Perimä liikunnan määrän sekä liikunnan ja kuolleisuuden yhteyden selittäjänä

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1 Perimä liikunnan määrän sekä liikunnan ja kuolleisuuden yhteyden selittäjänä Urho Kujala, MD, PhD Professor of Sports & Exercise Medicine Department of Health Sciences, University of Jyväskylä, Finland

2 Käsitteitä Geeni: DNA-molekyylin toiminnallinen osa. Voi olla joko yhtäjaksoinen tai hajaantuneina pätkinä DNA:n emäsjärjestyksessä. Geeni ohjaa tietyn valkuaisaineen (proteiinin) tai proteiiniryhmän synteesiä. Proteiinisynteesi: Geenin (DNA:n) tieto käännetään proteiinien rakenteiksi. Geeni luetaan, kopioidaan, käännetään aminohappojärjestykseksi ja lopuksi aminohappoketju jalostetaan proteiiniksi. Geenitesti: Selvittää löytyykö genomista tietty geenin muoto. Testi saattaa kertoa esim. taipumuksesta perinnölliseen ominaisuuteen tai sairauteen. Voidaan saada tietoa sukulaisuussuhteista.

3 Mitokondriaalinen DNA (mtdna) Ihmisen mtdna on kaksoiskierteinen rengasmainen DNA-molekyyli, jota esiintyy soluliman mitokondrioissa, periytyy maternaalisesti eli äidiltä munasolun välityksellä.

4 Epigenetiikka Epigeneettinen periytyminen tarkoittaa perinnöllisen tiedon siirtoa joko solun tai eliön jälkeläiselle ilman, että tieto on koodattuna DNA/RNA-segvenssiin. Epigeneettiset säätelytekijät voivat aktivoida tai passivoida geenejä. Näin myös hankitut ominaisuudet voivat periytyä. Epigeneettinen periytyminen voi tapahtua esimerkiksi DNA:han liittyneen proteiinin välityksellä. Esimerkiksi metyyliryhmät voivat passivoida geenin liittymällä muutoin luettavaan DNA-rihman osaan. Metyyliryhmät estävät geenejä lukevien entsyymien pääsyn geeniin asettumalla niiden tielle.

5 Runsaslukuinen suolistomikrobien DNA

6 Ominaisuuksien periytyvyyden arviointi Sitä, onko jokin ominaisuus periytyvä, voidaan tutkia kaksos- tai perhetutkimuksilla, vaikka ei varsinaisesti olisikaan analysoitu itse geenejä. Näin onkin saatu runsaasti tietoa siitä kuinka periytyviä erilaiset ominaisuudet ovat väestössä keskimäärin.

7 Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4 4 million participants Figure 3. Age-standardised prevalence of diabetes in adult men by country in 1980 and 2014 Figure 4. Age-standardised prevalence of diabetes in adult women by country in 1980 and 2014 Lancet, Volume 387, Issue 10027, 2016,

8 Age-standardized and crude prevalence of diabetes Lancet Apr 9;387(10027):

9 Long-Term Leisure-Time Physical Activity and Serum Metabolome Kujala et al. Circulation 2013;127:

10 Studies among London busmen (drivers vs. conductors) Morris JN et al. Coronary heart-disease and physical activity of work. Lancet 1953; Idea suggested by the observation of the transport workers that physical activity at work is important in relation to coronary heart-disease of middle aged men Morris JN et al. Physique of London busmen. Epidemiology of uniforms. Lancet 1956; Drivers are bigger than conductors even at ages when joining the service

11 Physical activity, morbidity and mortality Experiences from Finnish former athlete and twin studies

12 Prevalence of diabetes and CHD in male former elite athletes and controls ORs compared to controls, and adjusted for age, BMI, smoking, and SES 1,4 1,2 1 0,8 0,6 0,4 0,2 0 DM CHD (Kujala et al. Metabolism 1994;10: ) Controls Endurance Mixed Power The low prevalence of T2D and CHD among former endurance athletes is a combined effect of natural selection to aerobic sports (inherited fitness) and continuous physical activity. This type of selection bias/genetic pleiotropy is likely to be true for all observational follow-up studies on physical activity.

