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1.  Objectively measured physical activity in Finnish employees: a cross-sectional study 
BMJ Open  2014;4(12):e005927.
Objectives
To objectively measure the amount of intensity-specific physical activity by gender and age with respect to body mass index (BMI) during workdays and days off among Finnish employees.
Design
A cross-sectional study.
Setting
Primary care occupational healthcare units.
Participants
A sample of 9554 Finnish employees (4221 men and 5333 women; age range 18–65 years; BMI range 18.5–40 kg/m2) who participated in health assessments related to occupational health promotion.
Main outcome measurements
The amount of moderate-to-vigorous (MVPA) and vigorous (VPA) physical activity (≥3 and ≥6 metabolic equivalents, respectively) was assessed by estimating the minute-to-minute oxygen consumption from the recorded beat-to-beat R-R interval data. The estimation method used heart rate, respiration rate and on/off response information from R-R interval data calibrated by age, gender, height, weight and self-reported physical activity class. The proportion of participants fulfilling the aerobic physical activity recommendation of ≥150 min/week was calculated on the basis of ≥10 min bouts, by multiplying the VPA minutes by 2.
Results
Both MVPA and VPA were higher among men and during days off, and decreased with increasing age and BMI (p<0.001 for all). Similar results were observed when the probability of having a bout of MVPA or VPA lasting continuously for ≥10 min per measurement day was studied. The total amount of VPA was low among overweight (mean ≤2.6 min/day), obese (mean ≤0.6 min/day) and all women in the age group 51–65 years (mean ≤2.5 min/day) during both types of days. The proportion of participants fulfilling the aerobic physical activity recommendation was highest for normal weight men (65%; 95% CI 62% to 67%) and lowest for obese women (10%; 95% CI 8% to 12%).
Conclusions
Objectively measured physical activity is higher among men and during days off, and decreases with increasing age and BMI. The amount of VPA is very low among obese, overweight and older women.
doi:10.1136/bmjopen-2014-005927
PMCID: PMC4265094  PMID: 25500160
Physical activity; Obesity; Exercise intensity; Heart rate variability; Objective monitoring
2.  Increase in physical activity and cardiometabolic risk profile change during lifestyle intervention in primary healthcare: 1-year follow-up study among individuals at high risk for type 2 diabetes 
BMJ Open  2011;1(2):e000292.
Objectives
To investigate the association between increase in physical activity and changes in cardiometabolic risk factors during a lifestyle intervention programme in routine clinical settings.
Design
Prospective follow-up.
Setting
400 primary healthcare centres and occupational healthcare outpatient clinics in Finland.
Participants
Individuals at high risk for type 2 diabetes identified in the implementation project of the national diabetes prevention programme (FIN-D2D) and participating in baseline and 1-year follow-up visits. Final study group comprised the 1871 non-diabetic participants who responded at follow-up visit to a question on stability versus increase of physical activity.
Interventions
Lifestyle intervention.
Primary outcome measures
Cardiometabolic risk factors (body composition, blood pressure and those measured from fasting venous blood samples) measured at baseline and follow-up visits.
Results
Of the participants, 310 (16.6% of all responders) reported at follow-up having clearly increased their physical activity during the past year, while 1380 (73.8%) had been unable to increase their physical activity. Those who increased their activity decreased their weight by 3.6 kg (95% CI 2.9 to 4.3, age and sex adjusted, p<0.001) and waist circumference by 3.6 cm (95% CI 2.9 to 4.3, p<0.001) more than those who did not increase their activity. Similarly, those who increased their physical activity had greater reductions in total cholesterol (group difference in reduction 0.17 mmol/l, 95% CI 0.06 to 0.28, p=0.002), low-density lipoprotein cholesterol (0.16 mmol/l, 95% CI 0.06 to 0.26, p=0.001), low-density lipoprotein/high-density lipoprotein ratio (0.17, 95% CI 0.08 to 0.25, p<0.001) as well as fasting glucose (0.09 mmol/l, 95% CI 0.03 to 0.15, p=0.004) and 2 h glucose levels (0.36 mmol/l, 95% CI 0.17 to 0.55, p=0.023) than those who did not increase their physical activity.
