of angiotensinogen genewith increased risk of essential hypertension in Japanese. Hypertension 1997; 30 (3Pt1): 321–5PubMedCrossRefGoogle Scholar
  20. 20.
    Inoue I, Nakajima T, Williams CS, et al. A nucleotide substitution in the promoter of human angiotensinogen isassociated with essential hypertension and affects basaltranscription in vitro. J Clin Invest 1997; 99 (7): 1786–97PubMedCrossRefGoogle Scholar
  21. 21.
    Paillard F, Chansel D, Brand E, et al. Genotype-phenotype relationships for the renin-angiotensin-aldosterone systemin a normal population. Hypertension 1999; 34 (3): 423–9PubMedCrossRefGoogle Scholar
  22. 22.
    Mansego ML, Redon J, Marin R, et al. Renin polymorphisms and haplotypes are associated with bloodpressure levels and hypertension risk in postmenopausalwomen. J Hypertens 2008; 26 (2): 230–7PubMedCrossRefGoogle Scholar
  23. 23.
    Poirier O, Georges JL, Ricard S, et al. New polymorphisms of the angiotensin II type 1 receptor gene and their associationswith myocardial infarction and blood pressure:the ECTIM study. Etude Cas-Temoin de l’Infarctus duMyocarde J Hypertens 1998; 16 (10): 1443–7Google Scholar
  24. 24.
    Miller JA, Thai K, Scholey JW. Angiotensin II type 1 receptor gene polymorphism predicts response to losartanand angiotensin II. Kidney Int 1999; 56 (6): 2173–80PubMedCrossRefGoogle Scholar
  25. 25.
    Bonnardeaux A, Davies E, Jeunemaitre X, et al. Angiotensin II type 1 receptor gene polymorphisms in humanessential hypertension. Hypertension 1994; 24 (1): 63–9PubMedCrossRefGoogle Scholar
  26. 26.
    Martin MM, Elton TS. The sequence and genomic organization of the human type 2 angiotensin II receptor. Biochem Biophys Res Commun 1995; 209 (2): 554–62PubMedCrossRefGoogle Scholar
  27. 27.
    Alhenc-Gelas F, Richard J, Courbon D, et al. Distribution of plasma angiotensin I-converting enzyme levels inhealthymen: relationship to environmental and hormonalparameters. J Lab Clin Med 1991; 117 (1): 33–9PubMedGoogle Scholar
  28. 28.
    Woods D, Onambele G, Woledge R, et al. Angiotensin-I converting enzyme genotype-dependent benefit fromhormone replacement therapy in isometric musclestrength and bone mineral density. J Clin Endocrinol Metab 2001; 86 (5): 2200–4PubMedCrossRefGoogle Scholar
  29. 29.
    Myerson S, Hemingway H, Budget R, et al. Human angiotensin I-converting enzyme gene and enduranceperformance. J Appl Physiol 1999; 87 (4): 1313–6PubMedGoogle Scholar
  30. 30.
    Tsianos G, Sanders J, Dhamrait S, et al. The ACE gene insertion/deletion polymorphism and elite enduranceswimming. Eur J Appl Physiol 2004; 92 (3): 360–2PubMedCrossRefGoogle Scholar
  31. 31.
    Gayagay G, Yu B, Hambly B, et al. Elite endurance athletes and the ACE I allele: the role of genes in athleticperformance. Hum Genet 1998; 103 (1): 48–50PubMedCrossRefGoogle Scholar
  32. 32.
    Alvarez R, Terrados N, Ortolano R, et al. Genetic variation in the renin-angiotensin system and athletic performance. Eur J Appl Physiol 2000; 82 (1-2): 117–20PubMedCrossRefGoogle Scholar
  33. 33.
    Collins M, Xenophontos SL, Cariolou MA, et al. The ACE gene and endurance performance during the South African Ironman Triathlons. Med Sci Sports Exerc 2004; 36 (8): 1314–20PubMedCrossRefGoogle Scholar
  34. 34.
    Woods D, Hickman M, Jamshidi Y, et al. Elite swimmers and the D allele of the ACE I/D polymorphism. Hum Genet 2001; 108 (3): 230–2PubMedCrossRefGoogle Scholar
  35. 35.
    Costa A, Silva A, Garrido N, et al. Association between ACE D allele and elite short distance swimming. EurJ Appl Physiol 2009; 106 (6): 785–90CrossRefGoogle Scholar
  36. 36.
    Rankinen T, Wolfarth B, Simoneau JA, et al. No association between the angiotensin-converting enzyme IDpolymorphism and elite endurance athlete status. J Appl Physiol 2000; 88 (5): 1571–5PubMedGoogle Scholar
  37. 37.
    Montgomery H, Dhamrait S. ACE genotype and performance. J Appl Physiol 2002; 92 (4): 1774–5; author reply1776-7PubMedGoogle Scholar
  38. 38.
