Genomics of Aerobic Capacity and Endurance Performance: Clinical Implications

  • Yannis PitsiladisEmail author
  • Guan Wang
  • Bernd Wolfarth
Part of the Molecular and Translational Medicine book series (MOLEMED)


Many reports of genetic associations with health-related fitness phenotypes have been published over the past decade or so but there has been limited progress in discovering and characterizing the genetic contribution to these phenotypes due to few coordinated research efforts involving major funding initiatives/consortia and the use primarily of the candidate gene approach. Hence, it is timely that exercise genetic research has moved into the genomics era with new approaches that involve well-phenotyped, large cohorts, and genome-wide technologies: such approaches are now known to be required for meaningful progress to be made with reference to clinical significance. This chapter summarizes the most recent and significant findings from exercise genetics and explores future trends and possibilities.


Body mass index Coronary artery disease Genome-wide ­association study Knockout Linkage disequilibrium Maximal oxygen consumption (\( \dot{\rm V}{\rm O}_{2}\max\)Odds ratio Performance-associated polymorphism Recombinant human erythropoietin One-repetition maximum Single nucleotide polymorphism Triglyceride Type 2 diabetes mellitus 


  1. 1.
    Bray MS, Hagberg JM, PÉRusse L, Rankinen T, Roth SM, Wolfarth B, et al. The human gene map for performance and health-related fitness phenotypes: the 2006–2007 update. Med Sci Sports Exerc. 2009;41:35–73.PubMedGoogle Scholar
  2. 2.
    De Moor MH, Liu YJ, Boomsma DI, Li J, Hamilton JJ, Hottenga JJ, et al. Genome-wide association study of exercise behavior in Dutch and American adults. Med Sci Sports Exerc. 2009;41:1887–95.PubMedGoogle Scholar
  3. 3.
    Klissouras V. Heritability of adaptive variation. J Appl Physiol. 1971;31:338–44.PubMedGoogle Scholar
  4. 4.
    Klissouras V, Pirnay F, Petit J-M. Adaptation to maximal effort: genetics and age. J Appl Physiol. 1973;35:288–93.PubMedGoogle Scholar
  5. 5.
    Komi P, Viitasalo J, Havu M, Thorstensson A, Sjödin B, Karlsson J. Skeletal muscle fibres and muscle enzyme activities in monozygous and dizygous twins of both sexes. Acta Physiol Scand. 1977;100:385–92.PubMedGoogle Scholar
  6. 6.
    Weber G, Kartodihardjo W, Klissouras V. Growth and physical training with reference to heredity. J Appl Physiol. 1976;40:211–5.PubMedGoogle Scholar
  7. 7.
    Kovar R. Somatotypes of twins. Acta Univ Carol Gymn. 1977;13:49–59.Google Scholar
  8. 8.
    Sklad M. Skeletal maturation in monozygotic and dizygotic twins. J Hum Evol. 1977;6:145–9.Google Scholar
  9. 9.
    Williams LRT, Gross JB. Heritability of motor skill. Acta Genet Med. 1980;29:127–36.Google Scholar
  10. 10.
    Orvanova E. Body build, heredity and sport achievements. In: Wolanki N, Siniarska A, editors. Genetics of psychomotor traits in man. Warsaw: International Society of Sport Genetics and Somatology; 1984. p. 111–23.Google Scholar
  11. 11.
    Bouchard C, Lesage R, Lortie G, Simoneau JA, Hamel P, Boulay MR, et al. Aerobic performance in brothers, dizygotic and monozygotic twins. Med Sci Sports Exerc. 1986;18:639–46.PubMedGoogle Scholar
  12. 12.
    Fagard R, Bielen E, Amery A. Heritability of aerobic power and anaerobic energy generation during exercise. J Appl Physiol. 1991;70:357–62.PubMedGoogle Scholar
  13. 13.
    Missitzi J, Geladas N, Klissouras V. Heritability in neuromuscular coordination: implications for motor control strategies. Med Sci Sports Exerc. 2004;36:233–40.PubMedGoogle Scholar
  14. 14.
    Peeters M, Thomis M, Loos RJ, Derom CA, Fagard R, Claessens AL, et al. Heritability of somatotype components: a multivariate analysis. Int J Obes (Lond). 2007;31:1295–301.Google Scholar
  15. 15.
    Missitzi J, Geladas N, Klissouras V. Genetic variation of maximal velocity and EMG activity. Int J Sports Med. 2008;29:177–81.PubMedGoogle Scholar
  16. 16.
    Bouchard C, An P, Rice T, Skinner JS, Wilmore JH, Gagnon J, et al. Familial aggregation of VO2 max response to exercise training: results from the HERITAGE Family Study. J Appl Physiol. 1999;87:1003–8.PubMedGoogle Scholar
  17. 17.
    Bouchard C, Simoneau J, Lortie G, Boulay M, Marcotte M, Thibault M. Genetic effects in human skeletal muscle fiber type distribution and enzyme activities. Can J Physiol Pharmacol. 1986;64:1245–51.PubMedGoogle Scholar
  18. 18.
    Ahmetov I, Rogozkin V. Genes, athlete status and training – an overview. Med Sport Sci. 2009;54:43–71.PubMedGoogle Scholar
  19. 19.
    Bouchard C, Dionne FT, Simoneau JA, Boulay MR. Genetics of aerobic and anaerobic performances. Exerc Sport Sci Rev. 1992;20:27–58.PubMedGoogle Scholar
  20. 20.
    Huygens W, Thomis M, Peeters M, Aerssens J, Vlietinck R, Beunen GP. Quantitative trait loci for human muscle strength: linkage analysis of myostatin pathway genes. Physiol Genomics. 2005;22:390–7.PubMedGoogle Scholar
  21. 21.
    Mars GD, Windelinckx A, Huygens W, Peeters MW, Beunen GP, Aerssens J, et al. Genome-wide linkage scan for maximum and lengthdependent knee muscle strength in young men: significant evidence for linkage at chromosome 14q24.3. J Med Genet. 2008;45:275–83.PubMedGoogle Scholar
  22. 22.
    Mars GD, Windelinckx A, Huygens W, Peeters MW, Beunen GP, Aerssens J, et al. Genome-wide linkage scan for contraction velocity characteristics of knee musculature in the Leuven Genes for Muscular Strength Study. Physiol Genomics. 2008;35:36–44.PubMedGoogle Scholar
  23. 23.
    Stubbe JH, Boomsma DI, Vink JM, Cornes BK, Martin NG, Skytthe A et al. Genetic influences on exercise participation in 37, 051 twin pairs from seven countries. PLoS One. 2006;1:e22.PubMedGoogle Scholar
  24. 24.
    Amos C. Successful design and conduct of genome-wide association studies. Hum Mol Genet. 2007;16:R220–5.PubMedGoogle Scholar
  25. 25.
    Massey D, Parkes M. Genome-wide association scanning highlights two autophagy genes, ATG16L1 and IRGM, as being significantly associated with Crohn’s disease. Autophagy. 2007;3:649–51.PubMedGoogle Scholar
  26. 26.
    Preece MA. The genetic contribution to stature. Horm Res. 1996;45 Suppl 2:56–8.PubMedGoogle Scholar
  27. 27.
    Silventoinen K, Kaprio J, Lahelma E, Koskenvuo M. Relative effect of genetic and environmental factors on body height: differences across birth cohorts among Finnish mean and women. Am J Public Health. 2000;90:627–30.PubMedGoogle Scholar
  28. 28.
    Silventoinen K, Sammalisto S, Perola M, Boomsma DI, Cornes BK, Davis C, et al. Heritability of adult body height: a comparative study of twin cohorts in eight countries. Twin Res. 2003;6:399–408.PubMedGoogle Scholar
  29. 29.
    Macgregor S, Cornes B, Martin N, Visscher P. Bias, precision and heritability of selfreported and clinically measured height in Australian twins. Hum Genet. 2006;120:571–80.PubMedGoogle Scholar
  30. 30.
    Perola M, Sammalisto S, Hiekkalinna T, Martin NG, Visscher PM, Montgomery GW, et al. Combined genome scans for body stature in 6, 602 European twins: evidence for common Caucasian loci. PLoS Genet. 2007;3:e97.PubMedGoogle Scholar
  31. 31.
    Gudbjartsson DF, Walters GB, Thorleifsson G, Stefansson H, Halldorsson BV, Zusmanovich P, et al. Many sequence variants affecting diversity of adult human height. Nat Genet. 2008;40:609–15.PubMedGoogle Scholar
  32. 32.
    Maher B. Personal genomes: the case of the missing heritability. Nature. 2008;456:18–21.PubMedGoogle Scholar
  33. 33.
    Lango Allen H, Estrada K, Guillaume L, Berndt SI, Weedon MN, Rivadeneira F, et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature. 2010;467:832–8.Google Scholar
  34. 34.
    Heger M. Sequencing genes implicated in GWAS uncovers rare variants in disease cohort. Accessed 27 July 2010.
  35. 35.
    Yang W, Kelly T, He J. Genetic epidemiology of obesity. Epidemiol Rev. 2007;29:49–61.PubMedGoogle Scholar
  36. 36.
    Dean M. Approaches to identify genes for complex human diseases: lessons from Mendelian disorders. Hum Mutat. 2003;22:261–74.PubMedGoogle Scholar
  37. 37.
    Rohde K. Genome-wide linkage analysis and association studies using SNP genotypes from the Affymetrix 10K and 100K chips. Accessed July 2010.
  38. 38.
    Hirschhorn JN, Lindgren CM, Daly MJ, Kirby A, Schaffner SF, Burtt NP, et al. Genomewide linkage analysis of stature in multiple populations reveals several regions wtih evidence of linkage to adult height. Am J Hum Genet. 2001;69:106–16.PubMedGoogle Scholar
  39. 39.
    Cowley Jr AW. The genetic dissection of essential hypertension. Genetics. 2006;7:829–40.PubMedGoogle Scholar
  40. 40.
    Lalouel JM. Large-scale search for genes predisposing to essential hypertension. Am J Hypertens. 2003;16:163–6.PubMedGoogle Scholar
  41. 41.
    Lee WK, Padmanabhan S, Dominiczak AF. Genetics of hypertension: from experimental models to clinical applications. J Hum Hypertens. 2000;14:631–47.PubMedGoogle Scholar
  42. 42.
    Lifton RP, Jeunemaitre X. Finding genes that cause human hypertension. J Hypertens. 1993;11:236–9.Google Scholar
  43. 43.
    Carlson CS, Eberle MA, Kruglyak L, Nickerson DA. Mapping complex disease loci in whole-genome association studies. Nature. 2004;429:446–52.PubMedGoogle Scholar
  44. 44.
    Bouchard C, Leon A, Rao D, Skinner J, Wilmore J, Gagnon J. The HERITAGE family study. Aims, design, and measurement protocol. Med Sci Sports Exerc. 1995;27:721–9.PubMedGoogle Scholar
  45. 45.
    Defoor J, Martens K, Matthijs G, Zieliñska D, Schepers D, Philips T, et al. The caregene study: muscle-specific creatine kinase gene and aerobic power in coronary artery disease. Eur J Cardivasc Pre Rehabil. 2005;12:415–7.Google Scholar
  46. 46.
    Gene – Exercise Research Study (GERS). Accessed 22 Oct 2010.
  47. 47.
    Wilund KR, Ferrell RE, Phares DA, Goldberg AP, Hagberg JM. Changes in high-density lipoprotein-cholesterol subfractions with exercise training may be dependent on cholesteryl ester transfer protein (CETP) genotype. Metabolism. 2002;6:774–8.Google Scholar
  48. 48.