Conclusion
Increasing physical activity seems to be an important feature of cardiometabolic risk reduction among individuals at high risk for type 2 diabetes participating in preventive interventions in routine clinical settings.
Article summary
Article focus
There is evidence from randomised controlled trials that supervised exercise interventions improve cardiometabolic risk factor levels.
It is not known how knowledge from intensive interventions of randomised clinical trials can be applied in various real-life clinical settings with limited resources.
In this paper, we report the results of an analysis of physical activity changes and their association to cardiometabolic risk factors among individual at high risk for type 2 diabetes and participating in preventive lifestyle intervention in routine clinical settings of primary healthcare.
Key messages
Less than one-fifth of the participants reported at ‘1-year’ follow-up having clearly increased their physical activity during the past year.
Those who increased their activity improved clearly their cardiometabolic risk profile including reductions of waist circumference and fasting low-density lipoprotein cholesterol and glucose levels, which result persisted after the adjustment for dietary change.
Increasing physical activity seems to be an important feature of cardiometabolic risk reduction among individuals at high risk for type 2 diabetes participating in preventive interventions in routine clinical settings.
Strengths and limitations
FIN-D2D is the first national effort to implement the prevention of diabetes in a primary healthcare setting.
Follow-up data on the changes in physical activity are available from a subgroup of participants.
The limitations of this report include that physical activity changes are documented by a questionnaire.
doi:10.1136/bmjopen-2011-000292
PMCID: PMC3244658  PMID: 22184585
3.  The effectiveness and applicability of different lifestyle interventions for enhancing wellbeing: the study design for a randomized controlled trial for persons with metabolic syndrome risk factors and psychological distress 
BMC Public Health  2014;14:310.
Background
Obesity and stress are among the most common lifestyle-related health problems. Most of the current disease prevention and management models are not satisfactorily cost-effective and hardly reach those who need them the most. Therefore, novel evidence-based controlled interventions are necessary to evaluate models for prevention and treatment based on self-management. This randomized controlled trial examines the effectiveness, applicability, and acceptability of different lifestyle interventions with individuals having symptoms of metabolic syndrome and psychological distress. The offered interventions are based on cognitive behavioral approaches, and are designed for enhancing general well-being and supporting personalized lifestyle changes.
Methods/Design
339 obese individuals reporting stress symptoms were recruited and randomized to either (1) a minimal contact web-guided Cognitive Behavioral Therapy-based (CBT) intervention including an approach of health assessment and coaching methods, (2) a mobile-guided intervention comprising of mindfulness, acceptance and value-based exercises, (3) a face-to-face group intervention using mindfulness, acceptance and value-based approach, or (4) a control group. The participants were measured three times during the study (pre = week 0, post = week 10, and follow-up = week 36). Psychological well-being, lifestyles and habits, eating behaviors, and user experiences were measured using online surveys. Laboratory measurements for physical well-being and general health were performed including e.g. liver function, thyroid glands, kidney function, blood lipids and glucose levels and body composition analysis. In addition, a 3-day ambulatory heart rate and 7-day movement data were collected for analyzing stress, recovery, physical activity, and sleep patterns. Food intake data were collected with a 48 -hour diet recall interview via telephone. Differences in the effects of the interventions would be examined using multiple-group modeling techniques, and effect-size calculations.
Discussion
This study will provide additional knowledge about the effects of three low intensity interventions for improving general well-being among individuals with obesity and stress symptoms. The study will show effects of two technology guided self-help interventions as well as effect of an acceptance and value–based brief group intervention. Those who might benefit from the aforesaid interventions will increase knowledge base to better understand what mechanisms facilitate effects of the interventions.
Trial registration
Current Clinical Trials NCT01738256, Registered 17 August, 2012.
doi:10.1186/1471-2458-14-310
PMCID: PMC4006637  PMID: 24708617
Lifestyle; Well-being; Obesity; Stress; Acceptance and Commitment Therapy; Cognitive behavioral therapy; Mobile application; Web-based intervention; Technology-aided interventions
4.  Effects of a progressive aquatic resistance exercise program on the biochemical composition and morphology of cartilage in women with mild knee osteoarthritis: protocol for a randomised controlled trial 
Background
Symptoms associated with osteoarthritis of the knee result in decreased function, loss of working capacity and extensive social and medical costs. There is a need to investigate and develop effective interventions to minimise the impact of and even prevent the progression of osteoarthritis. Aquatic exercise has been shown to be effective at reducing the impact of osteoarthritis. The purpose of this article is to describe the rationale, design and intervention of a study investigating the effect of an aquatic resistance exercise intervention on cartilage in postmenopausal women with mild knee osteoarthritis.
