Abstract
Endurance performance is a complex phenotype subject to the influence of both environmental and genetic factors. Although the last decade has seen a variety of specific genetic factors proposed, many in metabolic pathways, each is likely to make a limited contribution to an ‘elite’ phenotype: it seems more likely that such status depends on the simultaneous presence of multiple such variants. The aim of the study was to investigate individually and in combination the association of common metabolic gene polymorphisms with endurance athlete status, the proportion of slow-twitch muscle fibers and maximal oxygen consumption. A total of 1,423 Russian athletes and 1,132 controls were genotyped for 15 gene polymorphisms, of which most were previously reported to be associated with athlete status or related intermediate phenotypes. Muscle fiber composition of m. vastus lateralis in 45 healthy men was determined by immunohistochemistry. Maximal oxygen consumption of 50 male rowers of national competitive standard was determined during an incremental test to exhaustion on a rowing ergometer. Ten ‘endurance alleles’ (NFATC4 Gly160, PPARA rs4253778 G, PPARD rs2016520 C, PPARGC1A Gly482, PPARGC1B 203Pro, PPP3R1 promoter 5I, TFAM 12Thr, UCP2 55Val, UCP3 rs1800849 T and VEGFA rs2010963 C) were first identified showing discrete associations with elite endurance athlete status. Next, to assess the combined impact of all 10 gene polymorphisms, all athletes were classified according to the number of ‘endurance’ alleles they possessed. The proportion of subjects with a high (≥9) number of ‘endurance’ alleles was greater in the best endurance athletes compared with controls (85.7 vs. 37.8%, P = 7.6 × 10−6). The number of ‘endurance’ alleles was shown to be positively correlated (r = 0.50; P = 4.0 × 10−4) with the proportion of fatigue-resistant slow-twitch fibers, and with maximal oxygen consumption (r = 0.46; P = 7.0 × 10−4). These data suggest that the likelihood of becoming an elite endurance athlete depends on the carriage of a high number of endurance-related alleles.
Similar content being viewed by others
References
Abernethy PJ, Thayer R, Taylor AW (1990) Acute and chronic responses of skeletal muscle to endurance and sprint exercise. Rev Sports Med 10:365–389
Ahmetov II, Rogozkin VA (2009) Genes, athlete status and training: an overview. In: Collins M (ed) Genetics and sports, vol 54. Basel, Karger pp 43–71
Ahmetov II, Mozhayskaya IA, Flavell DM, Astratenkova IV, Komkova AI, Lyubaeva EV, Tarakin PP, Shenkman BS, Vdovina AB, Netreba AI et al (2006) PPARα gene variation and physical performance in Russian athletes. Eur J Appl Physiol 97:103–108
Ahmetov II, Astratenkova IV, Rogozkin VA (2007a) Association of a PPARD polymorphism with human physical performance. Mol Biol 41:776–780
Ahmetov II, Popov DV, Mozhayskaya IA, Missina SS, Astratenkova IV, Vinogradova OL, Rogozkin VA (2007b) Association of regulatory genes polymorphisms with aerobic and anaerobic performance of athletes. Ross Fiziol Zh Im I M Sechenova 93:837–843
Ahmetov II, Khakimullina AM, Popov DV, Missina SS, Vinogradova OL, Rogozkin VA (2008a) Polymorphism of the vascular endothelial growth factor gene (VEGF) and aerobic performance in athletes. Hum Physiol 34:477–481
Ahmetov II, Linde EV, YuV Shikhova, Popov DV, Missina SS, Vinogradova OL, Rogozkin VA (2008b) The influence of calcineurin gene polymorphism on morphofunctional characteristics of cardiovascular system of athletes. Ross Fiziol Zh Im I M Sechenova 94:915–922
Ahmetov II, Popov DV, Astratenkova IV, Druzhevskaya AM, Missina SS, Vinogradova OL, Rogozkin VA (2008c) The use of molecular genetic methods for prognosis of aerobic and anaerobic performance in athletes. Hum Physiol 34:338–342
Allen DL, Sartorius CA, Sycuro LK, Leinwand LA (2001) Different Pathways regulate expression of the skeletal myosin heavy chain. Genes 276:43524–43533