    Phares DA, Halverstadt AA, Shuldiner AR, Ferrell RE, Douglass LW, Ryan AS, et al. Association between body fat response to exercise training and multilocus ADR genotypes. Obes Res. 2004;12:807–15.PubMedGoogle Scholar
  49. 49.
    Ghiu IA, Ferrell RE, Kulaputana O, Phares DA, Hagberg JM. Selected genetic polymorphisms and plasma coagulation factor VII changes with exercise training. J Appl Physiol. 2004;96:985–90.PubMedGoogle Scholar
  50. 50.
    McKenzie JA, Weiss EP, Ghiu IA, Kulaputana O, Phares DA, Ferrell RE, et al. Influence of the interleukin-6-174 G/C gene polymorphism on exercise training-induced changes in glucose tolerance indexes. J Appl Physiol. 2004;97:1338–42.PubMedGoogle Scholar
  51. 51.
    Weiss EP, Kulaputana O, Ghiu IA, Brandauer J, Wohn CR, Phares DA, et al. Endurance training-induced changes in the insulin response to oral glucose are associated with the peroxisome proliferator-activated receptor-gamma2 Pro12Ala genotype in men but not in women. Metabolism. 2005;54:97–102.PubMedGoogle Scholar
  52. 52.
    Halverstadt A, Phares DA, Wilund KR, Goldberg AP, Hagberg JM. Endurance exercise training raises high-density lipoprotein cholesterol and lowers small low-density lipoprotein and very low-density lipoprotein independent of body fat phenotypes in older men and women. Metabolism. 2007;56:444–50.PubMedGoogle Scholar
  53. 53.
    Obisesan TO, Ferrell RE, Goldberg AP, Phares DA, Ellis TJ, Hagberg JM. APOE genotype affects black-white responses of high-density lipoprotein cholesterol subspecies to aerobic exercise training. Metabolism. 2008;57:1669–76.PubMedGoogle Scholar
  54. 54.
    Jenkins NT, McKenzie JA, Damcott CM, Witkowski S, Hagberg JM. Endurance exercise training effects on body fatness, VO2max, HDL-C subfractions, and glucose tolerance are influenced by a PLIN haplotype in older Caucasians. J Appl Physiol. 2010;108:498–506.PubMedGoogle Scholar
  55. 55.
    Rivera MA, Dionne FT, Wolfarth B, Chagnon M, Simoneau JA, Pérusse L, et al. Muscle-specific creatine kinase gene polymorphisms in elite endurance athletes and sedentary controls. Med Sci Sports Exerc. 1997;29:1444–7.PubMedGoogle Scholar
  56. 56.
    Rankinen T, Wolfarth B, Simoneau JA, Maier-Lenz D, Rauramaa R, Rivera MA, et al. No association between the angiotensin-converting enzyme ID polymorphism and elite endurance athlete status. J Appl Physiol. 2000;88:1571–5.PubMedGoogle Scholar
  57. 57.
    Wolfarth B, Rankinen T, Mühlbauer S, Ducke M, Rauramaa R, Boulay MR, et al. Endothelial nitric oxide synthase gene polymorphism and elite endurance athlete status: the Genathlete study. Scand J Med Sci Sports. 2008;18:485–90.PubMedGoogle Scholar
  58. 58.
    Montgomery HE, Marshall R, Hemingway H, Myerson S, Clarkson P, Dollery C, et al. Human gene for physical performance. Nature. 1998;393:221–2.PubMedGoogle Scholar
  59. 59.
    Gayagay G, Yu B, Hambly B. Elite endurance athletes and the ACE I allele – the role of genes in athletic performance. Hum Genet. 1998;103:48–50.PubMedGoogle Scholar
  60. 60.
    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;87:1313–6.PubMedGoogle Scholar
  61. 61.
    Jelakovic B, Kuzmanic D, Milicic D. Influence of angiotensin converting enzyme (ACE) gene polymorphism and circadian blood pressure (BP) changes on left ventricle (LV) mass in competitive oarsmen. Am J Hypertens. 2000;13:182A.Google Scholar
  62. 62.
    Taylor R, CM CDS, Fallon K, Bockxmeer F. Elite athletes and the gene for angiotensin-converting enzyme. J Appl Physiol. 1999;87:1035–7.PubMedGoogle Scholar
  63. 63.
    Woods D, Hickman M, Jamshid Y, Brull D, Vassiliou V, Jones A, et al. Elite swimmers and the D allele of the ACE I/D polymorphism. Hum Genet. 2001;108:230–2.PubMedGoogle Scholar
  64. 64.
    Nazarov IB, Woods DR, Montgomery HE, Shneider OV, Kazakov VI, Tomilin NV, et al. The angiotensin converting enzyme I/D polymorphism in Russian athletes. Eur J Hum Genet. 2001;9:797–801.PubMedGoogle Scholar
  65. 65.
    Ahmetov II, Mozhayskaya IA, Flavell DM, Astratenkova IV, Komkova AI, Lyubaeva EV, et al. PPARa gene variation and physical performance in Russian athletes. Eur J Appl Physiol. 2006;97:103–8.PubMedGoogle Scholar
  66. 66.
    Ahmetov II, Williams AG, Popov DV, Lyubaeva EV, Hakimullina AM, Fedotovskaya ON, et al. The combined impact of metabolic gene polymorphisms on elite endurance athlete status and related phenotypes. Hum Genet. 2009;126:751–61.PubMedGoogle Scholar
  67. 67.
    Ash GI, Scott RA, Deason M, Dawson TA, Wolde B, Bekele Z, et al. No association between ACE gene variation and endurance athlete status in Ethiopians. Med Sci Sports Exerc. 2010 [Epub ahead of print], PMID: 20798657.Google Scholar
  68. 68.
    Onywera V, Scott R, Boit M, Pitsiladis Y. Demographic characteristics of elite Kenyan endurance runners. J Sports Sci. 2006;24:415–22.PubMedGoogle Scholar
  69. 69.
    Scott RA, Georgiades E, Wilson RH, Goodwin WH, Wolde B, Pitsiladis YP. Demographic characteristics of elite ethiopian endurance runners. Med Sci Sports Exerc. 2003;35:1727–32.PubMedGoogle Scholar
  70. 70.
    Scott RA, Pitsiladis YP. Genotypes and distance running: clues from Africa. Sports Med. 2007;37:1–4.Google Scholar
  71. 71.
    Moran CN, Scott RA, Adams SM. Y chromosome haplogroups of elite Ethiopian endurance runners. Hum Genet. 2004;115:492–7.PubMedGoogle Scholar
  72. 72.
    Scott RA, Wilson RH, Goodwin WH, Moran CN, Georgiades E, Wolde B, et al. Mitochondrial DNA lineages of Elite Ethiopian athletes. Comp Biochem Physiol B Biochem Mol Biol. 2005;140:497–503.PubMedGoogle Scholar
  73. 73.
    Scott RA, Moran CN, Wilson RH, Onywera V, Boit MK, Goodwin WH, et al. No association between angiotensin converting enzyme (ACE) gene variation and endurance athlete status in Kenyans. Comp Biochem Physiol A Mol Integr Physiol. 2005;141:169–75.PubMedGoogle Scholar
  74. 74.
    Gastin P. Energy system interaction and relative contribution during maximal exercise. Sports Med. 2001;31:725–41.PubMedGoogle Scholar
  75. 75.
    Yang N, MacArthur DG, Gulbin JP, Hahn AG, Beggs AH, Easteal S, et al. ACTN3 genotype is associated with human elite athletic performance. Am J Hum Genet. 2003;73:627–31.PubMedGoogle Scholar
  76. 76.
    Montgomery HE, Clarkson P, Dollery CM, Prasad K, Losi MA, Hemingway H, et al. Association of angiotensin-converting enzyme gene I/D polymorphism with change in left ventricular mass in response to physical training. Circulation. 1997;96:741–7.PubMedGoogle Scholar
  77. 77.
    Cerit M, Colakoglu M, Erdogan M, Berdeli A, Cam F. Relationship between ace genotype and short duration aerobic performance development. Eur J Appl Physiol. 2006;98:461–5.PubMedGoogle Scholar
  78. 78.
    He Z, Hu Y, Feng L, Lu Y, Liu G, Xi Y, et al. Polymorphisms in the HBB gene relate to individual cardiorespiratory adaptation in response to endurance training. Br J Sports Med. 2006;40:998–1002.PubMedGoogle Scholar
  79. 79.
    Hamilton B, Weston A. Perspectives on East African middle and long distance running. J Sci Med Sport. 2000;3:vi–viii.PubMedGoogle Scholar
  80. 80.
    Yu N, Chen FC, Ota S, Jorde LB, Pamilo P, Patthy L, et al. Larger genetic differences within Africans than between Africans and Eurasians. Genetics. 2002;161:269–74.PubMedGoogle Scholar
  81. 81.
    Burchard EG, Ziv E, Coyle N, Gomez SL, Tang H, Karter AJ, et al. The importance of race and Ethnic background in biomedical research and clinical practice. N Engl J Med. 2003;348:1170–5.PubMedGoogle Scholar
  82. 82.
    Cooper RS, Kaufman JS, Ward R. Race and genomics. N Engl J Med. 2003;348:1166–70.PubMedGoogle Scholar
  83. 83.
    Cavalli-Sforza LL, Feldman MW. The application of molecular genetic approaches to the study of human evolution. Nat Genet. 2003;33(Suppl):266–75.PubMedGoogle Scholar
  84. 84.
    International HapMap Consortium. A haplotype map of the human genome. Nature. 2005;437:1299–320.Google Scholar
  85. 85.
    Jobling MA, Hurles ME, Tyler-Smith C. Human evolutionary genetics: origins, peoples and disease. London: Garland Science Publishing; 2004. p. 523.Google Scholar
  86. 86.
    Weston AR, Mbambo Z, Myburgh KH. Running economy of African and Caucasian distance runners. Med Sci Sports Exerc. 2000;32:1130–40.PubMedGoogle Scholar
  87. 87.
    Ama PF, Simoneau JA, Boulay MR, Serresse O, Thériault G, Bouchard C. Skeletal muscle characteristics in sedentary black and Caucasian males. J Appl Physiol. 1986;61:1758–61.PubMedGoogle Scholar
  88. 88.
    Manners J. Kenya’s running tribe. Sports Hist. 1997;17:14–27.Google Scholar
  89. 89.
    Entine J. Taboo: why black athletes dominate sports and why we’re afraid to talk about it. New York: Public Affairs; 2001.Google Scholar
  90. 90.
    Larsen HB. Kenyan dominance in distance running. Comp Biochem Physiol A Mol Integr Physiol. 2003;136:161–70.PubMedGoogle Scholar
  91. 91.
    Scott RA, Pitsiladis YP. Genetics and the success of east African distance runners. Int Sports Med J. 2006;7:172–86.Google Scholar
  92. 92.
    Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest. 1990;86:1343–6.PubMedGoogle Scholar
  93. 93.
    Williams AG, Rayson MP, Jubb M, World M, Woods DR, Hayward M, et al. The ACE gene and muscle performance. Nature. 2000;403:614.PubMedGoogle Scholar
  94. 94.
    Woods DR, World M, Rayson MP, Williams AG, Jubb M, Jamshidi Y, et al. Endurance enhancement related to the human angiotensin I-converting enzyme I-D polymorphism is not due to differences in the cardiorespiratory response to training. Eur J Appl Physiol. 2002;86:240–4.PubMedGoogle Scholar
  95. 95.