Methods
A minimum of 80 volunteers who meet the inclusion criteria will be recruited from the local population through newspaper advertisements. Following initial assessment volunteers will be randomised into two groups. The intervention group will participate in a progressive aquatic resistance exercise program of 1-hour duration 3 times a week for four months. The control group will be asked to maintain normal care during this period. Primary outcome measure for this study is the biochemical composition of knee cartilage measured using quantitative magnetic resonance imaging; T2 relaxation time and delayed gadolinium-enhanced magnetic resonance imaging techniques. In addition, knee cartilage morphology as regional cartilage thickness will be studied. Secondary outcomes include measures of body composition and bone traits using dual energy x-ray absorptiometry and peripheral quantitative computed tomography, pain, function using questionnaires and physical performance tests and quality of life. Measurements will be performed at baseline, after the 4-month intervention period and at one year follow up.
Discussion
This randomised controlled trial will investigate the effect a progressive aquatic resistance exercise program has on the biochemical composition of cartilage in post-menopausal women with mild knee osteoarthritis. This is the first study to investigate what impact aquatic exercise has on human articular cartilage. In addition it will investigate the effect aquatic exercise has on physical function, pain, bone and body composition and quality of life. The results of this study will help optimise the prescription of aquatic exercise to persons with mild knee osteoarthritis.
Trial Registration
ISRCTN65346593
doi:10.1186/1471-2474-14-82
PMCID: PMC3599473  PMID: 23497162
Osteoarthritis; Quantitative MRI; T2 relaxation time; dGEMRIC; Bone; Aquatic exercise
5.  Perceived need to increase physical activity levels among adults at high risk of type 2 diabetes. A cross-sectional analysis within a community-based diabetes prevention project FIN-D2D 
BMC Public Health  2012;12:514.
Background
Increased physical activity is a cornerstone of type 2 diabetes prevention. The perception of a need to change is considered essential in behaviour change processes. However, the existing literature on individuals’ perceived need to change health behaviour is limited. In order to improve understanding of diabetes prevention through increased physical activity levels (PAL), we assessed factors associated with perceiving a need to increase PAL among adults at high risk of diabetes.
Methods
Opportunistic screening was used within a primary-care based lifestyle intervention covering 10 149 men and women at high risk of type 2 diabetes. Data were obtained at baseline visits. The explored determinants were demographic, anthropometric/clinical, behavioural and psychosocial characteristics, along with four categories of PAL awareness. Logistic regression was used in the analysis.
Results
74% of men (n = 2 577) and 76% of women (n = 4 551) perceived a need to increase their PAL. The participants most likely to perceive this need were inactive, had a larger waist circumference, rated their PAL as insufficient, and were at the contemplation stage of change. Smoking, elevated blood pressure, dyslipidaemia, and a family history of diabetes were not associated with this perception. The likelihood was also greater among women with less perceived fitness and less education. Demographic factors other than education did not determine participants’ perceived need to increase PAL. PAL overestimators were less likely to perceive the need to increase their PAL than realistic inactive participants.
Conclusions
Subjective rather than objective health factors appear to determine the perception of a need to increase PAL among adults at high risk of diabetes. Client perceptions need to be evaluated in health counselling in order to facilitate a change in PAL. Practical descriptions of the associations between metabolic risk factors, PAL, and diabetes are needed in order to make the risk factors concrete for at-risk individuals.
doi:10.1186/1471-2458-12-514
PMCID: PMC3506518  PMID: 22781026
Physical activity; Exercise; Behaviour change; Perception; Awareness; Type 2 diabetes; Prevention; FIN-D2D; Lifestyle intervention
6.  Effects of diet-induced obesity and voluntary wheel running on the microstructure of the murine distal femur 
Background
Obesity and osteoporosis, two possibly related conditions, are rapidly expanding health concerns in modern society. Both of them are associated with sedentary life style and nutrition. To investigate the effects of diet-induced obesity and voluntary physical activity we used high resolution micro-computed tomography (μCT) together with peripheral quantitative computed tomography (pQCT) to examine the microstructure of the distal femoral metaphysis in mice.