Alvarez V, Corao AI, Alonso-Montes C, Sánchez-Ferrero E, De Mena L, Morales B, García-Castro M, Coto E (2008) Mitochondrial transcription factor A (TFAM) gene variation and risk of late-onset Alzheimer’s disease. J Alzheimers Dis 13:275–280
Arany Z, Lebrasseur N, Morris C, Smith E, Yang W, Ma Y, Chin S, Spiegelman BM (2007) The transcriptional coactivator PGC-1β drives the formation of oxidative type IIX fibers in skeletal muscle. Cell Metab 5:35–46
Bassett DR Jr, Howley ET (2000) Limiting factors for maximum oxygen uptake and determinants of endurance performance. Med Sci Sports Exerc 32:70–84
Bouchard C, Daw EW, Rice T, Pérusse L, Gagnon J, Province MA, Leon AS, Rao DC, Skinner JS, Wilmore JH (1998) Familial resemblance for VO2max in the sedentary state: the HERITAGE family study. Med Sci Sports Exerc 30:252–258
Bouchard C, An P, Rice T, Skinner JS, Wilmore JH, Gagnon J, Pérusse L, Leon AS, Rao DC (1999) Familial aggregation of VO2max response to exercise training: results from the HERITAGE family study. J Appl Physiol 87:1003–1008
Brand MD, Esteves TC (2005) Physiological functions of the mitochondrial uncoupling proteins UCP2 and UCP3. Cell Metab 2:85–93
Bray MS, Hagberg JM, Perusse L, Rankinen T, Roth SM, Wolfarth B, Bouchard C (2009) The human gene map for performance and health-related fitness phenotypes: the 2006–2007 update. Med Sci Sports Exerc 41:35–73
Brutsaert TD, Parra EJ (2006) What makes a champion? Explaining variation in human athletic performance. Respir Physiol Neurobiol 151:109–123
Buemann B, Schierning B, Toubro S, Bibby BM, Sørensen T, Dalgaard L, Pedersen O, Astrup A (2001) The association between the val/ala-55 polymorphism of the uncoupling protein 2 gene and exercise efficiency. Int J Obes Relat Metab Disord 25:467–471
Chin ER, Olson EN, Richardson JA, Yang Q, Humphries C, Shelton JM, Wu H, Zhu W, Bassel-Duby R, Williams RS (1998) A calcineurin-dependent pathway controls skeletal muscle fiber type. Genes Dev 12:2499–2509
De Moor MH, Spector TD, Cherkas LF, Falchi M, Hottenga JJ, Boomsma DI, De Geus EJ (2007) Genome-wide linkage scan for athlete status in 700 British female DZ twin pairs. Twin Res Hum Genet 10:812–820
Dzau VJ (1988) Tissue renin-angiotensin system: physiologic and pharmacologic implications. Introduction. Circulation 77:I1–I13
Eid J, Fehr A, Gray J, Luong K, Lyle J, Otto G, Peluso P, Rank D, Baybayan P, Bettman B et al (2009) Real-time DNA sequencing from single polymerase molecules. Science 323:133–138
Ekstrand MI, Falkenberg M, Rantanen A, Park CB, Gaspari M, Hultenby K, Rustin P, Gustafsson CM, Larsson NG (2004) Mitochondrial transcription factor A regulates mtDNA copy number in mammals. Hum Mol Genet 13:935–944
Eynon N, Meckel Y, Sagiv M, Yamin C, Amir R, Sagiv M, Goldhammer E, Duarte JA, Oliveira J (2009) Do PPARGC1A and PPARalpha polymorphisms influence sprint or endurance phenotypes? Scand J Med Sci Sports. doi:10.1111/j.1600-0838.2009.00930.x
Ferrara N (2001) Role of vascular endothelial growth factor in regulation of physiological angiogenesis. Am J Physiol Cell Physiol 280:1358–1366
Flück M (2006) Functional, structural and molecular plasticity of mammalian skeletal muscle in response to exercise stimuli. J Exp Biol 209(Pt 12):2239–2248
Gayagay G, Yu B, Hambly B, Boston T, Hahn A, Celermajer DS, Trent RJ (1998) Elite endurance athletes and the ACE I allele: the role of genes in athletic performance. Hum Genet 103:48–50
Gómez-Gallego F, Santiago C, González-Freire M, Muniesa CA, Fernández Del Valle M, Pérez M, Foster C, Lucia A (2009) Endurance performance: genes or gene combinations? Int J Sports Med 30:66–72
Gonzalez-Freire M, Santiago C, Verde Z, Lao JI, Oiivan J, Gómez-Gallego F, Lucia A (2008) Unique among unique: is it genetically determined? Br J Sports Med. doi:10.1136/bjsm.2008.049809
Halsall DJ, Luan J, Saker P, Huxtable S, Farooqi IS, Keogh J, Wareham NJ, O’Rahilly S (2001) 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 25:472–477