    Zhang B, Tanka H, Shono N, Miura S, Kiyonaga A, Shindo M, et al. 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;63:139–44.PubMedGoogle Scholar
  96. 96.
    Collins M, Xenophontos SL, Cariolou MA, Mokone GG, Hudson DE, Anastasiades L, et al. The ACE gene and endurance performance during the South African Ironman Triathlons. Med Sci Sports Exerc. 2004;36:1314–20.PubMedGoogle Scholar
  97. 97.
    Zhao B, Moochhala SM, Tham S, Lu J, Chia M, Byrne C, et al. Relationship between angiotensin-converting enzyme ID polymorphism and VO(2max) of Chinese males. Life Sci. 2003;73:2625–30.PubMedGoogle Scholar
  98. 98.
    Hagberg JM, Ferrell RE, McCole SD, Wilund KR, Moore GE. VO2 max is associated with ACE genotype in postmenopausal women. J Appl Physiol. 1998;85:1842–6.PubMedGoogle Scholar
  99. 99.
    Scott RA, Irving R, Irwin L, Morrison E, Charlton V, Austin K, et al. ACTN3 and ACE genotypes in elite Jamaican and US sprinters. Med Sci Sports Exerc. 2010;42:107–12.PubMedGoogle Scholar
  100. 100.
    Kalson NS, Thompson J, Davies AJ, Stokes S, Earl MD, Whitehead A, et al. The effect of angiotensin-converting enzyme genotype on acute mountain sickness and summit success in trekkers attempting the summit of Mt. Kilimanjaro (5,895 m). Eur J Appl Physiol. 2009;105:373–9.PubMedGoogle Scholar
  101. 101.
    Woods DR, Brull D, Montgomery HE. Endurance and the ACE I/D polymorphism. Sci Prog. 2000;83:317–36.PubMedGoogle Scholar
  102. 102.
    Cambien F, Poirier O, Lecerf L, Evans A, Cambou JP, Arveiler D, et al. Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature. 1992;359:641–4.PubMedGoogle Scholar
  103. 103.
    Libby P. Atherosclerosis. In: BE FAS, Isselbacher KJ, Wilson JD, Martin JB, Kasper DL, Hauser SL, Longo DL, editors. Harrison’s principles of internal medicine. New York: McGraw-Hill; 1998. p. 1345–52.Google Scholar
  104. 104.
    Agerholm-Larsen B, Nordestgaard BG, Tybjaerg-Hansen A. ACE gene polymorphism in cardiovascular disease meta-analyses of small and large studies in Whites. Arterioscler Thromb Vasc Biol. 2000;20:484–92.PubMedGoogle Scholar
  105. 105.
    North KN, Yang N, Wattanasirichaigoon D, Mills M, Easteal S, Beggs AH. A common nonsense mutation results in alphaactinin-3 deficiency in the general population. Nat Genet. 1999;21:353–4.PubMedGoogle Scholar
  106. 106.
    Yang N, MacArthur DG, Wolde B, Onywera VO, Boit MK, Lau SY, et al. The ACTN3 R577X polymorphism in East and West African athletes. Med Sci Sports Exerc. 2007;39:1985–8.PubMedGoogle Scholar
  107. 107.
    Clarkson PM, Devaney JM, Gordish-Dressman H, Thompson PD, Hubal MJ, Urso M, et al. ACTN3 genotype is associated with increases in muscle strength in response to resistance training in women. J Appl Physiol. 2005;99:154–63.PubMedGoogle Scholar
  108. 108.
    Clarkson PM, Hoffman EP, Zambraski E, Gordish-Dressman H, Kearns A, Hubal M, et al. ACTN3 and MLCK genotype associations with exertional muscle damage. J Appl Physiol. 2005;99:564–9.PubMedGoogle Scholar
  109. 109.
    Delmonico MJ, Kostek MC, Doldo NA, Hand BD, Walsh S, Conway JM, et al. Alpha-actinin-3 (ACTN3) R577X polymorphism influences knee extensor peak power response to strength training in older men and women. J Gerontol A Biol Sci Med Sci. 2007;62:206–12.PubMedGoogle Scholar
  110. 110.
    Moran CN, Yang N, Bailey ME, Tsiokanos A, Jamurtas A, MacArthur DG, et al. Association analysis of the ACTN3 R577X polymorphism and complex quantitative body composition and performance phenotypes in adolescent Greeks. Eur J Hum Genet. 2007;15:88–93.PubMedGoogle Scholar
  111. 111.
    Walsh S, Liu D, Metter EJ, Ferrucci L, Roth SM. ACTN3 genotype is associated with muscle phenotypes in women across the adult age span. J Appl Physiol. 2008;105:1486–91.PubMedGoogle Scholar
  112. 112.
    Ahmetov II, Druzhevskaya AM, Astratenkova IV, Popov DV, Vinogradova OL, Rogozkin VA. The ACTN3 R577X polymorphism in Russian endurance athletes. Br J Sports Med. 2010;44:649–52.PubMedGoogle Scholar
  113. 113.
    Druzhevskaya AM, Ahmetov II, Astratenkova IV, Rogozkin VA. Association of the ACTN3 R577X polymorphism with power athlete status in Russians. Eur J Appl Physiol. 2008;103:631–4.PubMedGoogle Scholar
  114. 114.
    Niemi AK, Majamaa K. Mitochondrial DNA and ACTN3 genotypes in Finnish elite endurance and sprint athletes. Eur J Hum Genet. 2005;13:965–9.PubMedGoogle Scholar
  115. 115.
    Papadimitriou ID, Papadopoulos C, Kouvatsi A, Triantaphyllidis C. The ACTN3 gene in elite Greek track and field athletes. Int J Sports Med. 2008;29:352–5.PubMedGoogle Scholar
  116. 116.
    Roth SM, Walsh S, Liu D, Metter EJ, Ferrucci L, Hurley BF. The ACTN3 R577X nonsense allele is under-represented in elite-level strength athletes. Eur J Hum Genet. 2008;16:391–4.PubMedGoogle Scholar
  117. 117.
    MacArthur DG, Seto JT, Chan S, Quinlan KG, Raftery JM, Turner N, et al. An Actn3 knockout mouse provides mechanistic insights into the association between α-actinin-3 deficiency and human athletic performance. Hum Mol Genet. 2008;17:1076–86.PubMedGoogle Scholar
  118. 118.
    Cagliani R, Fumagalli M, Pozzoli U, Riva S, Comi GP, Torri F, et al. Diverse evolutionary histories for beta-adrenoreceptor genes in humans. Am J Hum Genet. 2009;85:64–75.PubMedGoogle Scholar
  119. 119.
    Kurnik D, Muszkat M, Li C, Sofowora GG, Solus J, Xie HG, et al. Variations in the alpha2A-adrenergic receptor gene and their functional effects. Clin Pharmacol Ther. 2006;79:173–85.PubMedGoogle Scholar
  120. 120.
    Yang-Feng TL, Xue FY, Zhong WW, Cotecchia S, Frielle T, Caron, MG, et al. Chromosomal organization of adrenergic receptor genes. Proc Natl Acad Sci U S A. 1990;87:1516–20.PubMedGoogle Scholar
  121. 121.
    Kobilka BK, Matsui H, Kobilka T-F, Francke U, Caron MG, Lefkowitz RJ, et al. Cloning, sequencing, and expression of the gene coding for the human platelet alpha 2-adrenergic receptor. Science. 1987;238:650–6.PubMedGoogle Scholar
  122. 122.
    Eisenach JH, Wittwer ED. Beta-adrenoceptor gene variation and intermediate physiological traits: prediction of distand phenotype. Exp Physiol. 2010;95:757–64.PubMedGoogle Scholar
  123. 123.
    Gauthier C, Langin D, Balligand JL. Beta3-adrenoceptors in the cardiovascular system. Trends Pharmacol Sci. 2000;21:426–31.PubMedGoogle Scholar
  124. 124.
    Chruscinski A, Brede ME, Meinel L, Lohse MJ, Kobilka BK, Hein L. Differential distribution of beta-adrenergic receptor subtypes in blood vessels of knockout mice lacking beta(1)- or beta(2)-adrenergic receptors. Mol Pharmacol. 2001;60:955–62.PubMedGoogle Scholar
  125. 125.
    Rohrer DK, Chruscinski A, Schauble EH, Bernstein D, Kobilka BK. Cardiovascular and metabolic alterations in mice lacking both beta1- and beta2-adrenergic receptors. J Biol Chem. 1999;274:16701–8.PubMedGoogle Scholar
  126. 126.
    Hoffmann C, Leitz MR, Oberdorf-Maass S, Lohse MJ, Klotz KN. Comparative pharmacology of human beta-adrenergic receptor subtypes – characterization of stably transfected receptors in CHO cells. Naunyn Schmiedebergs Arch Pharmacol. 2004;369:151–9.PubMedGoogle Scholar
  127. 127.
    Hoehe MR, Berrettini WH, Lentes KU. Dra I identifies a two allele DNA polymorphism in the human alpha 2-adrenergic receptor gene (ADRAR), using a 5.5 kb probe (p ADRAR). Nucleic Acids Res. 1988;16:9070.PubMedGoogle Scholar
  128. 128.
    Wolfarth B, Rivera MA, Oppert JM, Boulay MR, Dionne FT, Chagnon M, et al. A polymorphism in the alpha2a-adrenoceptor gene and endurance athlete status. Med Sci Sports Exerc. 2000;32:1709–12.PubMedGoogle Scholar
  129. 129.
    Rao DC, Province MA, Leppert MF, Oberman A, Heiss G, Ellison RC, et al. A genome-wide affected sibpair linkage analysis of hypertension: the HyperGEN network. Am J Hypertens. 2003;16:148–50.PubMedGoogle Scholar
  130. 130.
    Province MA, Kardia SL, Ranade K, Rao DC, Thiel BA, Cooper RS, et al. A meta-analysis of genome-wide linkage scans for hypertension: the National Heart, Lung and Blood Institute Family Blood Pressure Program. Am J Hypertens. 2003;16:144–7.PubMedGoogle Scholar
  131. 131.
    Wilk JB, Myers RH, Pankow JS, Hunt SC, Leppert MF, Freedman BI, et al. Adrenergic receptor polymorphisms associated with resting heart rate: the HyperGEN Study. Ann Hum Genet. 2006;70:566–73.PubMedGoogle Scholar
  132. 132.
    Heinonen P, Koulu M, Pesonen U, Karvonen MK, Rissanen A, Laakso M, et al. Identification of a three-amino acid deletion in the alpha2B-adrenergic receptor that is associated with reduced basal metabolic rate in obese subjects. J Clin Endocrinol Metab. 1999;84:2429–33.PubMedGoogle Scholar
  133. 133.
    Ueno LM, Frazzatto ES, Batalha LT, Trombetta IC, do Socorro BM, Irigoyen C, et al. Alpha2B-adrenergic receptor deletion polymorphism and cardiac autonomic nervous system responses to exercise in obese women. Int J Obes (Lond). 2006;30:214–20.Google Scholar
  134. 134.
    Small KM, Wagoner LE, Levin AM, Kardia SL, Liggett SB. Synergistic polymorphisms of beta1- and alpha2C-adrenergic receptors and the risk of congestive heart failure. N Engl J Med. 2002;47:1135–42.Google Scholar
  135. 135.
    Brede M, Wiesmann F, Jahns R, Hadamek K, Arnolt C, Neubauer S, et al. Feedback inhibition of catecholamine release by two different alpha2-adrenoceptor subtypes prevents progression of heart failure. Circulation. 2002;106:2491–6.PubMedGoogle Scholar
  136. 136.