Methods
Forty 7-week-old male C57BL/6J mice were assigned to 4 groups: control (C), control + running (CR), high-fat diet (HF), and high-fat diet + running (HFR). After a 21-week intervention, all the mice were sacrificed and the left femur dissected for pQCT and μCT measurements.
Results
The mice fed the high-fat diet showed a significant weight gain (over 70% for HF and 60% for HFR), with increased epididymal fat pad mass and impaired insulin sensitivity. These obese mice had significantly higher trabecular connectivity density, volume, number, thickness, area and mass, and smaller trabecular separation. At the whole bone level, they had larger bone circumference and cross-sectional area and higher density-weighted maximal, minimal, and polar moments of inertia. Voluntary wheel running decreased all the cortical bone parameters, but increased the trabecular mineral density, and decreased the pattern factor and structure model index towards a more plate-like structure.
Conclusions
The results suggest that in mice the femur adapts to obesity by improving bone strength both at the whole bone and micro-structural level. Adaptation to running exercise manifests itself in increased trabecular density and improved 3D structure, but in a limited overall bone growth
doi:10.1186/1743-7075-8-1
PMCID: PMC3034661  PMID: 21241467
7.  Differences in Muscle and Adipose Tissue Gene Expression and Cardio-Metabolic Risk Factors in the Members of Physical Activity Discordant Twin Pairs 
PLoS ONE  2010;5(9):e12609.
High physical activity/aerobic fitness predicts low morbidity and mortality. Our aim was to identify the most up-regulated gene sets related to long-term physical activity vs. inactivity in skeletal muscle and adipose tissues and to obtain further information about their link with cardio-metabolic risk factors. We studied ten same-sex twin pairs (age range 50–74 years) who had been discordant for leisure-time physical activity for 30 years. The examinations included biopsies from m. vastus lateralis and abdominal subcutaneous adipose tissue. RNA was analyzed with the genome-wide Illumina Human WG-6 v3.0 Expression BeadChip. For pathway analysis we used Gene Set Enrichment Analysis utilizing active vs. inactive co-twin gene expression ratios. Our findings showed that among the physically active members of twin pairs, as compared to their inactive co-twins, gene expression in the muscle tissue samples was chronically up-regulated for the central pathways related to energy metabolism, including oxidative phosphorylation, lipid metabolism and supportive metabolic pathways. Up-regulation of these pathways was associated in particular with aerobic fitness and high HDL cholesterol levels. In fat tissue we found physical activity-associated increases in the expression of polyunsaturated fatty acid metabolism and branched-chain amino acid degradation gene sets both of which associated with decreased ‘high-risk’ ectopic body fat and plasma glucose levels. Consistent with other findings, plasma lipidomics analysis showed up-regulation of the triacylglycerols containing the polyunsaturated fatty acids. Our findings identified skeletal muscle and fat tissue pathways which are associated with the long-term physical activity and reduced cardio-metabolic disease risk, including increased aerobic fitness. In particular, improved skeletal muscle oxidative energy and lipid metabolism as well as changes in adipocyte function and redistribution of body fat are associated with reduced cardio-metabolic risk.
doi:10.1371/journal.pone.0012609
PMCID: PMC2940764  PMID: 20862330
8.  Hormone replacement therapy enhances IGF-1 signaling in skeletal muscle by diminishing miR-182 and miR-223 expressions: a study on postmenopausal monozygotic twin pairs 
Aging Cell  2014;13(5):850-861.