    Woods DR, Humphries SE, Montgomery HE. The ACE I/D polymorphism and human physical performance. Trends Endocrinol Metab 2000; 11 (10): 416–20PubMedCrossRefGoogle Scholar
  39. 39.
    Sonna LA, Sharp MA, Knapik JJ, et al. Angiotensinconverting enzyme genotype and physical performanceduring US Army basic training. J Appl Physiol 2001; 91 (3): 1355–63PubMedGoogle Scholar
  40. 40.
    Karjalainen J, Kujala UM, Stolt A, et al. Angiotensinogen gene M235T polymorphism predicts left ventricular hypertrophyin endurance athletes. J Am Coll Cardiol 1999; 34 (2): 494–9PubMedCrossRefGoogle Scholar
  41. 41.
    Taylor RR, Mamotte CD, Fallon K, et al. Elite athletes and the gene for angiotensin-converting enzyme. J Appl Physiol 1999; 87 (3): 1035–7PubMedGoogle Scholar
  42. 42.
    Amir O, Amir R, Yamin C, et al. The ACE deletion allele is associated with Israeli elite endurance athletes. Exp Physiol 2007; 92 (5): 881–6PubMedCrossRefGoogle Scholar
  43. 43.
    Zoossmann-Diskin A. The association of the ACE gene and elite athletic performance in Israel may be an artifact. Exp Physiol 2008; 93 (11): 1220; author reply 1221PubMedCrossRefGoogle Scholar
  44. 44.
    Kim CH, Cho JY, Jeon JY, et al. ACE DD genotype is unfavorable to Korean short-term muscle power athletes. Int J Sports Med 2010; 31 (1): 65–71PubMedCrossRefGoogle Scholar
  45. 45.
    Cam FS, Colakoglu M, Sekuri C, et al. Association between the ACE I/D gene polymorphism and physicalperformance in a homogeneous non-elite cohort. Can JAppl Physiol 2005; 30 (1): 74–86CrossRefGoogle Scholar
  46. 46.
    Cerit M, Colakoglu M, Erdogan M, et al. Relationship between ace genotype and short duration aerobic performancedevelopment. Eur J Appl Physiol 2006; 98 (5): 461–5PubMedCrossRefGoogle Scholar
  47. 47.
    Colakoglu M, Cam FS, Kayitken B, et al. ACE genotype may have an effect on single versus multiple set preferencesin strength training. Eur J Appl Physiol 2005; 95 (1): 20–6PubMedCrossRefGoogle Scholar
  48. 48.
    Juffer P, Furrer R, Gonzalez-Freire M, et al. Genotype distributions in top-level soccer players: a role for ACE? Int J Sports Med 2009; 30 (5): 387–92PubMedCrossRefGoogle Scholar
  49. 49.
    Lucia A, Gomez-Gallego F, Chicharro JL, et al. Is there an association between ACE and CKMM polymorphismsand cycling performance status during 3-week races? Int J Sports Med 2005; 26 (6): 442–7PubMedCrossRefGoogle Scholar
  50. 50.
    Muniesa CA, Gonzalez-Freire M, Santiago C, et al. Worldclass performance in lightweight rowing: is it geneticallyinfluenced? A comparison with cyclists, runners and nonathletes. Br J Sports Med 2010; 44 (12): 898–901PubMedCrossRefGoogle Scholar
  51. 51.
    Winnicki M, Accurso V, Hoffmann M, et al. Physical activity and angiotensin-converting enzyme gene polymorphismin mild hypertensives. Am J Med Genet A 2004; 125A (1): 38–44PubMedCrossRefGoogle Scholar
  52. 52.
    Costa AM, Silva AJ, Garrido ND, et al. Association between ACE D allele and elite short distance swimming. Eur J Appl Physiol 2009; 106 (6): 785–90PubMedCrossRefGoogle Scholar
  53. 53.
    Giaccaglia V, Nicklas B, Kritchevsky S, et al. Interaction between angiotensin converting enzyme insertion/deletiongenotype and exercise training on knee extensor strengthin older individuals. Int J Sports Med 2008; 29 (1): 40–4PubMedCrossRefGoogle Scholar
  54. 54.
    Zhao B, Moochhala SM, Tham S, et al. Relationship between angiotensin-converting enzyme ID polymorphismand VO(2max) of Chinese males. Life Sci 2003; 73 (20): 2625–30PubMedCrossRefGoogle Scholar
  55. 55.
    Tsianos G, Eleftheriou KI, Hawe E, et al. Performance at altitude and angiotensin I-converting enzyme genotype. Eur J Appl Physiol 2005; 93 (5-6): 630–3PubMedCrossRefGoogle Scholar
  56. 56.
    Hruskovicova H, Dzurenkova D, Selingerova M, et al. The angiotensin converting enzyme I/D polymorphism in longdistance runners. J Sports Med Phys Fitness 2006; 46 (3): 509–13PubMedGoogle Scholar
  57. 57.