    Podlowski S, Wenzel K, Luther HP, Muller J, Bramlage P, Baumann G, et al. Beta1-adrenoceptor gene variations: a role in idiopathic dilated cardiomyopathy? J Mol Med. 2000;78:87–93.PubMedGoogle Scholar
  137. 137.
    Mason DA, Moore JD, Green SA, Liggett SB. A gain-of-function polymorphism in a G-protein coupling domain of the human beta1-adrenergic receptor. J Biol Chem. 1999;274:12670–4.PubMedGoogle Scholar
  138. 138.
    Buscher R, Belger H, Eilmes KJ, Tellkamp R, Radke J, Dhein S, et al. In-vivo studies do not support a major functional role for the Gly389Arg beta 1-adrenoceptor polymorphism in humans. Pharmacogenetics. 2001;11:199–205.PubMedGoogle Scholar
  139. 139.
    Xie HG, Dishy V, Sofowora G, Kim RB, Landau R, Smiley RM, et al. Arg389Gly beta 1-adrenoceptor polymorphism varies in frequency among different ethnic groups but does not alter response in vivo. Pharmacogenetics. 2001;11:191–7.PubMedGoogle Scholar
  140. 140.
    Rathz DA, Gregory KN, Fang Y, Brown KM, Liggett SB. Hierarchy of polymorphic variation and desensitization permutations relative to beta 1- and beta 2-adrenergic receptor signaling. J Biol Chem. 2003;278:10784–9.PubMedGoogle Scholar
  141. 141.
    Stanton T, Inglis GC, Padmanabhan S, Dominiczak AF, Jardine AG, Connell JM. Variation at the beta-1 adrenoceptor gene locus affects left ventricular mass in renal failure. J Nephrol. 2002;15:512–8.PubMedGoogle Scholar
  142. 142.
    Sandilands AJ, Parameshwar J, Large S, Brown MJ, O’Shaughnessy KM. Confirmation of a role for the 389R>G beta-1 adrenoceptor polymorphism on exercise capacity in heart failure. Heart. 2005;91:1613–4.PubMedGoogle Scholar
  143. 143.
    Moore JD, Mason DA, Green SA, Hsu J, Liggett SB. Racial differences in the frequencies of cardiac beta(1)-adrenergic receptor polymorphisms: analysis of c145A>G and c1165G>C. Hum Mutat. 1999;14:271.PubMedGoogle Scholar
  144. 144.
    Borjesson M, Magnusson Y, Hjalmarson A, Andersson B. A novel polymorphism in the gene coding for the beta(1)-adrenergic receptor associated with survival in patients with heart failure. Eur Heart J. 2000;21:1853–8.PubMedGoogle Scholar
  145. 145.
    Ranade K, Jorgenson E, Sheu WH, Pei D, Hsiung CA, Chiang FT, et al. A polymorphism in the beta1 adrenergic receptor is associated with resting heart rate. Am J Hum Genet. 2002;70:935–42.PubMedGoogle Scholar
  146. 146.
    Defoor J, Martens K, Zielinska D, Matthijs G, Van NH, Schepers D, et al. The CAREGENE study: polymorphisms of the beta1-adrenoceptor gene and aerobic power in coronary artery disease. Eur Heart J. 2006;27:808–16.PubMedGoogle Scholar
  147. 147.
    Reihsaus E, Innis M, MacIntyre N, Liggett SB. Mutations in the gene encoding for the beta 2-adrenergic receptor in normal and asthmatic subjects. Am J Respir Cell Mol Biol. 1993;8:334–9.PubMedGoogle Scholar
  148. 148.
    Heckbert SR, Hindorff LA, Edwards KL, Psaty BM, Lumley T, Siscovick DS, et al. Beta2-adrenergic receptor polymorphisms and risk of incident cardiovascular events in the elderly. Circulation. 2003;107:2021–4.PubMedGoogle Scholar
  149. 149.
    Dewar JC, Wheatley AP, Venn A, Morrison JF, Britton J, Hall IP. Beta2-adrenoceptor polymorphisms are in linkage disequilibrium, but are not associated with asthma in an adult population. Clin Exp Allergy. 1998;28:442–8.PubMedGoogle Scholar
  150. 150.
    Green SA, Turki J, Innis M, Liggett SB. Amino-terminal polymorphisms of the human beta 2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry. 1994;33:9414–9.PubMedGoogle Scholar
  151. 151.
    Bruck H, Leineweber K, Beilfuss A, Weber M, Heusch G, Philipp T, et al. Genotype-dependent time course of lymphocyte beta 2-adrenergic receptor down-regulation. Clin Pharmacol Ther. 2003;74:255–63.PubMedGoogle Scholar
  152. 152.
    Meirhaeghe A, Helbecque N, Cottel D, Amouyel P. Beta2-adrenoceptor gene polymorphism, body weight, and physical activity. Lancet. 1999;353:896.PubMedGoogle Scholar
  153. 153.
    Meirhaeghe A, Helbecque N, Cottel D, Amouyel P. Impact of polymorphisms of the human beta2-adrenoceptor gene on obesity in a French population. Int J Obes Relat Metab Disord. 2000;24:382–7.PubMedGoogle Scholar
  154. 154.
    Meirhaeghe A, Luan J, Selberg-Franks P, Hennings S, Mitchell J, Halsall D, et al. The effect of the Gly16Arg polymorphism of the beta(2)-adrenergic receptor gene on plasma free fatty acid levels is modulated by physical activity. J Clin Endocrinol Metab. 2001;86:5881–7.PubMedGoogle Scholar
  155. 155.
    Wolfarth B, Rankinen T, Mühlbauer S, Scherr J, Boulay MR, Pérusse L, et al. Association between a beta2-adrenergic receptor polymorphism and elite endurance performance. Metabolism. 2007;56:1649–51.PubMedGoogle Scholar
  156. 156.
    Giacobino JP. Beta 3-adrenoceptor: an update. Eur J Endocrinol. 1995;132:377–85.PubMedGoogle Scholar
  157. 157.
    Katzmarzyk PT, Perusse L, Bouchard C. Genetics of abdominal visceral fat levels. Am J Hum Biol. 1999;11:225–35.PubMedGoogle Scholar
  158. 158.
    Widen E, Lehto M, Kanninen T, Walston J, Shuldiner AR, Groop LC. Association of a polymorphism in the beta 3-adrenergic-receptor gene with features of the insulin resistance syndrome in Finns. N Engl J Med. 1995;333:348–51.PubMedGoogle Scholar
  159. 159.
    Kahara T, Takamura T, Hayakawa T, Nagai Y, Yamaguchi H, Katsuki T, et al. Prediction of exercise-mediated changes in metabolic markers by gene polymorphism. Diabetes Res Clin Pract. 2002;57:105–10.PubMedGoogle Scholar
  160. 160.
    Allison DB, Heo M, Faith MS, Pietrobelli A. Meta-analysis of the association of the Trp64Arg polymorphism in the beta3 adrenergic receptor with body mass index. Int J Obes Relat Metab Disord. 1998;22:559–66.PubMedGoogle Scholar
  161. 161.
    Fujisawa T, Ikegami H, Kawaguchi Y, Ogihara T. Meta-analysis of the association of Trp64Arg polymorphism of beta 3-adrenergic receptor gene with body mass index. J Clin Endocrinol Metab. 1998;83:2441–4.PubMedGoogle Scholar
  162. 162.
    Kurokawa N, Nakai K, Kameo S, Liu ZM, Satoh H. Association of BMI with the beta3-adrenergic receptor gene polymorphism in Japanese: meta-analysis.9: 741–745, 2001. Obes Res. 2001;9:741–5.PubMedGoogle Scholar
  163. 163.
    Fischer H, Esbjornsson M, Sabina RL, Stromberg A, Peyrard-Janvid M, Norman B. AMP deaminase deficiency is associated with lower sprint cycling performance in healthy subjects. J Appl Physiol. 2007;103:315–22.PubMedGoogle Scholar
  164. 164.
    Morisaki T, Gross M, Morisaki H, Pongratz D, Zollner N, Holmes EW. Molecular basis of AMP deaminase deficiency in skeletal muscle. Proc Natl Acad Sci U S A. 1992;89:6457–61.PubMedGoogle Scholar
  165. 165.
    Sabina RL, Fishbein WN, Pezeshkpour G, Clarke PR, Holmes EW. Molecular analysis of the myoadenylate deaminase deficiencies. Neurology. 1992;42:170–9.PubMedGoogle Scholar
  166. 166.
    Norman B, Glenmark B, Jansson E. Muscle AMP deaminase deficiency in 2% of a healthy population. Muscle Nerve. 1995;18:239–41.PubMedGoogle Scholar
  167. 167.
    Verzijl HT, van Engelen BG, Luyten JA, Steenbergen GC, van den Heuvel LP, ter Laak HJ, et al. Genetic characteristics of myoadenylate deaminase deficiency. Ann Neurol. 1998;44:140–3.PubMedGoogle Scholar
  168. 168.
    Sabina RL, Swain JL, Olanow CW, Bradley WG, Fishbein WN, DiMauro S, et al. Myoadenylate deaminase deficiency. Functional and metabolic abnormalities associated with disruption of the purine nucleotide cycle. J Clin Invest. 1984;73:720–30.PubMedGoogle Scholar
  169. 169.
    De Ruiter CJ, May AM, van Engelen BG, Wevers RA, Steenbergen-Spanjers GC, de Haan A. Muscle function during repetitive moderateintensity muscle contractions in myoadenylate deaminase-deficient Dutch subjects. Clin Sci (Lond). 2002;102:531–9.Google Scholar
  170. 170.
    Rico-Sanz J, Rankinen T, Joanisse DR, Leon AS, Skinner JS, Wilmore JH, et al. Associations between cardiorespiratory responses to exercise and the C34T AMPD1 gene polymorphism in the HERITAGE Family Study. Physiol Genomics. 2003;14:161–6.PubMedGoogle Scholar
  171. 171.
    Rubio JC, Martin MA, Rabadan M. Frequency of the C34T mutation of the AMPD1 gene in world-class endurance athletes: does this mutation impair performance? J Appl Physiol. 2005;98:2108–12.PubMedGoogle Scholar
  172. 172.
    Lucia A, Martin MA, Esteve-Lanao J, San Juan AF, Rubio JC, Olivan J, et al. C34T mutation of the AMPD1 gene in an elite white runner. Br J Sports Med. 2006;40:e7.PubMedGoogle Scholar
  173. 173.
    Sinkeler SP, Binkhorst RA, Joosten EM, Wevers RA, Coerwinkei MM, Oei TL. AMP deaminase deficiency: study of the human skeletal muscle purine metabolism during ischaemic isometric exercise. Clin Sci (Colch). 1987;72:475–82.Google Scholar
  174. 174.
    De Ruiter CJ, Van EBG, Wevers RA, De Haan A. Muscle functionv during fatigue in myoadenylate deaminase-deficient Dutch subjects. Clin Sci (Colch). 2000;98:579–85.Google Scholar
  175. 175.
    Norman B, Sabina RL, Jansson E. Regulation of skeletal muscle ATP catabolism by AMPD1 genotype during sprint exercise in asymptomatic subjects. J Appl Physiol. 2001;91:258–64.PubMedGoogle Scholar
  176. 176.
    Tarnopolsky MA, Parise G, Gibala MJ, Graham TE, Rush JW. Myoadenylate deaminase deficiency does not affect muscle anaplerosis during exhaustive exercise in humans. J Physiol. 2001;553:881–9.Google Scholar
  177. 177.
    Pollin TI, Damcott CM, Shen HQ. A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection. Science. 2008;322:1702–5.PubMedGoogle Scholar
  178. 178.