MiRNAs are fine-tuning modifiers of skeletal muscle regulation, but knowledge of their hormonal control is lacking. We used a co-twin case–control study design, that is, monozygotic postmenopausal twin pairs discordant for estrogen-based hormone replacement therapy (HRT) to explore estrogen-dependent skeletal muscle regulation via miRNAs. MiRNA profiles were determined from vastus lateralis muscle of nine healthy 54–62-years-old monozygotic female twin pairs discordant for HRT (median 7 years). MCF-7 cells, human myoblast cultures and mouse muscle experiments were used to confirm estrogen’s causal role on the expression of specific miRNAs, their target mRNAs and proteins and finally the activation of related signaling pathway. Of the 230 miRNAs expressed at detectable levels in muscle samples, qPCR confirmed significantly lower miR-182, miR-223 and miR-142-3p expressions in HRT using than in their nonusing co-twins. Insulin/IGF-1 signaling emerged one common pathway targeted by these miRNAs. IGF-1R and FOXO3A mRNA and protein were more abundantly expressed in muscle samples of HRT users than nonusers. In vitro assays confirmed effective targeting of miR-182 and miR-223 on IGF-1R and FOXO3A mRNA as well as a dose-dependent miR-182 and miR-223 down-regulations concomitantly with up-regulation of FOXO3A and IGF-1R expression. Novel finding is the postmenopausal HRT-reduced miRs-182, miR-223 and miR-142-3p expression in female skeletal muscle. The observed miRNA-mediated enhancement of the target genes’ IGF-1R and FOXO3A expression as well as the activation of insulin/IGF-1 pathway signaling via phosphorylation of AKT and mTOR is an important mechanism for positive estrogen impact on skeletal muscle of postmenopausal women.
doi:10.1111/acel.12245
PMCID: PMC4331762  PMID: 25040542
aging; AKT; FOXO3A; IGF-1 signaling; IGF-1R; menopause; miR-142-3p; miR-182; miR-223; mTOR; phosphorylation
9.  Motives for Physical Activity among Active and Inactive Persons in Their Mid-Thirties 
The purpose of this study was to examine the motives for leisure time physical activity among active and inactive men and women in their mid-thirties. We used both cross-sectional and longitudinal designs. Altogether, 2308 participants (mean age 33.9 years, 53.4 % women) were identified from the population-based FinnTwin16 Cohort. Physically active and inactive individuals were identified on the basis of their leisure time MET hours/day. We evaluated participants’ physical activity motivation with a modified version of the Recreational Exercise Motivation Measure. Comparisons between active and inactive individuals were analysed using the Wald test for equality of means, and effect sizes were calculated as Cohen’s d. Motives related to mastery, physical fitness, social aspect of physical activity, psychological state, enjoyment, willingness to be fitter/look better than others and appearance were significantly more important for the active than inactive participants. Conforming to others’ expectations was the only item on which the inactive persons scored higher than active persons. The longitudinal results for physical activity were parallel to the cross-sectional results. This study supports to the view that motivation factors differ between active and inactive persons, and that intrinsic motives are associated with consistent leisure time physical activity.
doi:10.1111/sms.12040
PMCID: PMC3646077  PMID: 23331765
intrinsic motivation; extrinsic motivation; exercise; leisure time physical activity; leisure time physical inactivity
10.  Associations of physical activity, fitness, and body composition with heart rate variability–based indicators of stress and recovery on workdays: a cross-sectional study 
Background
The purpose of this study was to investigate how physical activity (PA), cardiorespiratory fitness (CRF), and body composition are associated with heart rate variability (HRV)-based indicators of stress and recovery on workdays. Additionally, we evaluated the association of objectively measured stress with self-reported burnout symptoms.
Methods
Participants of this cross-sectional study were 81 healthy males (age range 26–40 y). Stress and recovery on workdays were measured objectively based on HRV recordings. CRF and anthropometry were assessed in laboratory conditions. The level of PA was based on a detailed PA interview (MET index [MET-h/d]) and self-reported activity class.
Results
PA, CRF, and body composition were significantly associated with levels of stress and recovery on workdays. MET index (P < 0.001), activity class (P = 0.001), and CRF (P = 0.019) were negatively associated with stress during working hours whereas body fat percentage (P = 0.005) was positively associated. Overall, 27.5% of the variance of total stress on workdays (P = 0.001) was accounted for by PA, CRF, and body composition. Body fat percentage and body mass index were negatively associated with night-time recovery whereas CRF was positively associated. Objective work stress was associated (P = 0.003) with subjective burnout symptoms.
