Teaduspõhine sport. Sulev Kõks. Tartu Ülikool patofüsioloogia osakond April 17, 2014

Transcription

1 Teaduspõhine sport Sulev Kõks Tartu Ülikool patofüsioloogia osakond April 17, 2014 Sulev Kõks (Patofüsioloogia) Teadus ja sport April 17, / 26

2 Ülevaade 1 Sissejuhatus 2 Kaasaegne geneetika Geneetika ja genoomika Kvantgeneetika 3 Sport ja geenid Küsimused Vastused Optimaalne võimekus Vigastusted 4 Kokkuvõte Teadus spordis Järeldused Sulev Kõks (Patofüsioloogia) Teadus ja sport April 17, / 26

3 Teaduse objektid Arstiteaduse üks põnevamaid küsimusi on fenotüübilise variatsiooni selgitamine Miks inimene ja hiir on erinevad? Miks ühed inimesed on pikad ja teised on paksud? Kuidas maksarakk on erinev sooleepiteelist? Miks ühed inimesed saavutavad edu sportlasena ja teised on edukad muusikuna? Millised faktorid tingivad selle, et oleme teineteisest erinevad? Sulev Kõks (Patofüsioloogia) Teadus ja sport April 17, / 26

4 Sarnasus ja erinevus Inimese lapsed on ikka inimesed Hiire järglased on ikka hiired Pikkadel inimestel on pikemad lapsed Seega pärilikkus muudab meid sarnaseks, aga ka erinevaks Pärilikkusaine on tuumas Geenid ehk DNA Sulev Kõks (Patofüsioloogia) Teadus ja sport April 17, / 26

5 Geenide töö 1 1 R.Robinson, 2004 Sulev Kõks (Patofüsioloogia) Teadus ja sport April 17, / 26

6 Geneetika Geenid määravad meie biokeemilise vundamendi Meie kehakaalu reguleerivad u 100 geeni Neil igaühel on oma väike mõju Mõnel geenil rohkem, mõnel vähem (FTO ca 0,5 kg) See aga ei tähenda, et mõju ei ole See on kompleksmõju Sulev Kõks (Patofüsioloogia) Teadus ja sport April 17, / 26

7 Genoomika Geneetika keskendub üksikutele geenidele KAS antud geen mõjutab uuritavat fenotüüpi? Genoomika vaatab probleemi laiemalt MIS mõjutab uuritavat fenotüüpi? Hüpoteesivaba, tulemuseks kompleksne nimekiri geenilookustest Kvantitaiivne geneetika Sulev Kõks (Patofüsioloogia) Teadus ja sport April 17, / 26

8 Luutiheduse kvantitatiivne geneetika 2 2 Genetics of Bone Biology and Skeletal Diseases Sulev Kõks (Patofüsioloogia) Teadus ja sport April 17, / 26

9 Luumurru individualiseeritud risk 3 REVIEWS In the translational genetics of osteo porosis e current questions of interest include: how ke use of the genetic data to predict an indiviof fracture?; can genetic variants alone ideni duals at high risk of fracture?; and can the ariants improve the prediction accuracy of eyond that obtained with conventional clinictors? Addressing these questions will help ances towards the in dividualization of fracture ction. this potential for individualized fracture risk n, the translation of genetic discoveries into pplications remains a major challenge. The w to assess the usefulness of genes in fracture and what metrics are suitable for the assessple measures of association, such as odds ratio, equate. 41 The usefulness of a genetic variant f fracture risk prediction should be assessed of discrimination, and more importantly, ation, as outlined below. ination measures how well a genetic variant ate individuals who will have a fracture from o will not. 42 The primary metric of discrimithe area under the receiver operating charac- OC) curve (AUC), which can be interpreted as bility that for a set of randomly selected pairs and nonfracture, the test result will be higher s that fracture than in individuals who do not n reality, AUC is a compromise between send specificity, and is thus a global estimate of c accuracy. As such, AUC is a rather insensitive f change. 43 For example, a meaningful differognostic value between two predictive models essarily reflected 3 Nat by Rev the Endocrinol AUC. Moreover, 2013 the no direct clinical meaning, and is therefore not r clinical decision making. SNPs rs rs rs rs rs rs rs rs rs rs rs rs rs rs rs rs rs rs rs rs rs rs rs rs rs rs rs rs rs rs rs rs Odds ratio Figure 1 Odds ratios and 95% confidence intervals for fracture for each of the 32 SNPs identified from genome-wide association study meta-analyses. Red circles indicate the mean values. Abbreviation: SNPs, single nucleotide polymorphisms. or accepted level-of-risk threshold for treatment critically affects the NRI metric. Similarly, the frequency of Sulev Kõks (Patofüsioloogia) a high-risk allele of the genetic Teadus variant ja in sport the general April 17, / 26