13 Life expectancy by type of sport Adjusted for SES and marital status Endurance sports 75.6 years Mixed sports 72.7 years Power sports 71.5 years Controls 69.9 years (Sarna et al. Med Sci Sports Exerc 1993;25: )

14 SMRs by Type of Sport (Kujala et al. JAMA 2001;285:44-45.) 1 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0 Population Endurance Mixed Power

15 Odds Ratio TWINS: Modifiable Risk Factors as Predictors of All-Cause Mortality: The Roles of Genetic and Childhood Environment 2 1,5 1 0,5 Control for childhood environment and genes Active Inactive 0 Individual DZ pairs MZ pairs Active participated in leisure-time physical activity which was more strenuous than normal walking in 1975 and in 1981; inactive did not. Follow-up of deaths from 1983 to Data sources for baseline health: Exclusion of subjects with chronic disease based on questionnaires in 1975 & 1981, hospital discharge reports, reimbursable medication reports, malignant cancer reports, deaths before Jan Kujala et al. Am J Epidemiol 2002;156:

16 Odds Ratio TWINS: Modifiable Risk Factors as Predictors of All-Cause Mortality: The Roles of Genetic and Childhood Environment Non-smoker Smoker 0 Individual DZ pairs MZ pairs Smoker smoked regularly in 1975 and in 1981; non-smoker did not. Follow-up of deaths from 1983 to Data sources for baseline health: Exclusion of subjects with chronic disease based on questionnaires in 1975 & 1981, hospital discharge reports, reimbursable medication reports, malignant cancer reports, deaths before Jan Kujala et al. Am J Epidemiol 2002;156:

17 Mortality in meta-analyses of exercise vs. control RCTs Exercise therapy, expected to lead to a decreased risk of death, is commonly practiced in well-planned RCTs for cardiac patients. No statistically significant reduction in all-cause mortality seen in the latest and largest meta-analyses inclusive of exercise-based cardiac rehabilitation for coronary heart disease (meta-analysis including 47 studies with 12,455 participants; Anderson L et al. J Am Coll Cardiol 2016; 67: 1-12), and exercise-based rehabilitation for heart failure (meta-analysis including 25 trials with 1,871 participants; Sagar VA et al. Open Heart 2015; 2: e000163). Select trials have reported long-term follow-up results with a tendency towards reduced all-cause mortality in exercise intervention groups compared to controls, but the issue of potential publication bias is difficult to analyse in these scenarios.

18 Heritability in twin studies Falconer's formula is the most simple way used in twin studies to determine the (genetic) heritability of a trait based on the difference between twin correlations. The formula is h 2 = 2(r mz - r dz ), where h 2 is the heritability, r mz is the (monozygotic, MZ) identical twin correlation, and r dz is the (dizygotic, DZ) fraternal twin correlation. ACE-models

19 Heritability of physical activity Australia Netherlands GB Sweden Finland Denmark 0 Heritability % by country (Stubbe et al. Plos One 2006)

20 Heritability of physical activity and inactivity Proportion of variance attributed to additive genetic effects for: Persistent vigorous physical activity participation 55% Persistently low vs. high activity volume 45% Persistently sedentary work 50% (Kujala et al. Am J Epidemiol 2002;156: ) Physical inactivity: 25 to 60% (A review by de Vilhena e Santos et al. 2012) Physical inactivity/sitting time in Finnish twins 35% (Piirtola et al. Biomed Res Int 2014)

21 Distribution of maximal oxygen uptake increase during 20 wk training 1,2 1 Change in VO 2max 0,8 0,6 0,4 0,2 0 Heritage family study. Med Sci Sports Exerc 2001;33:S446-S451. Need for control samples? Inter-Individual Responses of Maximal Oxygen Uptake to Exercise Training: A Critical Review. Williamson PJ, et al. Sports Med