    Cieszczyk P, Krupecki K, Maciejewska A, et al. The angiotensin converting enzyme gene I/D polymorphism inpolish rowers. Int J Sports Med 2009; 30 (8): 624–7PubMedCrossRefGoogle Scholar
  58. 58.
    Min SK, Takahashi K, Ishigami H, et al. Is there a gender difference between ACE gene and race distance? Appl Physiol Nutr Metab 2009; 34 (5): 926–32PubMedCrossRefGoogle Scholar
  59. 59.
    Cam S, Colakoglu M, Colakoglu S, et al. ACE I/D gene polymorphism and aerobic endurance development inresponse to training in a non-elite female cohort. J Sports Med Phys Fitness 2007; 47 (2): 234–8PubMedGoogle Scholar
  60. 60.
    Moran CN, Vassilopoulos C, Tsiokanos A, et al. The associations of ACE polymorphisms with physical, physiological and skill parameters in adolescents. Eur J Hum Genet 2006; 14 (3): 332–9PubMedCrossRefGoogle Scholar
  61. 61.
    Thompson J, Raitt J, Hutchings L, et al. Angiotensinconverting enzyme genotype and successful ascent to extremehigh altitude. High Alt Med Biol 2007; 8 (4): 278–85PubMedCrossRefGoogle Scholar
  62. 62.
    Hurlbut DE, Lott ME, Ryan AS, et al. Does age, sex, or ACE genotype affect glucose and insulin responses tostrength training? J Appl Physiol 2002; 92 (2): 643–50PubMedGoogle Scholar
  63. 63.
    Dekany M, Harbula I, Berkes I, et al. The role of insertion allele of angiotensin converting enzyme gene in higherendurance efficiency and some aspects of pathophysio-logical and drug effects. Curr Med Chem 2006; 13 (18): 2119–26PubMedCrossRefGoogle Scholar
  64. 64.
    Williams AG, Rayson MP, Jubb M, et al. The ACE gene and muscle performance [letter]. Nature 2000; 403 (6770): 614PubMedGoogle Scholar
  65. 65.
    Kritchevsky SB, Nicklas BJ, Visser M, et al. Angiotensinconverting enzyme insertion/deletion genotype, exercise,and physical decline. JAMA 2005; 294 (6): 691–8PubMedCrossRefGoogle Scholar
  66. 66.
    Goh KP, Chew K, Koh A, et al. The relationship between ACE gene IDpolymorphism and aerobic capacity in Asianrugby players. Singapore Med J 2009; 50 (10): 997–1003PubMedGoogle Scholar
  67. 67.
    Turgut G, Turgut S, Genc O, et al. The angiotensin converting enzyme I/D polymorphism in Turkish athletes andsedentary controls. Acta Medica (Hradec Kralove) 2004; 47 (2): 133–6Google Scholar
  68. 68.
    Scott RA, Irving R, Irwin L, et al. ACTN3 and ACE genotypes in elite Jamaican and US sprinters. Med Sci Sports Exerc 2010; 42 (1): 107–12PubMedCrossRefGoogle Scholar
  69. 69.
    Frederiksen H, Bathum L, Worm C, et al. ACE genotype and physical training effects: a randomized study amongelderly Danes. Aging Clin Exp Res 2003; 15 (4): 284–91PubMedGoogle Scholar
  70. 70.
    Scott RA, Moran C, Wilson RH, et al. No association between angiotensin converting enzyme (ACE) gene variationand endurance athlete status in Kenyans. Comp Biochem Physiol A Mol Integr Physiol 2005; 141 (2): 169–75PubMedCrossRefGoogle Scholar
  71. 71.
    Day SH, Gohlke P, Dhamrait SS, et al. No correlation between circulating ACE activity and. VO2max or mechanicalefficiency in women Eur J Appl Physiol 2007; 99 (1): 11–8PubMedGoogle Scholar
  72. 72.
    Oh SD. The distribution of I/D polymorphism in the ACE gene among Korean male elite athletes. J Sports Med Phys Fitness 2007; 47 (2): 250–4PubMedGoogle Scholar
  73. 73.
    Papadimitriou ID, Papadopoulos C, Kouvatsi A, et al. The ACE I/D polymorphism in elite Greek track and fieldathletes. J Sports Med Phys Fitness 2009; 49 (4): 459–63PubMedGoogle Scholar
  74. 74.
    Thomis MA, Huygens W, Heuninckx S, et al. Exploration of myostatin polymorphisms and the angiotensin-convertingenzyme insertion/deletion genotype in responsesof human muscle to strength training. Eur J Appl Physiol 2004; 92 (3): 267–74PubMedCrossRefGoogle Scholar
  75. 75.
    McCauley T, Mastana SS, Hossack J, et al. Human angiotensin-converting enzyme I/D and alpha-actinin 3R577X genotypes and muscle functional and contractileproperties. Exp Physiol 2009; 94 (1): 81–9PubMedCrossRefGoogle Scholar
  76. 76.