Conclusions
PA, CRF, and body composition are associated with HRV-based stress and recovery levels, which needs to be taken into account in the measurement, prevention, and treatment of work-related stress. The HRV-based method used to determine work-related stress and recovery was associated with self-reported burnout symptoms, but more research on the clinical importance of the methodology is needed.
doi:10.1186/1745-6673-9-16
PMCID: PMC3997193  PMID: 24742265
Body composition; Body fat percentage; BMI; Cardiorespiratory fitness; HRV; Physical activity; Recovery; Working hours; Work stress
11.  Factors behind Leisure-Time Physical Activity Behavior Based on Finnish Twin Studies: The Role of Genetic and Environmental Influences and the Role of Motives 
BioMed Research International  2014;2014:931820.
Different approaches are being taken to clarify the role of various factors in the development of physical activity behaviors. Genetic studies are a new area of physical activity research and also the motives for physical activity have been widely studied. The purpose of this paper is to review the findings emerging from the longitudinal genetic studies on leisure-time physical activity and to evaluate the associations between motivational factors and leisure-time physical activity. The focus is to review recent findings of longitudinal Finnish twin studies. The results of the latest longitudinal Finnish twin studies point to the existence of age-specific genetic and environmental influences on leisure-time physical activity. Variations in environmental factors seem to explain the observed deterioration in leisure-time physical activity levels. A decline in genetic influences is seen first from adolescence to young adulthood and again from the age of thirty to the mid-thirties. In the Finnish twin participants, mastery, physical fitness, and psychological state were the major motivation factors associated with consistent leisure-time physical activity behavior. The results also indicate that intrinsic motivation factors may be important for engagement in leisure-time physical activity.
doi:10.1155/2014/931820
PMCID: PMC3997869  PMID: 24809061
12.  Serum metabolic profiles in overweight and obese women with and without metabolic syndrome 
Objective
To identify serum biomarkers through metabolomics approach that distinguishes physically inactive overweight/obese women with metabolic syndrome from those who are metabolically healthy, independent of body weight and fat mass.
Methods
We applied nuclear magnetic resonance spectroscopy-based profiling of fasting serum samples to examine the metabolic differences between 78 previously physically inactive, body weight and fat mass matched overweight/obese premenopausal women with and without MetS. MetS was defined as the presence of at least three of the following five criteria: waist circumference ≥88 cm, serum triacylglycerol ≥1.7 mmol/L, and high density lipoprotein cholesterol (HDL-C) <1.30 mmol/L, blood pressure ≥ 130/85 mmHg and fasting glucose ≥5.6 mmol/L). Principal component analysis was used to reduce the large number of correlated variables to fewer uncorrelated factors.
Results
Two metabolic factors were associated with MetS independent of BMI, fat mass, waist circumference and physical activity/fitness. Factor comprising branched-chain amino acids (BCAA) and aromatic amino acids (AAA) and orosomucoid was associated with all clinical risk factors (p < 0.01 for all).
Conclusion
Two metabolic factors distinguish overweight/obese women with metabolic syndrome from those who are metabolically healthy independent of body weight, fat mass and physical activity/fitness. In particular, factor comprising BCAA, AAA and orosomucoid seems auspicious biomarker determining metabolic health as it was associated with all clinical risk factors. Further research is needed to determine the public health and clinical significance of these results in terms of screening to identify those at greatest cardio-metabolic risk for whom appropriate intervention strategies should be developed.