Jamshidi Y, Montgomery HE, Hense H-W, Myerson SG, Torra IP, Staels B, World MJ, Doering A, Erdmann J, Hengstenberg C et al (2002) Peroxisome proliferators-activated receptor α gene regulates left ventricular growth in response to exercise and hypertension. Circulation 105:950–955
Lefebvre P, Chinetti G, Fruchart JC, Staels B (2006) Sorting out the roles of PPARα in energy metabolism and vascular homeostasis. J Clin Invest 116:571–580
Lin J, Wu H, Tarr PT, Zhang CY, Wu Z, Boss O, Michael LF, Puigserver P, Isotani E, Olson EN et al (2002) Transcriptional co-activator PGC-1α drives the formation of slow-twitch muscle fibres. Nature 418:797–801
Ling C, Poulsen P, Carlsson E, Ridderstrale M, Almgren P, Wojtaszewski J, Beck-Nielsen H, Groop L, Vaag A (2004) Multiple environmental and genetic factors influence skeletal muscle PGC-1α and PGC-1β gene expression in twins. J Clin Invest 114:1518–1526
Ling C, Wegner L, Andersen G, Almgren P, Hansen T, Pedersen O, Groop L, Vaag A, Poulsen P (2007) Impact of the peroxisome proliferator activated receptor-γ coactivator-1β (PGC-1β) Ala203Pro polymorphism on in vivo metabolism, PGC-1β expression and fibre type composition in human skeletal muscle. Diabetologia 50:1615–1620
Long YC, Glund S, Garcia-Roves PM, Zierath JR (2007) Calcineurin regulates skeletal muscle metabolism via coordinated changes in gene expression. J Biol Chem 282:1607–1614
Lowenstein JM (1972) Ammonia production in muscle and other tissues: the purine nucleotide cycle. Physiol Rev 52:382–414
Lucia A, Gómez-Gallego F, Barroso I, Rabadán M, Bandrés F, San Juan AF, Chicharro JL, Ekelund U, Brage S, Earnest CP et al (2005) PPARGC1A genotype (Gly482Ser) predicts exceptional endurance capacity in European men. J Appl Physiol 99:344–348
MacArthur DG, North KN (2007) ACTN3: a genetic influence on muscle function and athletic performance. Exerc Sport Sci Rev 35:30–34
Mardis ER (2006) Anticipating the 1, 000 dollar genome. Genome Biol 7:112
Metzker ML (2005) Emerging technologies in DNA sequencing. Genome Res 15:1767–1776
Montgomery HE, Marshall R, Hemingway H, Myerson S, Clarkson P, Dollery C, Hayward M, Holliman DE, Jubb M, World M et al (1998) Human gene for physical performance. Nature 393:221–222
Moore RL (1998) Cellular adaptations of the heart muscle to exercise training. Ann Med 30(Suppl 1):46–53
Muniesa CA, González-Freire M, Santiago C, Lao JI, Buxens A, Rubio JC, Martín MA, Arenas J, Gomez-Gallego F, Lucia A (2008) World-class performance in lightweight rowing: is it genetically influenced? A comparison with cyclists, runners and non-athletes. Br J Sports Med. doi:10.1136/bjsm.2008.051680
Narravula S, Colgan SP (2001) Hypoxia-inducible factor 1-mediated inhibition of peroxisome proliferator-activated receptor alpha expression during hypoxia. J Immunol 2001(166):7543–7548
Poirier O, Nicaud V, McDonagh T, Dargie HJ, Desnos M, Dorent R, Roizès G, Schwartz K, Tiret L, Komajda M et al (2003) Polymorphisms of genes of the cardiac calcineurin pathway and cardiac hypertrophy. Eur J Hum Genet 11:659–664
Prior SJ, Hagberg JM, Paton CM, Douglass LW, Brown MD, McLenithan JC, Roth SM (2006) DNA sequence variation in the promoter region of the VEGF gene impacts VEGF gene expression and maximal oxygen consumption. Am J Physiol Heart Circ Physiol 290:1848–1855
Rico-Sanz J, Rankinen T, Joanisse DR, Leon AS, Skinner JS, Wilmore JH, Rao DC, Bouchard C, HERITAGE Family study (2003) Associations between cardiorespiratory responses to exercise and the C34T AMPD1 gene polymorphism in the HERITAGE Family Study. Physiol Genomics 14:161–166
Ruiz JR, Gómez-Gallego F, Santiago C, González-Freire M, Verde Z, Foster C, Lucia A (2009) Is there an optimum endurance polygenic profile? J Physiol 587(Pt 7):1527–1534
Saunders CJ, Xenophontos SL, Cariolou MA, Anastassiades LC, Noakes TD, Collins M (2006) The bradykinin b2 receptor (BDKRB2) and endothelial nitric oxide synthase 3 (NOS3) genes and endurance performance during Ironman Triathlons. Hum Mol Genet 15:979–987