    Bennani-Baiti IM, Jones BK, Liebhaber SA, et al. Physical linkage of the human growth hormone gene cluster andthe skeletal muscle sodium channel alpha-subunit gene(SCN4A) on chromosome 17. Genomics 1995; 29 (3): 647–52PubMedCrossRefGoogle Scholar
  77. 77.
    Hasegawa Y, Fujii K, Yamada M, et al. Identification of novel human GH-1 gene polymorphisms that are associatedwith growth hormone secretion and height. J Clin Endocrinol Metab 2000; 85 (3): 1290–5PubMedCrossRefGoogle Scholar
  78. 78.
    Walpole B, Noakes TD, Collins M. Growth hormone 1 (GH1) gene and performance and post-race rectal temperatureduring the South African Ironman triathlon. Br J Sports Med 2006; 40 (2): 145–50; discussion 145–50PubMedCrossRefGoogle Scholar
  79. 79.
    Huang S, Chen XH, Payne JR, et al. Haplotype of growth hormone and angiotensin I-converting enzyme genes,serum angiotensin I-converting enzyme and ventriculargrowth: pathway inference in pharmacogenetics. Pharmacogenet Genomics 2007; 17 (4): 291–4PubMedCrossRefGoogle Scholar
  80. 80.
    Berge KE, Bakken A, Bohn M, et al. A DNA polymorphism at the angiotensin II type 1 receptor (AT1R) locusand myocardial infarction. Clin Genet 1997; 52 (2): 71–6PubMedCrossRefGoogle Scholar
  81. 81.
    Diet F, Graf C, Mahnke N, et al. ACE and angiotensinogen gene genotypes and left ventricular mass in athletes. Eur J Clin Invest 2001; 31 (10): 836–42PubMedCrossRefGoogle Scholar
  82. 82.
    Delmonico MJ, Ferrell RE, Meerasahib A, et al. Blood pressure response to strength training may be influencedby angiotensinogen A-20C and angiotensin II type I receptorA1166C genotypes in older men and women. J Am Geriatr Soc 2005; 53 (2): 204–10PubMedCrossRefGoogle Scholar
  83. 83.
    Fatini C, Guazzelli R, Manetti P, et al. RAS genes influence exercise-induced left ventricular hypertrophy: an eliteathletes study. Med Sci Sports Exerc 2000; 32 (11): 1868–72PubMedCrossRefGoogle Scholar
  84. 84.
    Bae JS, Kang BY, Lee KO, et al. Genetic variation in the renin-angiotensin system and response to endurancetraining. Med Princ Pract 2007; 16 (2): 142–6PubMedCrossRefGoogle Scholar
  85. 85.
    Hotta J, Hanaoka M, Droma Y, et al. Polymorphisms of renin-angiotensin system genes with high-altitude pulmonaryedema in Japanese subjects. Chest 2004; 126 (3): 825–30PubMedCrossRefGoogle Scholar
  86. 86.
    Koehle MS, Wang P, Guenette JA, et al. No association between variants in the ACE and angiotensin II receptor 1genes and acute mountain sickness in Nepalese pilgrims tothe Janai Purnima Festival at 4380 m. High Alt Med Biol 2006; 7 (4): 281–9PubMedCrossRefGoogle Scholar
  87. 87.
    Houle S, Landry M, Audet R, et al. Effect of allelic polymorphism of the B(1) and B(2) receptor genes on thecontractile responses of the human umbilical vein to kinins. J Pharmacol Exp Ther 2000; 294 (1): 45–51PubMedGoogle Scholar
  88. 88.
    Lung CC, Chan EK, Zuraw BL. Analysis of an exon 1 polymorphism of the B2 bradykinin receptor gene and itstranscript in normal subjects and patients with C1 inhibitordeficiency. J Allergy Clin Immunol 1997; 99 (1Pt1): 134–46PubMedGoogle Scholar
  89. 89.
    Williams AG, Dhamrait SS, Wootton PT, et al. Bradykinin receptor gene variant and human physical performance. J Appl Physiol 2004; 96 (3): 938–42PubMedCrossRefGoogle Scholar
  90. 90.
    Saunders CJ, Xenophontos SL, Cariolou MA, et al. The bradykinin {beta}2 receptor (BDKRB2) and endothelialnitric oxide synthase 3 (NOS3) genes and endurance performanceduring ironman triathlons. Hum Mol Genet 2006; 15 (6): 979–87PubMedCrossRefGoogle Scholar
  91. 91.
    Yamin C, Amir O, Sagiv M, et al. ACE ID genotype affects blood creatine kinase response to eccentric exercise. J Appl Physiol 2007; 103 (6): 2057–61PubMedCrossRefGoogle Scholar
  92. 92.
    Liu Y, Leri A, Li B, et al. Angiotensin II stimulation in vitro induces hypertrophy of normal and postinfarcted ventricularmyocytes. Circ Res 1998; 82 (11): 1145–59PubMedCrossRefGoogle Scholar
  93. 93.