22 We know the heritability of at least 8x as many traits as have undergone gwas: Mission: incomplete

23 Tunnetaanko geenit? Fyysistä aktiivisuutta selittäviä yksittäisiä geenejä tunnetaan vielä varsin huonosti. Fyysiseen aktiivisuuteen vaikuttaa suuri joukko geenejä. Analyysiä mutkistaa se, että aktiivisuuden taustalla on useita eri ominaisuuksia (motivaatio, suorituskyky yms.). Lisäksi on monia tekijöitä, jotka vaikuttavat siihen, miten tietyt geenit valmistavat niitä vastaavia proteiineja. Viime vuosina on lisäksi alettu ymmärtää, että asiaa voi mutkistaa vielä geeneihin liittyvät ympäristötekijöiden aiheuttamat muutokset (epigenetiikka), jotka nekin voivat periytyä seuraavalle sukupolvelle. Geenitestein ei tällä hetkellä kannata selvittää minkälaista liikuntaa kannattaisi harrastaa muut mittaukset parempia.

24 Karvinen S, Waller K, Silvennoinen M, Koch LG, Britton SL, Kaprio J, Kainulainen H, Kujala UM: Physical activity in adulthood: genes and mortality. Scientific Reports 2015;5:18259; doi: /srep

25 Genetic background and lifespan Animal model of intrinsic aerobic capacity HCR (High-capacity runner) LCR (Low-capacity runner) Maximal running distance of HCR/LCR rats from generations 0 to 28: Violin-plots" for individual Generations. Yellow oval represents the founder population (NIH:H). Modified from Ren et al High intrinsic aerobic capacity >> Long lifespan Read more: Koch L G et al. Circulation Research 2011;109:

26 Physical activity questionnaires: 1975, 1981, 1990 DZ = dizygotic MZ = monozygotic n = 134 n = 34 DZ = dizygotic MZ = monozygotic Non-active Active Non-active Active MET 1.2 ± ± ± ± 2.0 Karvinen et al. Scientific Reports 2015;5:18259

27 Survival % Survival % HCR HCR- R LCR LCR-R Results: Rats Age (months) Age (months) The pool of LCR and HCR runner rats had an increased risk of death compared to control groups: HR 2.1 (95% CI 1.3 to 3.4), p< The finding persisted after adjustment for strain, age at randomization and body weight at 9 months: HR 2.3 (95% CI ), p<0.001 Karvinen et al. Scientific Reports 2015;5:18259

28 Pairwise Hazard Ratio Pairwise HRs of death among DZ and MZ twin pairs discordant for vigorous physical activity in 1975 & 1981 and healthy at baseline 1,2 Inactive co-twins Active co-twins HR ,8 HR ,6 0,4 0,2 0 DZ pairs (N=778) MZ pairs (N=231) Karvinen et al. Scientific Reports 2015;5:18259

29 Results, conclusions and future aspects Previous observational follow-up studies in humans suggested that increasing physical activity levels could prolong life» Our controlled intervention study with rats showed contrasting results» We did not see the suggested association in pairwise analysis among monozygotic twin pairs Genetic pleiotropy might explain at least part of the previously observed associations between high baseline physical activity and later reduced mortality in humans We showed that the same genetic factors influenced physical activity levels, cardiorespiratory fitness and risk of death Our results also supported the notion that inherited aerobic capacity is a strong determinant of longevity Further study is required to determine whether this is true for aerobic capacity enhanced by exercise In our animal experiment, divergence in physical activity started in early adulthood, which is typically the case in physical activity-discordant MZ twin pairs More studies are needed to determine whether physical activity might affect lifespan differently when started early in life

30 Concluding comments:

31 Absolute intensity categories (METs) Relative intensity categories (%VO 2 reserve) Physical activity: Absolute intensity versus relative-to-fitness-level volumes Vigorous intensity; VPA Abs 60% 40% 6 METs 3 METs Moderate intensity; MPA Abs Low-fit individuals High-fit individuals Kujala et al. Med Sci Sports Exerc 2017; 49:

32 Thank You! Key-collaorators: Jaakko Kaprio, Markku Koskenvuo, Seppo Sarna, Heikki Kainulainen, Kirsi Pietiläinen, Karri Silventoinen, Mika Ala-Korpela, Alfredo Ortega-Alonso, Katja Waller, Tuija Leskinen, Sari Aaltonen, Sara Mutikainen, Sira Karvinen, Mirva Rottensteiner Key funding: NIH, EU, Academy of Finland, Finnish Ministry of Education and Culture, Juho Vainio Foundation and other Finnish foundations