10 Olulised küsimused spordis KAS geenid mõjutavad sportlikke võimeid, ei ole üldse enam küsimus! Küsimus 1 Millised geenid ja kombinatsioon on seotud võimekusega? Koondskoor Küsimus 2 Millised geenid ja kombinatsioon on seotud vigastuste riskiga? Vastused nendele küsimustele võimaldavad meil valida ÕIGE taktika Sulev Kõks (Patofüsioloogia) Teadus ja sport April 17, / 26

11 Kaksikute uuring Genome-Wide Linkage Scan for Athlete Status in 700 British Female DZ Twin Pairs Marleen H. M. De Moor, 1 Tim D. Spector, 2 Lynn F. Cherkas, 2 Mario Falchi, 2 Jouke Jan Hottenga, 1 Dorret I. Boomsma, 1 and Eco J. C. De Geus 1 1 Department of Biological Psychology,Vrije Universiteit Amsterdam, the Netherlands 2 Twin Research and Genetic Epidemiology Unit, St Thomas Hospital, London, United Kingdom ssociation studies, comparing elite athletes (Bouchard et al., 1998; Bouchard et al., 1999; Perusse Awith sedentary controls, have reported a Uuriti 4488 kaksiku spordivõimeid et 1946 al., 2001) markeri and skeletomuscular abil strength and performance (De Mars et al., 2007; Thomis et al., 1998). number of genes that may be related to athlete status. The present study reports the first genome The number of studies aiming to identify the 66% wide spordivõimekusest linkage scan for athlete status. on Subjects pärilik actual genetic variants that account for the heritability of physical performance phenotypes is were 4488 adult female twins from the TwinsUK Adult Twin Registry (793 monozygotic [MZ] and increasing and are summarized in the human gene 3q22-q dizygotic ja 4q31-q34 [DZ] complete lookused twin pairs, and map for performance and health-related exercise single twins). Athlete status was measured by phenotypes, which is regularly updated (Perusse et asking the twins whether they had ever competed FABP2, UCP1, SLC9A9 geenid al., 2003; Rankinen et al., 2001; Rankinen et al., in sports and what was the highest level obtained. 2002; Rankinen et al., 2004; Wolfarth et al., 2005). Twins who had competed at the county or national Besides linkage and association studies on different level were considered elite athletes. Using structural equation modeling in Mx, the heritability of physiological parameters related to exercise, the human gene map also includes a number of association studies of candidate genes, in which elite athlete status was estimated at 66%. Seven hundred DZ twin pairs that were successfully athletes are compared with sedentary controls. genotyped for 1946 markers (736 microsatellites Genes that have been related to elite athlete status and 1210 SNPs) were included in the linkage are, for example, the angiotensin-converting analysis. Identical-by-descent probabilities were Sulev Kõks (Patofüsioloogia) Teadus ja enzyme sport (ACE) gene (Woods et al., 2000), April and 17, the / 26

12 Assotsiatsiooniuuringud 4 ippi et al. Table 1: Major candidate genes associated with human athletic performances. Endurance capacity PPARD Nuclear respiratory factors (NRF2) PGC-1 alpha HIF-1 alpha EPAS-1 and HIF-2 alpha Haemoglobin Skeletal muscle glycogen synthase (GYS1) ADRB2 CHRM2 VEGF Muscle performance CK-MM ACTN3 MLCK ACE AMPD1 IGF-1 Tendon apparatus ABO blood group COL1A1 and COL5A1 TNC Psychological aptitude Serotonin transporter gene (5HTT) BDNF UCP2 4 British Medical biogenesis Bulletin 2010 and respiration. Carriers of a polymorphism in the sequence Sulev Kõks (Patofüsioloogia) of translation initiator ATG Teadus in thejanrf2 sport gene have higher training April 17, / 26 Downloaded from at Tartu Univ