    Wollert KC, Drexler H. The renin-angiotensin system and experimental heart failure. Cardiovasc Res 1999; 43 (4): 838–49PubMedCrossRefGoogle Scholar
  94. 94.
    Danser AH, Saris JJ, Schuijt MP, et al. Is there a local renin-angiotensin system in the heart? Cardiovasc Res 1999; 44 (2): 252–65PubMedCrossRefGoogle Scholar
  95. 95.
    Schunkert H, Dzau VJ, Tang SS, et al. Increased rat cardiac angiotensin converting enzyme activity and mRNA expressionin pressure overload left ventricular hypertrophy:effects on coronary resistance, contractility, and relaxation. J Clin Invest 1990; 86 (6): 1913–20PubMedCrossRefGoogle Scholar
  96. 96.
    Beinlich CJ, White GJ, Baker KM, et al. Angiotensin II and left ventricular growth in newborn pig heart. J Mol Cell Cardiol 1991; 23 (9): 1031–8PubMedCrossRefGoogle Scholar
  97. 97.
    Schmieder RE, Martus P, Klingbeil A. Reversal of left ventricular hypertrophy in essential hypertension: a metaanalysisof randomized double-blind studies. JAMA 1996; 275 (19): 1507–13PubMedCrossRefGoogle Scholar
  98. 98.
    Cruickshank JM, Lewis J, Moore V, et al. Reversibility of left ventricular hypertrophy by differing types of antihypertensivetherapy. J Hum Hypertens 1992; 6 (2): 85–90PubMedGoogle Scholar
  99. 99.
    Schmieder RE, Schlaich MP, Klingbeil AU, et al. Update on reversal of left ventricular hypertrophy in essentialhypertension (a meta-analysis of all randomized doubleblindstudies until December 1996). Nephrol Dial Transplant 1998; 13 (3): 564–9PubMedCrossRefGoogle Scholar
  100. 100.
    Buhl R, Ersboll AK, Eriksen L, et al. Changes over time in echocardiographic measurements in young standardbredracehorses undergoing training and racing and associationwith racing performance. J Am Vet Med Assoc 2005; 226 (11): 1881–7PubMedCrossRefGoogle Scholar
  101. 101.
    Young LE. Equine athletes, the equine athlete’s heart and racing success. Exp Physiol 2003; 88 (5): 659–63PubMedCrossRefGoogle Scholar
  102. 102.
    Young LE, Rogers K, Wood JL. Left ventricular size and systolic function in thoroughbred racehorses and theirrelationships to race performance. J Appl Physiol 2005; 99 (4): 1278–85PubMedCrossRefGoogle Scholar
  103. 103.
    Montgomery HE, Clarkson P, Dollery CM, et al. Association of angiotensin-converting enzyme gene I/D polymorphismwith change in left ventricular mass in responseto physical training. Circulation 1997; 96 (3): 741–7PubMedCrossRefGoogle Scholar
  104. 104.
    Di Mauro M, Izzicupo P, Santarelli F, et al. ACE and AGTR1 polymorphisms and left ventricular hypertrophy inendurance athletes. Med Sci Sports Exerc 2010; 42 (5): 915–21PubMedCrossRefGoogle Scholar
  105. 105.
    Kasikcioglu E, Kayserilioglu A, Ciloglu F, et al. Angiotensinconverting enzyme gene polymorphism, left ventricularremodeling, and exercise capacity in strength-trainedathletes. Heart Vessels 2004; 19 (6): 287–93PubMedCrossRefGoogle Scholar
  106. 106.
    Hernandez D, de la Rosa A, Barragan A, et al. The ACE/DD genotype is associated with the extent of exercise-induced left ventricular growth in endurance athletes. J Am Coll Cardiol 2003; 42 (3): 527–32PubMedCrossRefGoogle Scholar
  107. 107.
    Lindpaintner K, Lee M, Larson MG, et al. Absence of association or genetic linkage between the angiotensinconverting-enzyme gene and left ventricular mass. N EnglJ Med 1996; 334 (16): 1023–8CrossRefGoogle Scholar
  108. 108.
    Staessen JA, Wang JG, Ginocchio G, et al. The deletion/insertion polymorphism of the angiotensin convertingenzyme gene and cardiovascular-renal risk. J Hypertens 1997; 15 (12 Pt 2): 1579–92PubMedCrossRefGoogle Scholar
  109. 109.
    Yildiz A, Akkaya V, Hatemi AC, et al. No association between deletion-type angiotensin-converting enzyme genepolymorphism and left-ventricular hypertrophy in hemodialysispatients. Nephron 2000; 84 (2): 130–5PubMedCrossRefGoogle Scholar
  110. 110.
    Dursunoglu D, Evrengul H, Tanriverdi H, et al. Angiotensin- converting enzyme polymorphism in healthyyoung subjects: relationship to left ventricular mass andfunctions. Acta Cardiol 2005; 60 (2): 153–8PubMedCrossRefGoogle Scholar
  111. 111.