Schrauwen P, Xia J, Walder K, Snitker S, Ravussin E (1999) 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 23:1242–1245
Semenza GL (2000) HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol 88:1474–1480
Semple RK, Chatterjee VK, O’Rahilly S (2006) PPAR gamma and human metabolic disease J Clin Invest 116:581–589
Simoneau J-A, Bouchard C (1995) Genetic determinism of fiber type proportion in human skeletal muscle. FASEB J 9:1091–1095
Skogsberg J, Kannisto K, Cassel TN, Hamsten A, Eriksson P, Ehrenborg E (2003) Evidence that peroxisome proliferator-activated receptor delta influences cholesterol metabolism in men. Arterioscler Thromb Vasc Biol 23:637–643
St-Pierre J, Lin J, Krauss S, Tarr PT, Yang R, Newgard CB, Spiegelman BM (2003) Bioenergetic analysis of peroxisome proliferator-activated receptor gamma coactivators 1α and 1β (PGC-1α and PGC-1β) in muscle cells. J Biol Chem 278:26597–26603
Tang W, Arnett DK, Devereux RB, Panagiotou D, Province MA, Miller MB, de Simone G, Gu C, Ferrell RE (2005) Identification of a novel 5-base pair deletion in calcineurin B (PPP3R1) promoter region and its association with left ventricular hypertrophy. Am Heart J 150:845–851
Vanttinen M, Nuutila P, Kuulasmaa T, Pihlajamaki J, Hallsten K, Virtanen KA, Lautamaki R, Peltoniemi P, Takala T, Viljanen AP, Knuuti J, Laakso M (2005) Single nucleotide polymorphisms in the peroxisome proliferator-activated receptor delta gene are associated with skeletal muscle glucose uptake. Diabetes 54:3587–3591
Wang YX, Zhang CL, Yu RT, Cho HK, Nelson MC, Bayuga-Ocampo CR, Ham J, Kang H, Evans RM (2004) Regulation of muscle fiber type and running endurance by PPARδ. PLoS Biol 2:294
Wang D, Wang H, Guo Y, Ning W, Katkuri S, Wahli W, Desvergne B, Dey SK, DuBois RN (2006) Crosstalk between peroxisome proliferator-activated receptor delta and VEGF stimulates cancer progression. Proc Natl Acad Sci USA 103:19069–19074
Watson CJ, Webb NJ, Bottomley MJ, Brenchley PE (2000) Identification of polymorphisms within the vascular endothelial growth factor (VEGF) gene: correlation with variation in VEGF protein production. Cytokine 12:1232–1235
Williams AG, Folland JP (2008) Similarity of polygenic profiles limits the potential for elite human physical performance. J Physiol 586:113–121
Williams AG, Dhamrait SS, Wootton PTE, Day SH, Hawe E, Payne JR, Myerson SG, World M, Budgett R, Humphries SE, Montgomery HE (2004) Bradykinin receptor gene variant and human physical performance. J Appl Physiol 96:938–942
Yang TTC, Suk HY, Yang X, Olabisi O, Yu RY, Durand J, Jelicks LA, Kim JY, Scherer PE, Wang Y et al (2006) Role of transcription factor NFAT in glucose and insulin homeostasis. Mol Cell Biol 26:7372–7387
Acknowledgments
The authors thank A. Komkova, J. Shihova, A. Druzhevskaya and S. Khalchitsky (St Petersburg Research Institute of Physical Culture, St Petersburg) for their contributions to sample collection, genotyping and data management. We are also thankful to S. Missina for help with rowing spiroergometry, to B. Shenkman and P. Tarakin (SSC RF Institute for Biomedical Problems of the Russian Academy of Sciences, Moscow) for technical assistance in immunohistochemistry. This work was supported by grants from the Federal Agency for Physical Culture and Sport of the Russian Federation and the Ministry of Education and Science of the Russian Federation (contract number 02.522.11.2004).
Conflict of interest statement
The authors declare no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Electronic Supplementary Material
Rights and permissions
About this article
Cite this article
Ahmetov, I.I., Williams, A.G., Popov, D.V. et al. The combined impact of metabolic gene polymorphisms on elite endurance athlete status and related phenotypes. Hum Genet 126, 751–761 (2009). https://doi.org/10.1007/s00439-009-0728-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-009-0728-4