13 Talendiotsingud Invited Editorial J Appl Physiol 108: , 2010; doi: /japplphysiol Genetics-based performance talent research: polymorphisms as predictors of endurance performance M. Schoenfelder Technical University Munich, Institute of Public Health Research, Munich, Germany IN THE ANCIENT GREEK, talent was one of several mass units, indicating approximately the amount of water required to fill an amphora. The parable of the talents of the New Testament leads, in the 16th century, to changing the sense of the word talent to meaning gift or skill. In sport science, the talent of a sportsman could be defined by the complement of genes he inherited from his parents. De Moor and coworkers provided indirect support for this thesis in their twin pair study, which was the first genomewide linkage scan for sports participation (6). They estimated the heritability of athlete status at 66%. However, such data do not reveal whether physical performance in endurance exercise or athletic sport is influenced by a single or multiple genes. For instance, mutations in the negative muscle mass regulator myostatin gene lead to tremendous increases in muscle tissue mass (12, 13), and yet nobody inducible factor-1 (HIF1A) gene in elite endurance athletes. HIF1A regulates the transcription of numerous genes in response to hypoxic stimuli. A number of genes responsive to HIF1 relate to erythropoiesis, angiogenesis, and metabolism. VO2max vastus treeningule on ennustatav 30 geeni RNA analüüsiga By using the Geneathlete cohort, Döring and colleagues found a statistically significant difference in the distribution of HIF1A Pro582Ser (rs ) genotypes between a sedentary control group [maximum O2 uptake (V O2max) of ml kg 1 min 1 ] and highly trained endurance athletes (V O2max of ml kg 1 min 1 ). Although the HIF1A Pro582Ser Inimesel on pärilik soodumus reageerida treeningule Teades isiku geneetilist profiili, saame leida temale sobivaima lahenduse Näiteks NRF2 geeni teatud vormid sobivad 6,5 korda paremini variant was shown to have reduced transcription capacity in prior studies, differences among genotypes could also play a role in the stability of the hypoxia-induced dimerization of HIF1A with its counterpart HIF1B responsible for induction of specific gene expression. Alternatively, Döring et al. specu- would claim that myostatin is the sole determinant of muscular lated that the HIF1A variant could evoke a faster transcription performance. The potential for genes to influence human variation in physical performance is illustrated by the fact that Although the evidence of an association with endurance induction of related genes. vastupidavusalale there are more than 30,000 genes in the human genome and performance remains weak, the results of this study represent 10 million single nucleotide polymorphisms. Moreover, superimposed on this genetic variability, epigenetic modifica- determinants of athletic status. The findings in the Geneathlete an important milestone in the effort to understand the multiple tions thought to be modulated by environmental and lifestyle cohort in a Caucasian population are concordant with those of factors, such as nutrition and hormonal status, could amplify Prior and colleagues (15, 16), who reported that the same biological diversity (9). Epigenetic processes include covalent HIF1A sequence variant was associated with V O2max before modifications of histones, methylation of cytosines in DNA, and after aerobic exercise training in elderly humans. More and gene regulation by noncoding RNA (14). Furthermore, replication studies in other cohorts are needed to firm up this finding. Sulev Kõks epigenetic (Patofüsioloogia) processes are potentially involved in skeletal Teadus muscleja sport Interestingly, HIF1A-related gene expressions April have 17, 2014 been 13 / 26

14 Kestvusalad 5 7 geeni profiil ACE, ACTN3, AMPD1, CKMM, HFE, GDF8, PPARGC1A Skoor üle 74,7 suurendab ORi 5,4 5 J Physiol 2009 Sulev Kõks (Patofüsioloogia) Teadus ja sport April 17, / 26

15 Jõualad 6 6 geeni profiil ACE, ACTN3, AGT, GDF8, IL6, NOS3 Skoor üle 71 viitab suuremale võimalusele olla tipus 6 J Appl Physiol 2010 Sulev Kõks (Patofüsioloogia) Teadus ja sport April 17, / 26

16 Sporditraumad 7 Muskuloskeletaalsete vigastuste tekkimine ja nendest paranemine on treeningprogrammiga samaväärse tähtsusega Vigastuste ennetamine on kõige parem ravi Sarnaselt spordivõimetele on pärilik eelsoodumus ka vigastuste tekkeks COL1A1, COL5A1, COL12A1, COL14A1, TNC, MMP3, TGFB1, GDF5 7 Recent Patents 2012 Sulev Kõks (Patofüsioloogia) Teadus ja sport April 17, / 26

17 th Africa Provisional ZAPPAx2012/01 for determining a predisposition to soft tissue injuries COL5A1 Collins M et al. C G I I COL5A1 Genetic Continuum 2 copies of mutated COL5A1 gene 1 copy of mutated COL5A1 gene? Allelic form of the COL5A1 gene Allelic form of the COL5A1 gene Lethal in utero EDS BJHS Increased Injury Risk Decreased Injury Risk Classical Monogenic Disorder Environmental Exposure NOT Required Environmental Exposure Interacting with Genetic Background A1 gene variant continuum. Two functional copies of COL5A1 is required for life. This is illustrated in utero [24]. Furthermore, rare disease-causing mutations, which inactivate one copy of COL5A1 (ha the Mendelian connective tissue disorder, types I and II Ehlers-Danlos syndrome (EDS) [25]. Since jo Sulev Kõks (Patofüsioloogia) Teadus ja sport April 17, / 26