doi:10.1186/1758-5996-6-40
PMCID: PMC3998195  PMID: 24650495
Obesity; Metabolic syndrome; Metabolomics; Women
13.  Meta-analysis of genome-wide association studies confirms a susceptibility locus for knee osteoarthritis on chromosome 7q22 
Evangelou, Evangelos | Valdes, Ana M. | Kerkhof, Hanneke J.M | Styrkarsdottir, Unnur | Zhu, YanYan | Meulenbelt, Ingrid | Lories, Rik J. | Karassa, Fotini B. | Tylzanowski, Przemko | Bos, Steffan D. | Akune, Toru | Arden, Nigel K. | Carr, Andrew | Chapman, Kay | Cupples, L. Adrienne | Dai, Jin | Deloukas, Panos | Doherty, Michael | Doherty, Sally | Engstrom, Gunnar | Gonzalez, Antonio | Halldorsson, Bjarni V. | Hammond, Christina L. | Hart, Deborah J. | Helgadottir, Hafdis | Hofman, Albert | Ikegawa, Shiro | Ingvarsson, Thorvaldur | Jiang, Qing | Jonsson, Helgi | Kaprio, Jaakko | Kawaguchi, Hiroshi | Kisand, Kalle | Kloppenburg, Margreet | Kujala, Urho M. | Lohmander, L. Stefan | Loughlin, John | Luyten, Frank P. | Mabuchi, Akihiko | McCaskie, Andrew | Nakajima, Masahiro | Nilsson, Peter M. | Nishida, Nao | Ollier, William E.R. | Panoutsopoulou, Kalliope | van de Putte, Tom | Ralston, Stuart H. | Rivadeneira, Fernado | Saarela, Janna | Schulte-Merker, Stefan | Slagboom, P. Eline | Sudo, Akihiro | Tamm, Agu | Tamm, Ann | Thorleifsson, Gudmar | Thorsteinsdottir, Unnur | Tsezou, Aspasia | Wallis, Gillian A. | Wilkinson, J. Mark | Yoshimura, Noriko | Zeggini, Eleftheria | Zhai, Guangju | Zhang, Feng | Jonsdottir, Ingileif | Uitterlinden, Andre G. | Felson, David T | van Meurs, Joyce B. | Stefansson, Kari | Ioannidis, John P.A. | Spector, Timothy D.
Annals of the rheumatic diseases  2010;70(2):349-355.
Osteoarthritis (OA) is the most prevalent form of arthritis and accounts for substantial morbidity and disability, particularly in the elderly. It is characterized by changes in joint structure including degeneration of the articular cartilage and its etiology is multifactorial with a strong postulated genetic component. We performed a meta-analysis of four genome-wide association (GWA) studies of 2,371 knee OA cases and 35,909 controls in Caucasian populations. Replication of the top hits was attempted with data from additional ten replication datasets. With a cumulative sample size of 6,709 cases and 44,439 controls, we identified one genome-wide significant locus on chromosome 7q22 for knee OA (rs4730250, p-value=9.2×10−9), thereby confirming its role as a susceptibility locus for OA. The associated signal is located within a large (500kb) linkage disequilibrium (LD) block that contains six genes; PRKAR2B (protein kinase, cAMP-dependent, regulatory, type II, beta), HPB1 (HMG-box transcription factor 1), COG5 (component of oligomeric golgi complex 5), GPR22 (G protein-coupled receptor 22), DUS4L (dihydrouridine synthase 4-like), and BCAP29 (the B-cell receptor-associated protein 29). Gene expression analyses of the (six) genes in primary cells derived from different joint tissues confirmed expression of all the genes in the joint environment.
doi:10.1136/ard.2010.132787
PMCID: PMC3615180  PMID: 21068099
14.  Recommendations for standardization and phenotype definitions in genetic studies of osteoarthritis: the TREAT-OA consortium 
Objective
To address the need for standardization of osteoarthritis (OA) phenotypes by examining the effect of heterogeneity among symptomatic (SOA) and radiographic osteoarthritis (ROA) phenotypes.
Methods
Descriptions of OA phenotypes of the 28 studies involved in the TREAT-OA consortium were collected. To investigate whether different OA definitions result in different association results, we created hip OA definitions used within the consortium in the Rotterdam Study-I and tested the association of hip OA with gender, age and BMI using one-way ANOVA. For radiographic OA, we standardized the hip, knee and hand ROA definitions and calculated prevalence's of ROA before and after standardization in 9 cohort studies. This procedure could only be performed in cohort studies and standardization of SOA definitions was not feasible at this moment.
Results
In this consortium, all studies with symptomatic OA phenotypes (knee, hip and hand) used a different definition and/or assessment of OA status. For knee, hip and hand radiographic OA 5, 4 and 7 different definitions were used, respectively. Different hip OA definitions do lead to different association results. For example, we showed in the Rotterdam Study-I that hip OA defined as “at least definite JSN and one definite osteophyte” was not associated with gender (p=0.22), but defined as “at least one definite osteophyte” was significantly associated with gender (p=3×10−9). Therefore, a standardization process was undertaken for radiographic OA definitions. Before standardization a wide range of ROA prevalence's was observed in the 9 cohorts studied. After standardization the range in prevalence of knee and hip ROA was small. Standardization of SOA phenotypes was not possible due to the case-control design of the studies.