    Rizzo M, Gensini F, Fatini C, et al. ACE I/D polymorphism and cardiac adaptations in adolescent athletes. Med Sci Sports Exerc 2003; 35 (12): 1986–90PubMedCrossRefGoogle Scholar
  112. 112.
    Estacio RO, Jeffers BW, Havranek EP, et al. Deletion polymorphism of the angiotensin converting enzyme geneis associated with an increase in left ventricular mass inmen with type 2 diabetes mellitus. Am J Hypertens 1999; 12 (6): 637–42PubMedCrossRefGoogle Scholar
  113. 113.
    Kuznetsova T, Staessen JA, Wang JG, et al. Antihypertensive treatment modulates the association betweenthe D/I ACE gene polymorphism and left ventricular hypertrophy:a meta-analysis. J Hum Hypertens 2000; 14 (7): 447–54PubMedCrossRefGoogle Scholar
  114. 114.
    Yoneya K, Okamoto H, Machida M, et al. Angiotensinconverting enzyme gene polymorphism in Japanesepatients with hypertrophic cardiomyopathy. Am HeartJ 1995; 130 (5): 1089–93CrossRefGoogle Scholar
  115. 115.
    Dellgren G, Eriksson MJ, Blange I, et al. Angiotensinconverting enzyme gene polymorphism influences degreeof left ventricular hypertrophy and its regression inpatients undergoing operation for aortic stenosis. AmJ Cardiol 1999; 84 (8): 909–13CrossRefGoogle Scholar
  116. 116.
    Ashley EA, Kardos A, Jack ES, et al. Angiotensin-converting enzyme genotype predicts cardiac and autonomicresponses to prolonged exercise. J Am Coll Cardiol 2006; 48 (3): 523–31PubMedCrossRefGoogle Scholar
  117. 117.
    Tanriverdi H, Evrengul H, Kaftan A, et al. Effects of angiotensin-converting enzyme polymorphism on aorticelastic parameters in athletes. Cardiology 2005; 104 (3): 113–9PubMedCrossRefGoogle Scholar
  118. 118.
    Myerson SG, Montgomery HE, Whittingham M, et al. Left ventricular hypertrophy with exercise and ACE geneinsertion/deletion polymorphism: a randomized controlledtrial with losartan. Circulation 2001; 103 (2): 226–30PubMedCrossRefGoogle Scholar
  119. 119.
    Hallberg P, Lind L, Michaelsson K, et al. B2 bradykinin receptor (B2BKR) polymorphism and change in left ventricularmass in response to anti hypertensive treatment:results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial. J Hypertens 2003; 21 (3): 621–4PubMedCrossRefGoogle Scholar
  120. 120.
    Brull D, Dhamrait S, Myerson S, et al. Bradykinin B2BKR receptor polymorphism and left-ventricular growth response. Lancet 2001; 358 (9288): 1155–6PubMedCrossRefGoogle Scholar
  121. 121.
    Folland J, Leach B, Little T, et al. Angiotensin-converting enzyme genotype affects the response of human skeletalmuscle to functional overload. Exp Physiol 2000; 85 (5): 575–9PubMedCrossRefGoogle Scholar
  122. 122.
    Williams AG, Day SH, Folland JP, et al. Circulating angiotensin converting enzyme activity is correlated withmuscle strength. Med Sci Sports Exerc 2005; 37 (6): 944–8PubMedGoogle Scholar
  123. 123.
    Hopkinson NS, Nickol AH, Payne J, et al. Angiotensin converting enzyme genotype and strength in chronicobstructive pulmonary disease. Am J Respir Crit Care Med 2004; 170 (4): 395–9PubMedCrossRefGoogle Scholar
  124. 124.
    Zhang B, Tanaka H, Shono N, et al. The I allele of the angiotensin-converting enzyme gene is associated with anincreased percentage of slow-twitch type I fibers in humanskeletal muscle. Clin Genet 2003; 63 (2): 139–44PubMedCrossRefGoogle Scholar
  125. 125.
    Caldiz CI, de Cingolani GE. Insulin resistance in adipocytes from spontaneously hypertensive rats: effect of long-term treatment with enalapril and losartan. Metabolism 1999; 48 (8): 1041–6PubMedCrossRefGoogle Scholar
  126. 126.
    Foianini KR, Steen MS, Kinnick TR, et al. Effects of exercise training and ACE inhibition on insulin action in ratskeletal muscle. J Appl Physiol 2000; 89 (2): 687–94PubMedGoogle Scholar
  127. 127.
    Henriksen EJ, Jacob S. Effects of captopril on glucose transport activity in skeletal muscle of obese Zucker rats. Metabolism 1995; 44 (2): 267–72PubMedCrossRefGoogle Scholar
  128. 128.
    Linz W, Wiemer G, Scholkens BA. Role of kinins in the pathophysiology of myocardial ischemia: in vitro andin vivo studies. Diabetes 1996; 45 Suppl.1: S51–8Google Scholar
  129. 129.