    Woo SK, Kang HS. Apolipoprotein C-III Sstl genotypes modulate exercise-induced hypotriglyceridemia. Med Sci Sports Exerc. 2004;36:955–9.PubMedGoogle Scholar
  179. 179.
    Yoshitomi H, Yamashita K, Abe S, Tanak I. Differential regulation of mouse uncoupling proteins among brown adipose tissue, white adipose tissue, and skeletal muscle in chronic beta 3 adrenergic receptor agonist treatment. Biochem Biophys Res Commun. 1998;253:85–91.PubMedGoogle Scholar
  180. 180.
    Gleeson M, Blannin AK, Walsh NP, Field CN, Pritchard JC. Effect of exercise-induced muscle damage on the blood lactate response to incremental exercise in humans. Eur J Appl Physiol Occup Physiol. 1998;77:292–5.PubMedGoogle Scholar
  181. 181.
    Boss O, Hagen T, Lowell BB. Uncoupling proteins 2 and 3: potential regulators of mitochondrial energy metabolism. Diabetes. 2000;49:143–56.PubMedGoogle Scholar
  182. 182.
    Nedergaard J, Ricquier D, Kozak LP. Uncoupling proteins: current status and therapeutic prospects. EMBO Rep. 2005;6:917–21.PubMedGoogle Scholar
  183. 183.
    Klaus S, Casteilla L, Bouillaud F, Ricquier D. The uncouplingprotein UCP: a membraneous mitochondrial ion carrier exclusively expressed in brown adipose tissue. Int J Biochem. 1991;23:791–801.PubMedGoogle Scholar
  184. 184.
    Monemdjou S, Hofmann WE, Kozak LP, Harper ME. Increased mitochondrial proton leak in skeletal muscle mitochondria of UCP1-deficient mice. Am J Physiol Endocrinol Metab. 2000;279:E941–6.PubMedGoogle Scholar
  185. 185.
    Erlanson-Albertsson C. The role of uncoupling proteins in the regulation of metabolism. Acta Physiol Scand. 2003;178:405–12.PubMedGoogle Scholar
  186. 186.
    Klaus S, Rudolph B, Dohrmann C, Wehr R. Expression of uncoupling protein 1 in skeletal muscle decreases muscle energy efficiency and affects thermoregulation and substrate oxidation. Physiol Genomics. 2005;21:193–200.PubMedGoogle Scholar
  187. 187.
    Garruti G, Ricquier D. Analysis of uncoupling protein and its mRNA in adipose tissue deposits of adult humans. Int J Obes Relat Metab Disord. 1992;16:383–90.PubMedGoogle Scholar
  188. 188.
    Krauss S, Zhang CY, Lowell BB. The mitochondrial uncoupling-protein homologues. Nat Rev Mol Cell Biol. 2005;6:248–61.PubMedGoogle Scholar
  189. 189.
    Hawley JA, Brouns F, Jeukendrup A. Strategies to enhance fat utilisation during exercise. Sports Med. 1998;25:241–57.PubMedGoogle Scholar
  190. 190.
    Astrup A, Toubro S, Dalgaard LT, Urhammer SA, Sùrensen TIA, Pedersen O. Impact of the v/v 55 polymorphism of the uncoupling protein 2 gene on 24-h energy expenditure and substrate oxidation. Int J Obes Relat Metab Disord. 1999;23:1030–4.PubMedGoogle Scholar
  191. 191.
    Buemann B, Schierning B, Toubro S, Bibby BM, Sørensen T, Dalgaard L, et al. The association between the val/ala-55 polymorphism of the uncoupling protein 2 gene and exercise efficiency. Int J Obes Relat Metab Disord. 2001;25:467–71.PubMedGoogle Scholar
  192. 192.
    Ahmetov II, Hakimullina AM, Shikhova JV, Rogozkin VA. The ability to become an elite endurance athlete depends on the carriage of high number of endurance-related alleles. Eur J Hum Gene. 2008;16:341.Google Scholar
  193. 193.
    Halsall DJ, Luan J, Saker P. Uncoupling protein 3 genetic variants in human obesity: the c-55t promoter polymorphism is negatively correlated with body mass index in a UK Caucasian population. Int J Obes Relat Metab Disord. 2001;25:472–7.PubMedGoogle Scholar
  194. 194.
    Schrauwen P, Xia J, Walder K, Snitker S, Ravussin E. A novel polymorphism in the proximal UCP3 promoter region: effect on skeletal muscle UCP3 mRNA expression and obesity in male non-diabetic Pima Indians. Int J Obes Relat Metab Disord. 1999;23:1242–5.PubMedGoogle Scholar
  195. 195.
    Hudson DE, Mokone GG, Noakes TD, Collins M. The –55 C/T polymorphism within the UCP3 gene and performance during the South African Ironman Triathlon. Int J Sports Med. 2004;25:427–32.PubMedGoogle Scholar
  196. 196.
    Noland RC, Hickner RC, Jimenez-Linan M. Acute endurance exercise increases skeletal muscle uncoupling protein-3 gene expression in untrained but not trained humans. Metabolism. 2003;52:152–8.PubMedGoogle Scholar
  197. 197.
    Turner DC, Wallimann T, Eppenberger HM. A protein that binds specifically to the M-ine of skeletal muscle is identified as the muscle form of creatine kinase. Proc Natl Acad Sci U S A. 1972;70:702–5.Google Scholar
  198. 198.
    Wallimann T, Schlosser T, Eppenberger HM. Function of M-line-bound creatine kinase as intramyofibrillar ATP regenerator at the receiving end of the phosphorylcreatine shuttle in muscle. J Biol Chem. 1984;259:5238–46.PubMedGoogle Scholar
  199. 199.
    Holloszy JO, Coyle EF. Adaptations of skeletal muscle to endurance exercise and their metabolic consequences. J Appl Physiol. 1984;56:831–8.PubMedGoogle Scholar
  200. 200.
    Yamashita K, Yoshioka T. Profiles of creatine kinase isoenzyme compositions in single muscle fibers of different types. J Muscle Res Cell Motil. 1991;12:37–44.PubMedGoogle Scholar
  201. 201.
    van Deursen J, Heerschap A, Oeriemans F, Ruitenbeek W, Jap P, ter Laak H, et al. Skeletal muscles of mice deficient in muscle creatine kinase lack burst activity. Cell. 1993;74:621–31.PubMedGoogle Scholar
  202. 202.
    Rivera MA, Dionne FT, Simoneau JA, Pérusse L, Chagnon M, Chagnon Y, et al. Muscle-specific creatine kinase gene polymorphism and VO2max in the HERITAGE Family Study. Med Sci Sports Exerc. 1997;29:1311–7.PubMedGoogle Scholar
  203. 203.
    Rivera MA, Pérusse L, Simoneau JA, Gagnon J, Dionne FT, Leon AS, et al. Linkage between a muscle-specific CK gene marker and VO2max in the HERITAGE Family Study. Med Sci Sports Exerc. 1999;31:698–701.PubMedGoogle Scholar
  204. 204.
    Zhou DQ, Hu Y, Liu G, Gong L, Xi Y, Wen L. Muscle-specific creatine kinase gene polymorphism and running economy responses to an 18-week 5000-m training programme. Br J Sports Med. 2006;40:988–91.PubMedGoogle Scholar
  205. 205.
    Jiang BH, Rue E, Wang GL, Roe R, Semenza GL. Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1. J Biol Chem. 1996;271:17771–8.PubMedGoogle Scholar
  206. 206.
    Jiang C, Lu H, Vincent KA, Sankara S, Belanger AJ, Cheng SH, et al. Shankara S, Belanger AJ, Cheng SH, Gene expression profiles in human cardiac cells subjected to hypoxia or expressing a hybrid form of HIF-1 alpha. Physiol Genomics. 2002;8:23–32.PubMedGoogle Scholar
  207. 207.
    Semenza GL. HIF-1 and human disease: one highly involved factor. Genes Dev. 2000;14:1983–91.PubMedGoogle Scholar
  208. 208.
    Semenza GL. HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol. 2000;88:1474–80.PubMedGoogle Scholar
  209. 209.
    Jiang BH, Semenza GL, Bauer C, Marti HH. Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension. Am J Physiol. 1996;271:C1172–80.PubMedGoogle Scholar
  210. 210.
    Prior SJ, Hagberg JM, Phares DA, Brown MD, Fairfull L, Ferrell RE, et al. Sequence variation in hypoxia-inducible factor 1alpha (HIF1A): association with maximal oxygen consumption. Physiol Genomics. 2003;15:20–6.PubMedGoogle Scholar
  211. 211.
    Döring F, Onur S, Fischer A, Boulay MR, Pérusse L, Rankinen T, et al. A common haplotype and the Pro582Ser polymorphism of the hypoxia-inducible factor-1alpha (HIF1A) gene in elite endurance athletes. J Appl Physiol. 2010;108:1497–500.PubMedGoogle Scholar
  212. 212.
    Sander M, Chavoshan B, Victor RG. A large blood pressure-raising effect of nitric oxide synthase inhibition in humans. Hypertension. 1999;33:937–42.PubMedGoogle Scholar
  213. 213.
    Zatz R, Baylis C. Chronic nitric oxide inhibition model six years on. Hypertension. 1998;32:958–64.PubMedGoogle Scholar
  214. 214.
    Higashi Y, Sasaki S, Kurisu S, Yoshimizu A, Sasaki N, Matsuura H, et al. Regular aerobic exercise augments endothelium-dependent vascular relaxation in normotensive as well as hypertensive subjects: role of endothelium-derived nitric oxide. Circulation. 1999;100:1194–202.PubMedGoogle Scholar
  215. 215.
    Wang J, Wolin MS, Hintze TH. Chronic exercise enhances endothelium-mediated dilation of epicardial coronary artery in conscious dogs. Circ Res. 1993;73:829–38.PubMedGoogle Scholar
  216. 216.
    Kelley GA. Aerobic exercise and resting blood pressure among women: a meta-analysis. Prev Med. 1999;28:264–75.PubMedGoogle Scholar
  217. 217.
    Kingwell BA, Sherrard B, Jennings GL, Dart AM. Four weeks of cycle training increases basal production of nitric oxide from the forearm. Am J Physiol. 1997;272:H1070–7.PubMedGoogle Scholar
  218. 218.
    Woodman CR, Muller JM, Laughlin MH, Price EM. Induction of nitric oxide synthase mRNA in coronary resistance arteries isolated from exercise-trained pigs. Am J Physiol. 1997;273:H2575–9.PubMedGoogle Scholar
  219. 219.
    Testa M, Ennezat PV, Vikstrom KL, Demopoulos L, Gentilucci M, Loperfido F, et al. Modulation of vascular endothelial gene expression by physical training in patients with chronic heart failure. Ital Heart J. 2000;1:426–30.PubMedGoogle Scholar
  220. 220.
    Marsden PA, Heng HH, Scherer SW, Stewart RJ, Hall AV, Shi XM, et al. Structure and chromosomal localization of the human constitutive endothelial nitric oxide synthase gene. J Biol Chem. 1993;268:17478–88.PubMedGoogle Scholar
  221. 221.
    Yoshimura M, Yasue H, Nakayama M, Shimasaki Y, Ogawa H, Kugiyama K, et al. Genetic risk factors for coronary artery spasm: significance of endothelial nitric oxide synthase gene T-786–>C and missense Glu298Asp variants. J Investig Med. 2000;48:367–74.PubMedGoogle Scholar
  222. 222.