18 1(XII) chains. It is a member of the Fibril Associated Collagens with Interrupted Triple helices (FACITs) [41]. The 1(XII) chains are encoded by the COL12A1 gene. Type XII collagen, is also believed to regulate microfibril diameter (fibrillogenesis) [42, 43]. We have shown that the COL12A1 Alu Irestriction fragment length polymorphism (RFLP, SNP Nõustamise skeem Population of Athletes microsatellite) within the TNC gene was associated with risk of Achilles tendinopathy and rupture [50]. The functiona effect of this microsatellite remains unknown. Further work is required to identify the functional variant within the TNC or flanking genes, which predisposes individual to Achille tendinopathy. 1. History Medical Injury Physical Activity 2. Clinical Examination 3. Genotyping High Risk Intermediate Risk Low Risk Reduce Injury Risk:- 1. Personalized Training Programmes 2. Alter Exposure to Other Modifiable Risk Factors Fig. (3). Schematic diagram illustrating the use of traditional examinations and specialized investigations together with the aid of the athletes genetic profile (testing of multiple genetic variants) to stratify a population of athletes into those at high, intermediate and low risk for musculoskeletal soft tissue injuries, such as chronic Achilles tendinoapthy and ACL ruptures. The risk of injury can therefore be reduced in the high-risk athletes by personalizing their training programmes and/or exposure to other modifiable risk factors. Sulev Kõks (Patofüsioloogia) Teadus ja sport April 17, / 26

19 Terviklik nõustamine 8 8 Br J Sports Med 2014 Sulev Kõks (Patofüsioloogia) Teadus ja sport April 17, / 26

20 Kas teadust saab spordis rakendada? Teadus on nii keeruline, on seda ikka vaja? Geene on ju palju, seega ei saa nad ju midagi mõjutada Teadusest arusaamises ollakse tihti alles 18. sajandis Ometi on Eestis tingimused teaduse levikuks olemas - emakeelne ülikool, emakeelsed tippteadlased Teaduse roll julgeoleku tagamisel Teaduse ja teadmiste roll vabaduse loomisel Eestile on teadus üks väheseid teid rikkuse juurde Positiivseid näiteid kuidas teadusest on spordis kasu (GH juhtum) Sulev Kõks (Patofüsioloogia) Teadus ja sport April 17, / 26

21 Newtoni juhtum 9 Terry Newton, former Great Britain hooker, has been found hanged Rugby league star was the first professional sportsman in the world to test positive for human growth hormone Andy Wilson The Guardian, Sunday 26 September BST Terry Newton during the Super League Magic Weekend match between Wakefield Wildcats and Bradford Bulls. Photograph: Hamish Blair/Getty Images Terry Newton, one of the best British rugby league players of the last two decades, who earlier this year became the first professional sportsman in the world to test positive for human growth hormone (HGH), was found hanged today. Newton had left a message on his Facebook page in the early hours of the morning 9 stating "Luv U all but it's end time". Police were called to his house in Orrell, on the outskirts of Wigan, shortly after 2pm, Sulev Kõks (Patofüsioloogia) and discovered the body of the 31-year-old Teadusin jathe sport garage where, in the past, he had April 17, / 26

22 Teaduspõhisuse raskused Teaduspõhisus on teaduslikult tõestatud soovituste kasutamine Elu on teadusest läbipõimunud, kuid seda ei tunnistata Teaduspõhisust hävitab primitiivne ja kallutatud maailmavaade Arrogantsed asjaarmastajad täidavad kogu meedia pseudoteadusega Arvamusliider ei ole teadmiste liider, mitte kõik kes nimetavad end teadlaseks, ei ole seda Liiga jäik suhtumine ja vähene avatus Sulev Kõks (Patofüsioloogia) Teadus ja sport April 17, / 26

23 Teaduse olulisus Ennustatavus Teadus muudab sportlase arengu ennustatavaks Planeerimine Teadus aitab planeerida tegevusi ja prioriteete Ressursid Teadus aitab ressurssi kasutada optimaalselt Talendid Teadus aitab talendid ülesse leida Sulev Kõks (Patofüsioloogia) Teadus ja sport April 17, / 26

24 Järeldused Järeldus 1 Kui me soovime spordis tipptasemel konkurentsis olla, tuleb tippteadus appi võtta Järeldus 2 Teaduse rakendamine vajab strateegilist otsust koos vastavate vahendite tagamisega Järeldus 3 Poole teraga pole mõtet edasi minna, see on enesepetmine Sulev Kõks (Patofüsioloogia) Teadus ja sport April 17, / 26

25 Tänan tähelepanu eest! Sulev Kõks (Patofüsioloogia) Teadus ja sport April 17, / 26

26 Viidatud kirjandus PLoS Biol, 2004 Genetics of Bone Biology and Skeletal Diseases, 2013, San Diego Nat Rev Endocrinol, 2013 Twin Res Hum Genet, 2007 British Medical Bulletin, 2010 J Appl Physiol, 2010 J Physiol, 2011 Recent Patents on DNA and Gene Sequences, 2012 Br J Sports Med, 2014 Sulev Kõks (Patofüsioloogia) Teadus ja sport April 17, / 26