    Wicklmayr M, Dietze G, Gunther B, et al. The kallikreinkinin system and muscle metabolism—clinical aspects. Agents Actions 1980; 10 (4): 339–43PubMedCrossRefGoogle Scholar
  130. 130.
    Taguchi T, Kishikawa H, Motoshima H, et al. Involvement of bradykinin in acute exercise-induced increase of glucoseuptake and GLUT-4 translocation in skeletal muscle:studies in normal and diabetic humans and rats. Metabolism 2000; 49 (7): 920–30PubMedCrossRefGoogle Scholar
  131. 131.
    Hopkinson NS, Eleftheriou KI, Payne J, et al. +9/+9 Homozygosity of the bradykinin receptor gene polymorphismis associated with reduced fat-free mass inchronic obstructive pulmonary disease. Am J Clin Nutr 2006; 83 (4): 912–7PubMedGoogle Scholar
  132. 132.
    Wagner H, Thaller S, Dahse R, et al. Biomechanical muscle properties and angiotensin-converting enzyme gene polymorphism:a model-based study. Eur J Appl Physiol 2006; 98 (5): 507–15PubMedCrossRefGoogle Scholar
  133. 133.
    Montgomery H, Clarkson P, Clarkson P, et al. Angiotensinconverting- enzyme gene insertion/deletion polymorphismand response to physical training. Lancet 1999; 353 (9152): 541–5PubMedCrossRefGoogle Scholar
  134. 134.
    Heled Y, Moran DS, Mendel L, et al. Human ACE I/D polymorphism is associated with individual differences inexercise heat tolerance. J Appl Physiol 2004; 97 (1): 72–6PubMedCrossRefGoogle Scholar
  135. 135.
    Tanriverdi H, Evrengul H, Tanriverdi S, et al. Improved endothelium dependent vasodilation in endurance athletesand its relation with ACE I/D polymorphism. CircJ 2005; 69 (9): 1105–10CrossRefGoogle Scholar
  136. 136.
    Dengel DR, Brown MD, Ferrell RE, et al. Exercise-induced changes in insulin action are associated with ACE gene polymorphisms in older adults. Physiol Genomics 2002; 11 (2): 73–80PubMedGoogle Scholar
  137. 137.
    Woods DR, Montgomery HE. Angiotensin-converting enzyme and genetics at high altitude. High Alt Med Biol 2001; 2 (2): 201–10PubMedCrossRefGoogle Scholar
  138. 138.
    Kalson N, Thompson J, Davies A, et al. The effect of angiotensin-converting enzyme genotype on acute mountainsickness and summit success in trekkers attemptingthe summit of Mt. Kilimanjaro (5,895 m) Eur J ApplPhysiol 2009; 105 (3): 373–9Google Scholar
  139. 139.
    Dehnert C, Weymann J, Montgomery HE, et al. No association between high-altitude tolerance and the ACE I/Dgene polymorphism. Med Sci Sports Exerc 2002; 34 (12): 1928–33PubMedCrossRefGoogle Scholar
  140. 140.
    Qi Y, Niu W, Zhu T, et al. Synergistic effect of the genetic polymorphisms of the reninangiotensinaldosteronesystem on high-altitude pulmonary edema: a study fromQinghai-Tibet altitude. Eur J Epidemiol 2008; 23 (2): 143–52PubMedCrossRefGoogle Scholar
  141. 141.
    Droma Y, Hanaoka M, Basnyat B, et al. Adaptation to high altitude in sherpas: association with the insertion/deletion polymorphism in the angiotensin-convertingenzyme gene. Wilderness Environ Med 2009; 19 (1): 22–9CrossRefGoogle Scholar
  142. 142.
    Patel S, Woods DR, Macleod NJ, et al. Angiotensinconverting enzyme genotype and the ventilatory responseto exertional hypoxia. Eur Respir J 2003; 22 (5): 755–60PubMedCrossRefGoogle Scholar
  143. 143.
    Woods DR, Pollard AJ, Collier DJ, et al. Insertion/deletion polymorphism of the angiotensin I-converting enzymegene and arterial oxygen saturation at high altitude. AmJ Respir Crit Care Med 2002; 166 (3): 362–6CrossRefGoogle Scholar
  144. 144.
    Bigham AW, Kiyamu M, León-Velarde F, et al. Angiotensin- converting enzyme genotype and arterial oxygensaturation at high altitude in Peruvian Quechua. High Alt Med Biol 2008; 9 (2): 167–78PubMedCrossRefGoogle Scholar
  145. 145.
    Qadar Pasha MA, Khan AP, Kumar R, et al. Angiotensin converting enzyme insertion allele in relation to high altitudeadaptation. Ann Hum Genet 2001; 65 (6): 531–6PubMedCrossRefGoogle Scholar
  146. 146.