    Erbs S, Baither Y, Linke A, Adams V, Shu Y, Lenk K, et al. Promoter but not exon 7 polymorphism of endothelial nitric oxide synthase affects training-induced correction of endothelial dysfunction. Arterioscler Thromb Vasc Biol. 2003;23:1814–9.PubMedGoogle Scholar
  223. 223.
    Data SA, Roltsch MH, Hand B, Ferrell RE, Park JJ, Brown MD. eNOS T-786C genotype, physical activity, and peak forearm blood flow in females. Med Sci Sports Exerc. 2003;35:1991–7.PubMedGoogle Scholar
  224. 224.
    Kimura T, Yokoyama T, Matsumura Y, Yoshiike N, Date C, Muramatsu M, et al. NOS3 genotype-dependent correlation between blood pressure and physical activity. Hypertension. 2003;41:355–60.PubMedGoogle Scholar
  225. 225.
    Rankinen T, Rice T, Perusse L, Chagnon YC, Gagnon J, Leon AS, et al. NOS3 Glu298Asp genotype and blood pressure response to endurance training: the HERITAGE family study. Hypertension. 2000;36:885–9.PubMedGoogle Scholar
  226. 226.
    Schoonjans K, Staels B, Auwerx J. Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression. J Lipid Res. 1996;37:907–25.PubMedGoogle Scholar
  227. 227.
    Auboeuf D, Rieusset J, Fajas L, Vallier P, Frering V, Riou JP, et al. Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-a in humans: no alteration in adipose tissue of obese and NIDDM patients. Diabetes. 1997;46:1319–27.PubMedGoogle Scholar
  228. 228.
    Krey G, Braissant O, L’Horset F, Kalkhoven E, Perroud M, Parker MG, et al. Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay. Mol Endocrinol. 1997;11:779–91.PubMedGoogle Scholar
  229. 229.
    Kersten S, Desvergne B, Wahli W. Roles of PPARs in health and disease. Nature. 2000;405:421–4.PubMedGoogle Scholar
  230. 230.
    Holst D, Luquet S, Nogueira V, Kristiansen K, Leverve X, Grimaldi PA. Nutritional regulation and role of peroxisome proliferator-activated receptor δ in fatty acid catabolism in skeletal muscle. Biochim Biophys Acta. 2003;1633:43–50.PubMedGoogle Scholar
  231. 231.
    Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med. 2002;53:409–35.PubMedGoogle Scholar
  232. 232.
    Wang YX, Zhang CL, Yu RT. Regulation of muscle fiber type and running endurance by PPARδ. PLoS Biol. 2004;2:e294.PubMedGoogle Scholar
  233. 233.
    Schuler M, Ali F, Chambon C. PGC1alpha expression is controlled in skeletal muscles by PPARbeta, whose ablation results in fiber-type switching, obesity, and type 2 diabetes. Cell Metab. 2006;4:407–14.PubMedGoogle Scholar
  234. 234.
    Pilegaard H, Richter EA. PGC-1α: important for exercise performance? J Appl Physiol. 2008;104:1264–5.PubMedGoogle Scholar
  235. 235.
    Jamshidi Y, Montgomery HE, Hense HW. Peroxisome proliferator – activated receptor alpha gene regulates left ventricular growth in response to exercise and hypertension. Circulation. 2002;105:950–5.PubMedGoogle Scholar
  236. 236.
    Uthurralt J, Gordish-Dressman H, Bradbury M. PPARalpha L162V underlies variation in serum triglycerides and subcutaneous fat volume in young males. BMC Med Genet. 2007;8:55.PubMedGoogle Scholar
  237. 237.
    Russell AP, Feilchenfeldt J, Schreiber S. Endurance training in humans leads to fiber type-specific increases in levels of peroxisome proliferator-activated receptor-gamma coactivator-1 and peroxisome proliferator-activated receptor-alpha in skeletal muscle. Diabetes. 2003;52:2874–81.PubMedGoogle Scholar
  238. 238.
    Kagaya Y, Kanno Y, Takeyama D, Ishide N, Maruyama Y, Takahashi T, et al. Effects of long-term pressure overload on regional myocardial glucose and free fatty acid uptake in rats. A quantitative autoradiographic study. Circulation. 1990;81:1353–61.PubMedGoogle Scholar
  239. 239.
    Allard MF, Schonekess BO, Henning SL, English DR, Lopaschuk GD. Contribution of oxidative metabolism and glycolysis to ATP production in hypertrophied hearts. Am J Physiol Heart Circ Physiol. 1994;267:742–50.Google Scholar
  240. 240.
    Barger PM, Brandt JM, Leone TC, Weinheimer CJ, Kelly DP. Deactivation of peroxisome proliferator-activated receptor a during cardiac hypertrophic frowth. J Clin Invest. 2000;105:1723–30.PubMedGoogle Scholar
  241. 241.
    Wang YX, Lee CH, Tiep S, Yu RT, Ham J, Kang H, et al. Peroxisomeproliferator-activated receptor d activates fat metabolism to prevent obesity. Cell. 2003;113:159–70.PubMedGoogle Scholar
  242. 242.
    Tanaka T, Yamamoto J, Iwasaki S, Asaba H, Hamura H, Ikeda Y, et al. Activation of peroxisome proliferator-activated receptor d induces fatty acid b-oxidation in skeletal muscle and attenuates metabolic syndrome. Proc Natl Acad Sci U S A. 2003;100:15924–9.PubMedGoogle Scholar
  243. 243.
    Dressel U, Allen TL, Pippal JB. The peroxisome proliferator-activated receptor beta/delta agonist, GW501516, regulates the expression of genes involved in lipid catabolism and energy uncoupling in skeletal muscle cells. Mol Endocrinol. 2003;17:2477–93.PubMedGoogle Scholar
  244. 244.
    Amri EZ, Bonino F, Ailhaud G, Abumrad NA, Grimaldi PA. Cloning of a protein that mediates transcriptional effects of fatty acids in preadipocytes. J Biol Chem. 1995;270:2367–71.PubMedGoogle Scholar
  245. 245.
    Goto M, Terada S, Kato M, Katoh M, Yokozeki T, Tabata I, et al. cDNA cloning and mRNA analysis of PGC-1 in epitrochlearis muscle in swimming-exercised rats. Biochem Biophys Res Commun. 2000;274:350–4.PubMedGoogle Scholar
  246. 246.
    Ahmetov II, Astranenkova IV, Rogozkin VA. Association of PPARD gene polymorphism with human physical performance. Mol Biol (Mosk). 2007;41:852–7.Google Scholar
  247. 247.
    Hautala AJ, Leon AS, Skinner JS, Rao DC, Bouchard C, Rankinen T. Peroxisome proliferator-activated receptor-delta polymorphisms are associated with physical performance and plasma lipids: the HERITAGE Family Study. Am J Physiol Heart Circ Physiol. 2007;292:H2498–505.PubMedGoogle Scholar
  248. 248.
    Eynon N, Meckel Y, Alves AJ, Yamin C, Sagiv M, Goldhammer E, et al. Is there an interaction between PPARD T294C and PPARGC1A Gly482Ser polymorphisms and human endurance performance? Exp Physiol. 2009;94:1147–52.PubMedGoogle Scholar
  249. 249.
    Auwerx J. PPARgamma, the ultimate thrifty gene. Diabetologia. 1999;42:1033–49.PubMedGoogle Scholar
  250. 250.
    Masud S, Ye S, SAS Group. Effect of the peroxisome proliferator activated receptor-gamma gene Pro12Ala variant on body mass index: a meta-analysis. J Med Genet. 2003;40:773–80.PubMedGoogle Scholar
  251. 251.
    Yen CJ, Beamer BA, Negri C, Silver K, Brown KA, Yarnall DP, et al. Molecular scanning of the human peroxisome proliferator activated receptor-g (hPPARg) gene in diabetic Caucasians: identification of a Pro12Ala missense mutation. Biochem Biophys Res Commun. 1997;241:270–4.PubMedGoogle Scholar
  252. 252.
    Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl MC, Nemesh J, et al. The common PPAR Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet. 2000;26:76–80.PubMedGoogle Scholar
  253. 253.
    Vänttinen M, Nuutila P, Pihlajamäki J, Hällsten K, Virtanen KA, Lautamäki R, et al. The effect of the Ala12 allele of the peroxisome proliferator-activated receptor-gamma2 gene on skeletal muscle glucose uptake uepends on obesity: a positron emission tomography study. J Clin Endocrinol Metab. 2005;90:4249–54.PubMedGoogle Scholar
  254. 254.
    Nelson TL, Fingerlin TE, Moss LK, Barmada MM, Ferrell RE, Norris JM. Association of the peroxisome proliferator-activated receptor gamma gene with type 2 diabetes mellitus varies by physical activity among non-Hispanic whites from Colorado. Metabolism. 2007;56:388–93.PubMedGoogle Scholar
  255. 255.
    Hamilton B. Vitamin D and human skeletal muscle. Scand J Med Sci Sports. 2010;20:182–90.PubMedGoogle Scholar
  256. 256.
    Hoberman J. Faster, higher, stronger. A history of doping in sport. New York: The Free Press; 1992. p. 100–53.Google Scholar
  257. 257.
    Cannell J, Hollis B, Sorenson M, Taft T, Anderson J. Athletic performance and vitamin D. Med Sci Sports Exerc. 2009;41:1102–10.PubMedGoogle Scholar
  258. 258.
    Floyd F, Ayyar D, Barwick D, Hudgson P, Weightman D. Myopathy in chronic renal failure. Q J Med. 1974;XLIII:509–24.Google Scholar
  259. 259.
    Irani P. Electromyography in nutritional osteomalaic myopathy. J Neurol Neurosurg Psychiatry. 1976;39:686–93.PubMedGoogle Scholar
  260. 260.
    Russell J. Osteomalacic myopathy. Muscle Nerve. 1994;17:578–80.PubMedGoogle Scholar
  261. 261.
    Ceglia L. Vitamin D and skeletal muscle tissue and function. Mol Aspects Med. 2008;29:407–14.PubMedGoogle Scholar
  262. 262.
    Bischoff H, Borchers M, Gudat F, Duermueller U, Theiler R, Stahelin H, et al. In situ detection of 1, 25-dihydroxyvitamin D3 receptor in human skeletal muscle tissue. Histochem J. 2001;33:19–24.PubMedGoogle Scholar
  263. 263.
    Bischoff-Ferrari HA, Borchers M, Gudat F, Dürmüller U, Stähelin HB, Dick W. Vitamin D receptor expression in human muscle tissue decreases with age. J Bone Miner Res. 2004;19:265–9.PubMedGoogle Scholar
  264. 264.
    Bischoff-Ferrari HA, Dietrich T, Orav EJ, Hu FB, Zhang Y, Karlson EW, et al. Higher 25-hydroxyvitamin D concentrations are associated with better lower-extremity function in both active and inactive persons aged > or =60 y. Am J Clin Nutr. 2004;80:752–8.PubMedGoogle Scholar
  265. 265.
    Pfeifer M, Begerow B, Minne H. Vitamin D and muscle function. Osteoporos Int. 2002;13:187–94.PubMedGoogle Scholar
  266. 266.
    Nibbelink KA, Tishkoff DX, Hershey SD, Rahman A, Simpson RU. 1, 25(OH)2-vitamin D3 actions on cell proliferation, size, gene expression, and receptor localization, in the HL-1 cardiac myocyte. J Steroid Biochem Mol Biol. 2007;103:533–7.PubMedGoogle Scholar
  267. 267.
    Geusens P, Vandevyver C, Vanhoof J, Cassiman J, Boonen S, Raus J. Quadriceps and grip strength are related to vitamin D receptor genotype in elderly nonobese women. J Bone Miner Res. 1997;12:2082–8.PubMedGoogle Scholar
  268. 268.
    Morrison NA, Yeoman R, Kelly PJ, Eisman JA. Contribution of trans-acting factor alleles to normal physiological variability: vitamin D receptor gene polymorphisms and circulating osteocalcin. Proc Natl Acad Sci U S A. 1992;89:6665–9.PubMedGoogle Scholar
  269. 269.
    Morrison NA, Qi JC, Tokita A, Kelly PJ, Crofts L, Nguyen TV, et al. Prediction of bone density from vitamin D receptor alleles. Nature. 1994;367:284–7.PubMedGoogle Scholar
  270. 270.
    Kikuchi R, Uemura T, Gorai I, Ohno S, Minaguchi H. Early and late postmenopausal bone loss is associated with BsmI vitamin D receptor gene polymorphism in Japanese women. Calcif Tissue Int. 1999;64:102–6.PubMedGoogle Scholar
  271. 271.
    Van Pottelbergh I, Goemaere S, De Bacquer D, De Paepe A, Kaufman M. Vitamin D receptor gene allelic variants, bone density, and bone turnover in community-dwelling men. Bone. 2002;31:631–7.PubMedGoogle Scholar
  272. 272.
    Duman BS, Tanakol R, Erensoy N, Oztürk M, Yilmazer S. Vitamin D receptor alleles, bone mineral density and turnover in postmenopausal osteoporotic and healthy women. Med Princ Pract. 2004;13:260–6.PubMedGoogle Scholar
  273. 273.
    Remes T, Väisänen SB, Mahonen A, Huuskonen J, Kröger H, Jurvelin JS, et al. Bone mineral density, body height, and vitamin D receptor gene polymorphism in middle-aged men. Ann Med. 2005;37:383–92.PubMedGoogle Scholar
  274. 274.
    Uitterlinden AG, Pols HA, Burger H, Huang Q, Van Daele PL, Van Duijn CM, et al. A large-scale population-based study of the association of vitamin D receptor gene polymorphisms with bone mineral density. J Bone Miner Res. 1996;11:1241–8.PubMedGoogle Scholar
  275. 275.
    Aerssens J, Dequeker J, Peeters J, Breemans S, Broos P, Boonen S. Polymorphisms of the VDR, ER and COLIA1 genes and osteoporotic hip fracture in elderly postmenopausal women. Osteoporos Int. 2000;11:583–91.PubMedGoogle Scholar
  276. 276.
    van der Sluis IM, de Muinck Keizer-Schrama SM, Krenning EP, Pols HA, Uitterlinden AG. Vitamin D receptor gene polymorphism predicts height and bone size, rather than bone density in children and young adults. Calcif Tissue Int. 2003;73:332–8.PubMedGoogle Scholar
  277. 277.
    Dvornyk V, Liu PY, Long JR, Zhang YY, Lei SF, Recker RR, et al. Contribution of genotype and ethnicity to bone mineral density variation in Caucasians and Chinese: a test for five candidate genes for bone mass. Chin Med J (Engl ). 2005;118:1235–44.Google Scholar
  278. 278.
    Macdonald HM, McGuigan FE, Stewart A, Black AJ, Fraser WD, Ralston S, et al. Largescale population-based study shows no evidence of association between common polymorphism of the VDR gene and BMD in British women. J Bone Miner Res. 2006;21:151–62.PubMedGoogle Scholar
  279. 279.
    Rabon-Stith KM, Hagberg JM, Phares DA. Vitamin D receptor FokI genotype influences bone mineral density response to strength training, but not aerobic training. Exp Physiol. 2005;90:653–61.PubMedGoogle Scholar
  280. 280.
    Hopkinson NS, Li KW, Kehoe A, Humphries SE, Roughton M, Moxham J, et al. Vitamin D receptor genotypes influence quadriceps strength in chronic obstructive pulmonary disease. Am J Clin Nutr. 2008;87:385–90.PubMedGoogle Scholar
  281. 281.
    Guo SW, Magnuson VL, Schiller JJ, Wang X, Wu Y, Ghosh S. Meta-analysis of vitamin D receptor polymorphisms and type 1 diabetes: a HuGE review of genetic association studies. Am J Epidemiol. 2006;164:711–24.PubMedGoogle Scholar
  282. 282.
    Grundberg E, Brändström H, Ribom EL, Ljunggren O, Mallmin H, Kindmark A. Genetic variation in the human vitamin D receptor is associated with muscle strength, fat mass and body weight in Swedish women. Eur J Endocrinol. 2004;150:323–8.PubMedGoogle Scholar
  283. 283.
    Roth SM, Zmuda JM, Cauley JA, Shea PR, Ferrell RE. Vitamin D receptor genotype is associated with fat-free mass and sarcopenia in elderly men. J Gerontol A Biol Sci Med Sci. 2004;59:10–5.PubMedGoogle Scholar
  284. 284.
    Tajima O, Ashizawa N, Ishii T. Interaction of the effects between vitamin D receptor polymorphism and exercise training on bone metabolism. J Appl Physiol. 2000;88:1271–6.PubMedGoogle Scholar
  285. 285.
    Nakamura O, Ishii T, Ando Y. Potential role of vitamin D receptor gene polymorphism in determining bone phenotype in young male athletes. J Appl Physiol. 2002;283:1973–9.Google Scholar
  286. 286.
    Pitsiladis YP, Scott R. The makings of the perfect athlete. Lancet. 2005;366:S16–7.PubMedGoogle Scholar
  287. 287.
    Clarke IJ, Henry BA. Targeting energy expenditure in muscle as a means of combating obesity. Clin Exp Pharmacol Physiol. 2010;37:121–4.PubMedGoogle Scholar
  288. 288.
    Stump CS, Henriksen EJ, Wei Y, Sowers JR. The metabolic syndrome: role of skeletal muscle metabolism. Ann Med. 2006;38:389–402.PubMedGoogle Scholar
  289. 289.
    Kelley DE. Skeletal muscle fat oxidation: timing and flexibility are everything. J Clin Invest. 2005;115:1699–702.PubMedGoogle Scholar
  290. 290.
    Kiens B. Skeletal muscle lipid metabolism in exercise and insulin resistance. Physiol Rev. 2006;85:205–43.Google Scholar
  291. 291.
    Mounier R, Pedersen BK, Plomgaard P. Muscle-specific expression of hypoxia-inducible factor in human skeletal muscle. Exp Physiol. 2010;95:899–907.PubMedGoogle Scholar
  292. 292.
    Tsianos GI, Evangelou E, Boot A, Zillikens MC, van Meurs JB, Uitterlinden AG, et al. Associations of polymorphisms of eight muscle- or metabolism-related genes with performance in Mount Olympus marathon runners. J Appl Physiol. 2010;108:567–74.PubMedGoogle Scholar
  293. 293.
    Schneider AJ, Friedmann T. Gene transfer in sports: an opening scenario for genetic enhancement of normal “human traits”. Adv Genet. 2006;51:37–49.Google Scholar
  294. 294.
    Dartmouth scientists genetically engineer muscular mice. Accessed 16 Nov 2006.
  295. 295.
    Keim B. Athletes beware, scientists hot on gene doping trail. Accessed 4 Feb 2010.
  296. 296.
    Hernandez J, Cooper J, Babel N, Morton C, Rosemurgy AS. TNFalpha gene delivery therapy for solid tumors. Expert Opin Biol Ther. 2010;10:993–9.PubMedGoogle Scholar
  297. 297.
    López-Lázaro M. A new view of carcinogenesis and an alternative approach to cancer therapy. Mol Med. 2010;16:144–53.PubMedGoogle Scholar
  298. 298.
    Muntoni F, Wells D. Genetic treatments in muscular dystrophies. Curr Opin Neurol. 2007;20:590–4.PubMedGoogle Scholar
  299. 299.
    Bushby K, Lochmüller H, Lynn S, Straub V. Interventions for muscular dystrophy: molecular medicines entering the clinic. Lancet. 2009;374:1849–56.PubMedGoogle Scholar
  300. 300.
    Gene therapy for cancer. Accessed Oct 2010.
  301. 301.
    Kulkarni M. Gene therapy for human severe combined immunodeficiency disease. Accessed Oct 2010.
  302. 302.
    Gene therapy for Parkinson’s disease is safe and some patients benefit, according to study. Accessed 25 June 2007.
  303. 303.
    Lagay F. Gene therapy or genetic enhancement: does it make a difference? Virtual Mentor. 2001;3:2.Google Scholar
  304. 304.
    Hanna KE. Genetic enhancement. Accessed April 2006.
  305. 305.
    Jelkmann W. Erythropoietin: structure, control of production, and function. Physiol Rev. 1992;72:449–89.PubMedGoogle Scholar
  306. 306.
    Eckardt KU. After 15 years of success – perspectives of erythropoietin therapy. Nephrol Dial Transplant. 2001;16:1745–9.PubMedGoogle Scholar
  307. 307.
    Gaffney GR, Parisotto R. Gene doping: a review of performance-enhancing genetics. Pediatr Clin North Am. 2007;54:807–22.PubMedGoogle Scholar
  308. 308.
    Osborne WR, Ramesh N, Lau S, Clowes MM, Dale DC, Clowes AW. Gene therapy for long-term expression of erythropoietin in rats. Proc Natl Acad Sci U S A. 1995;92:8055–8.PubMedGoogle Scholar
  309. 309.
    Seppen J, Barry SC, Harder B, Osborne WR. Lentivirus administration to rat muscle provides efficient sustained expression of erythropoietin. Blood. 2001;98:594–6.PubMedGoogle Scholar
  310. 310.
    Tripathy SK, Goldwasser E, Lu MM, Barr E, Leiden JM. Stable delivery of physiologic levels of recombinant erythropoietin to the systemic circulation by intramuscular injection of replication-defective adenovirus. Proc Natl Acad Sci U S A. 1994;91:11557–61.PubMedGoogle Scholar
  311. 311.
    Macdougall IC, Gray SJ, Elston O, Breen C, Jenkins B, Browne J, et al. Pharmacokinetics of novel erythropoiesis stimulating protein compared with epoetin alfa in dialysis patients. J Am Soc Nephrol. 1999; 10:2392–5.PubMedGoogle Scholar
  312. 312.
    Vanrenterghem Y, Barany P, Mann J. Novel erythropoiesis stimulating protein (NESP) maintains hemoglobin (Hb) in ESRD patients when administered once weekly or once every other week. J Am Soc Nephrol. 1999;10:A1365.Google Scholar
  313. 313.
    Graf H, Lacombe JL, Braun J, Gomes da Costa AA. Novel erythropoiesis stimulating protein (NESP) effectively maintains hemoglobin (Hb) when administered at a reduced dose frequency compared with recombinant human erythropoietin (rHuEpo) in ESRD patients. J Am Soc Nephrol. 2000;11:A1317.Google Scholar
  314. 314.
    Weiss LG, Clyne N, Divino Filho J, Frisenette-Fich C, Kurkus J, Svensson B. The efficacy of once weekly compared with two or three times weekly subcutaneous Epoetin beta: results from a randomized controlled multicentre trial. Swedish Study Group. Nephrol Dial Transplant. 2000;15:2014–9.PubMedGoogle Scholar
  315. 315.
    Regulier E, Schneider BL, Deglon N, Beuzard Y, Aebischer P. Continuous delivery of human and mouse erythropoietin in mice by genetically engineered polymer encapsulated myoblasts. Gene Ther. 1998;5:1014–22.PubMedGoogle Scholar
  316. 316.