    Gonzalez AJ, Hernandez D, De Vera A, et al. ACE gene polymorphism and erythropoietin in endurance athletesat moderate altitude. Med Sci Sports Exerc 2006; 38 (4): 688–93PubMedCrossRefGoogle Scholar
  147. 147.
    Heled Y, Bloom MS, Wu TJ, et al. CK-MM and ACE genotypes and physiological prediction of the creatinekinase response to exercise. J Appl Physiol 2007; 103 (2): 504–10PubMedCrossRefGoogle Scholar
  148. 148.
    Di Bari M, van de Poll-Franse LV, Onder G, et al. Antihypertensive medications and differences in muscle massin older persons: the Health, Aging and Body Composition Study. J Am Geriatr Soc 2004; 52 (6): 961–6PubMedCrossRefGoogle Scholar
  149. 149.
    Levine BD. V̇O2max: what do we know, and what do westill need to know? J Physiol 2008; 586 (1): 25–34PubMedCrossRefGoogle Scholar
  150. 150.
    Hagerman FC, Connors MC, Gault JA, et al. Energy expenditure during simulated rowing. J Appl Physiol 1978; 45 (1): 87–93PubMedGoogle Scholar
  151. 151.
    Abraham MR, Olson LJ, Joyner MJ, et al. Angiotensinconverting enzyme genotype modulates pulmonary functionand exercise capacity in treated patients with congestivestable heart failure. Circulation 2002; 106 (14): 1794–9PubMedCrossRefGoogle Scholar
  152. 152.
    Hagberg JM, Ferrell RE, McCole SD, et al. VO2 max isassociated with ACE genotype in postmenopausalwomen. J Appl Physiol 1998; 85 (5): 1842–6PubMedGoogle Scholar
  153. 153.
    Roltsch MH, Brown MD, Hand BD, et al. No association between ACE I/D polymorphism and cardiovascular hemodynamicsduring exercise in young women. Int J Sports Med 2005; 26 (8): 638–44PubMedCrossRefGoogle Scholar
  154. 154.
    Woods DR, World M, Rayson MP, et al. Endurance enhancement related to the human angiotensin I-convertingenzyme I-D polymorphism is not due to differences in thecardiorespiratory response to training. Eur J Appl Physiol 2002; 86 (3): 240–4PubMedCrossRefGoogle Scholar
  155. 155.
    Bouchard C, Rankinen T, Chagnon YC, et al. Genomic scan for maximal oxygen uptake and its response totraining in the HERITAGE Family Study. J Appl Physiol 2000; 88 (2): 551–9PubMedGoogle Scholar
  156. 156.
    Bouchard C, Leon AS, Rao DC, et al. The HERITAGE family study: aims, design, and measurement protocol. Med Sci Sports Exerc 1995; 27 (5): 721–9PubMedGoogle Scholar
  157. 157.
    Zhang X, Wang C, Dai H, et al. Association between angiotensin-converting enzyme gene polymorphisms andexercise performance in patients with COPD. Respirology 2008; 13 (5): 683–8PubMedCrossRefGoogle Scholar
  158. 158.
    Kanazawa H, Otsuka T, Hirata K, et al. Association between the angiotensin-converting enzyme gene polymorphismsand tissue oxygenation during exercise inpatients with COPD. Chest 2002; 121 (3): 697–701PubMedCrossRefGoogle Scholar
  159. 159.
    Defoor J, Vanhees L, Martens K, et al. The CAREGENE study: ACE gene I/D polymorphism and effect of physicaltraining on aerobic power in coronary artery disease. Heart 2006; 92 (4): 527–8PubMedCrossRefGoogle Scholar
  160. 160.
    Welsby IJ, Podgoreanu MV, Phillips-Bute B, et al. Genetic factors contribute to bleeding after cardiac surgery. J Thromb Haemost 2005; 3 (6): 1206–12PubMedCrossRefGoogle Scholar
  161. 161.
    Harding D, Baines PB, Brull D, et al. Severity of meningococcal disease in children and the angiotensin-convertingenzyme insertion/deletion polymorphism. Am J Respir Crit Care Med 2002; 165 (8): 1103–6PubMedGoogle Scholar
  162. 162.
    Wang P, Fedoruk MN, Rupert JL. Keeping pace with ACE: are ACE inhibitors and angiotensin II type 1 receptorantagonists potential doping agents? Sports Med 2008; 38 (12): 1065–79PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2011

Authors and Affiliations

  • Zudin Puthucheary
    • 1
    • 2
  • James R. A. Skipworth
    • 1
  • Jai Rawal
    • 1
    • 2
  • Mike Loosemore
    • 2
    • 3
  • Ken Van Someren
    • 2
    • 3
  • Hugh E. Montgomery
    • 1
    • 2
  1. 1.University College London Institute for Human Health and Performance, Archway Campus, University College London, ArchwayLondonUK
  2. 2.University College London Institute for Sport, Exercise & HealthLondonUK
  3. 3.English Institute of Sport, Bisham Abbey National Sports CentreMarlowUK

Personalised recommendations