    Chenuaud P, Larcher T, Rabinowitz JE, Provost N, Cherel Y, Casadevall N, et al. Autoimmune anemia in macaques following erythropoietin gene therapy. Blood. 2004;103:3303–4.PubMedGoogle Scholar
  317. 317.
    Gao G, Lebherz C, Weiner DJ, Grant R, Calcedo R, McCullough B, et al. Erythropoietin gene therapy leads to autoimmune anemia in macaques. Blood. 2004;103:3300–2.PubMedGoogle Scholar
  318. 318.
    Binley K, Askham Z, Iqball S, Spearman H, Martin L, de AM, et al. Long-term reversal of chronic anemia using a hypoxia-regulated erythropoietin gene therapy. Blood. 2002;100:2406–13.PubMedGoogle Scholar
  319. 319.
    Fandrey J. Oxygen-dependent and tissue-specific regulation of erythropoietin gene expression. Am J Physiol Regul Integr Comp Physiol. 2004;286:R977–88.PubMedGoogle Scholar
  320. 320.
    Noguchi CT, Bae KS, Chin K, Wada Y, Schechter AN, Hankins WD. Cloning of the human erythropoietin receptor gene. Blood. 1991;78:2548–56.PubMedGoogle Scholar
  321. 321.
    Juvonen E, Ikkala E, Fyhrquist F, Ruutu T. Autosomal dominant erythrocytosis caused by increased sensitivity to erythropoietin. Blood. 1991;78:3066–9.PubMedGoogle Scholar
  322. 322.
    de la Chapelle A, Träskelin AL, Juvonen E. Truncated erythropoietin receptor causes dominantly inherited benign human erythrocytosis. Proc Natl Acad Sci U S A. 1993;90:4495–9.PubMedGoogle Scholar
  323. 323.
    de la Chapelle A, Sistonen P, Lehvaslaiho H, Ikkala E, Juvonen E. Familial erythrocytosis genetically linked to erythropoietin receptor gene. Lancet. 1993;341:82–4.PubMedGoogle Scholar
  324. 324.
    Longmore GD. Erythropoietin receptor mutations and Olympic glory [news]. Nat Genet. 1993;4:108–10.PubMedGoogle Scholar
  325. 325.
    Lee RJ, Springer ML, Blanco-Bose WE, Shaw R, Ursell PC, Blau HM. VEGF gene delivery to myocardium: deleterious effects of unregulated expression. Circulation. 2000;102:898–901.PubMedGoogle Scholar
  326. 326.
    Walgenbach KJ, Gratas C, Shestak KC, Becker D. Ischaemia-induced expression of bFGF in normal skeletal muscle: a potential paracrine mechanism for mediating angiogenesis in ischaemic skeletal muscle. Nat Med. 1995;1:453–9.PubMedGoogle Scholar
  327. 327.
    Bray MS. Implications of gene-behavior interactions: prevention and intervention for obesity. Obesity (Silver Spring). 2008;16:S72–8.Google Scholar
  328. 328.
    Fernández JR, Casazza K, Divers J, López-Alarcón M. Disruptions in energy balance: does nature overcome nurture? Physiol Behav. 2008;22:105–12.Google Scholar
  329. 329.
    Stefan N, Vozarova B, Del Parigi A. The Gln223Arg polymorphism of the leptin receptor in Pima Indians: influence on energy expenditure, physical activity and lipid metabolism. Int J Obes Relat Metab Disord. 2002;26:1629–32.PubMedGoogle Scholar
  330. 330.
    Meier U, Gressner AM. Endocrine regulation of energy metabolism: review of pathobiochemical and clinical chemical aspects of leptin, ghrelin, adiponectin, and resistin. Clin Chem. 2004;50:1511–25.PubMedGoogle Scholar
  331. 331.
    Pistilli EE, Gordish-Dressman H, Seip RL, Devaney JM, Thompson PD, Price TB, et al. Resistin polymorphisms are associated with muscle, bone, and fat phenotypes in White men and women. Obesity (Silver Spring). 2007;15:392–402.Google Scholar
  332. 332.
    Richert L, Chevalley T, Manen D, Bonjour JP, Rizzoli R, Ferrari S. Substitution in the leptin receptor bone mass in prepubertal boys is associated with a Gln223Arg amino acid. J Clin Endocrinol Metab. 2007;92:4380–6.PubMedGoogle Scholar
  333. 333.
    Frayn KN, Arner P, Yki-Järvinen H. Fatty acid metabolism in adipose tissue, muscle and liver in health and disease. Essays Biochem. 2006;42:89–103.PubMedGoogle Scholar
  334. 334.
    Dyck DJ, Heigenhauser GJ, Bruce CR. The role of adipokines as regulators of skeletal muscle fatty acid metabolism and insulin sensitivity. Acta Physiol (Oxf). 2006;186:5–16.Google Scholar
  335. 335.
    Bruce CR, Dyck DJ. Cytokine regulation of skeletal muscle fatty acid metabolism: effect of interleukin-6 and tumor necrosis factor alpha. Am J Physiol Endocrinol Metab. 2004;287:E616–21.PubMedGoogle Scholar
  336. 336.
    Junkin KA, Dyck DJ, Mullen KL, Chabowski A, Thrush AB. Resistin acutely impairs insulin-stimulated glucose transport in rodent muscle in the presence, but not absence, of palmitate. Am J Physiol Regul Integr Comp Physiol. 2009;296:R944–51.PubMedGoogle Scholar
  337. 337.
    Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 2001;7:941–6.PubMedGoogle Scholar
  338. 338.
    Singh MK, Krisan AD, Crain AM, Collins DE, Yaspelkis III BB. High-fat diet and leptin treatment alter skeletal muscle insulin-stimulated phosphatidylinositol 3-kinase activity and glucose transport. Metabolism. 2003;52:1196–205.PubMedGoogle Scholar
  339. 339.
    Yaspelkis BB 3rd, Singh MK, Krisan AD, Krisan AD, Collins DE, Kwong CC, et al. Chronic leptin treatment enhances insulin-stimulated glucose disposal in skeletal muscle of high-fat fed rodents. Life Sci. 2004;74:1801–16.PubMedGoogle Scholar
  340. 340.
    Dyck DJ. Adipokines as regulators of muscle metabolism and insulin sensitivity. Appl Physiol Nutr Metab. 2009;34:396–402.PubMedGoogle Scholar
  341. 341.
    Question of the Year. NG: what would you do if it became possible to sequence the equivalent of a full human genome for only $1,000? Accessed Jan 2007.
  342. 342.
    Applied Biosystems: Applied Biosystems Surpasses Industry Milestone in Lowering the Cost of Sequencing Human Genome; Data made available to worldwide scientific community; Project completed for less than $60,000. Accessed 23 Jan 2011.
  343. 343.
    Telegraph completely mangles debate over value of genetic research. Accessed 21 April 2009.
  344. 344.
    Bammann K, Peplies J, Sjöström M, Lissner L, De Henauw S, Galli C, et al. Assessment of diet, physical activity and biological, social and environmental factors in a multi-centre European project on diet- and lifestyle-related disorders in children (IDEFICS). J Public Health. 2006;14:279–89.Google Scholar
  345. 345.
    Philibert RA, Zadorozhnyaya O, Beach SR, Brody GH. Comparison of the genotyping results using DNA obtained from blood and saliva. Psychiatr Genet. 2008;18:275–81.PubMedGoogle Scholar
  346. 346.
    Matheson LA, Duong TT, Rosenberg AM, Yeung RS. Assessment of sample collection and storage methods for multicenter immunologic research in children. J Immunol Methods. 2008;339:82–9.PubMedGoogle Scholar
  347. 347.
    Koni AC, Scott RA, Wang G, Bailey MES, Peplies J, Bammann K, et al. DNA yield and quality of saliva samples and suitability for large scale epidemiological studies in children. Int J Obes (Lond). 2010, in press. ISSN 0307–0565Google Scholar
  348. 348.
    Streckfus CF, Bigler LR. Saliva as a diagnostic fluid. Oral Dis. 2002;8:69–76.PubMedGoogle Scholar
  349. 349.
    Ng DP, Koh D, Choo S, Chia KS. Saliva as a viable alternative source of human genomic DNA in genetic epidemiology. Clin Chim Acta. 2006;367:81–5.PubMedGoogle Scholar
  350. 350.
    McMichael GL, Gibson CS, O’Callaghan ME, Goldwater PN, Dekker GA, Haan EA, et al. DNA from buccal swabs suitable for high-throughput SNP multiplex analysis. J Biomol Tech. 2009;20:232–5.PubMedGoogle Scholar
  351. 351.
    Nishita DM, Jack LM, McElroy M, McClure JB, Richards J, Swan GE, et al. Clinical trial participant characteristics and saliva and DNA metrics. BMC Med Res Methodol. 2009;9:71.PubMedGoogle Scholar
  352. 352.
    Rylander-Rudqvist T, Hakansson N, Tybring G, Wolk A. Quality and quantity of saliva DNA obtained from the self-administrated oragene method – a pilot study on the cohort of Swedish men. Cancer Epidemiol Biomarkers Prev. 2006;15:1742–5.PubMedGoogle Scholar
  353. 353.
    Garcia-Closas M, Egan KM, Abruzzo J, Newcomb PA, Titus-Ernstoff L, Franklin T, et al. Collection of genomic DNA from adults in epidemiological studies by buccal cytobrush and mouthwash. Cancer Epidemiol Biomarkers Prev. 2001;10:687–96.PubMedGoogle Scholar
  354. 354.
    Feigelson HS, Rodriguez C, Robertson AS, Jacobs EJ, Calle EE, Reid YA, et al. Determinants of DNA yield and quality from buccal cell samples collected with mouthwash. Cancer Epidemiol Biomarkers Prev. 2001;10:1005–8.PubMedGoogle Scholar
  355. 355.
    King IB, Satia-Abouta J, Thornquist MD, Bigler J, Patterson RE, Kristal AR, et al. Buccal cell DNA yield, quality, and collection costs: comparison of methods for large-scale studies. Cancer Epidemiol Biomarkers Prev. 2002;11:1130–3.PubMedGoogle Scholar
  356. 356.
    Quinque D, Kittler R, Kayser M, Stoneking M, Nasidze I. Evaluation of saliva as a source of human DNA for population and association studies. Anal Biochem. 2006;353:272–7.PubMedGoogle Scholar
  357. 357.
    Hansen TV, Simonsen MK, Nielsen FC, Hundrup YA. Collection of blood, saliva, and buccal cell samples in a pilot study on the Danish nurse cohort: comparison of the response rate and quality of genomic DNA. Cancer Epidemiol Biomarkers Prev. 2007;16:2072–6.PubMedGoogle Scholar
  358. 358.
    Rogers NL, Cole SA, Lan HC, Crossa A, Demerath EW. New saliva DNA collection method compared to buccal cell collection techniques for epidemiological studies. Am J Hum Biol. 2007;19:319–26.PubMedGoogle Scholar
  359. 359.
    Fuku N, Scott RA, Mikami E, Wang G, Deason M, Irwin L, et al. Analysis of multiple performance-associated genetic polymorphisms in sprint and endurance running world record holders. Med Sci Sports Exerc. 2010;42:795.Google Scholar
  360. 360.
    Grobet L, Martin LJ, Poncelet D, Pirottin D, Brouwers B, Riquet J, et al. A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle. Nat Genet. 1997;17:71–4.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.College of Medicine, Veterinary and Life Sciences, Institute of Cardiovascular and Medical SciencesUniversity of GlasgowGlasgowUK

Personalised recommendations