Conclusion
Phenotype definitions influence the prevalence of OA and association with clinical variables. ROA phenotypes within the TREAT-OA consortium were standardized to reduce heterogeneity and improve power in future genetics studies.
doi:10.1016/j.joca.2010.10.027
PMCID: PMC3236091  PMID: 21059398
15.  Power training and postmenopausal hormone therapy affect transcriptional control of specific co-regulated gene clusters in skeletal muscle 
Age  2010;32(3):347-363.
At the moment, there is no clear molecular explanation for the steeper decline in muscle performance after menopause or the mechanisms of counteractive treatments. The goal of this genome-wide study was to identify the genes and gene clusters through which power training (PT) comprising jumping activities or estrogen containing hormone replacement therapy (HRT) may affect skeletal muscle properties after menopause. We used musculus vastus lateralis samples from early stage postmenopausal (50–57 years old) women participating in a yearlong randomized double-blind placebo-controlled trial with PT and HRT interventions. Using microarray platform with over 24,000 probes, we identified 665 differentially expressed genes. The hierarchical clustering method was used to assort the genes. Additionally, enrichment analysis of gene ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways was carried out to clarify whether assorted gene clusters are enriched with particular functional categories. The analysis revealed transcriptional regulation of 49 GO/KEGG categories. PT upregulated transcription in “response to contraction”—category revealing novel candidate genes for contraction-related regulation of muscle function while HRT upregulated gene expression related to functionality of mitochondria. Moreover, several functional categories tightly related to muscle energy metabolism, development, and function were affected regardless of the treatment. Our results emphasize that during the early stages of the postmenopause, muscle properties are under transcriptional modulation, which both PT and HRT partially counteract leading to preservation of muscle power and potentially reducing the risk for aging-related muscle weakness. More specifically, PT and HRT may function through improving energy metabolism, response to contraction as well as by preserving functionality of the mitochondria.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-010-9140-1) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-010-9140-1
PMCID: PMC2926854  PMID: 20640546
Transcriptome-wide study; Power training; Plyometric training; Estrogen deprivation; Hormone replacement therapy; Menopause; Skeletal muscle characteristics
16.  Allelic variants of IL1R1 gene associate with severe hand osteoarthritis 
BMC Medical Genetics  2010;11:50.
Background
In search for genes predisposing to osteoarthritis (OA), several genome wide scans have provided evidence for linkage on 2q. In this study we targeted a 470 kb region on 2q11.2 presenting the locus with most evidence for linkage to severe OA of distal interphalangeal joints (DIP) in our genome wide scan families.
Methods
We genotyped 32 single nucleotide polymorphisms (SNPs) in this 470 kb region comprising six genes belonging to the interleukin 1 superfamily and monitored for association with individual SNPs and SNP haplotypes among severe familial hand OA cases (material extended from our previous linkage study; n = 134), unrelated end-stage bilateral primary knee OA cases (n = 113), and population based controls (n = 436).
Results
Four SNPs in the IL1R1 gene, mapping to a 125 kb LD block, provided evidence for association with hand OA in family-based and case-control analysis, the strongest association being with SNP rs2287047 (p-value = 0.0009).
Conclusions
This study demonstrates an association between severe hand OA and IL1R1 gene. This gene represents a highly relevant biological candidate since it encodes protein that is a known modulator of inflammatory processes associated with joint destruction and resides within a locus providing consistent evidence for linkage to hand OA. As the observed association did not fully explain the linkage obtained in the previous study, it is plausible that also other variants in this genome region predispose to hand OA.
doi:10.1186/1471-2350-11-50
PMCID: PMC2859817  PMID: 20353565
17.  Effects of Long-Term Physical Activity on Cardiac Structure and Function: A Twin Study 
Previous studies have shown that athletic training or other physical activity causes structural and functional adaptations in the heart, but less is known how long-term physical activity affects heart when genetic liability and childhood environment are taken into account. The aim of this study was to investigate the effects of long-term physical activity vs. inactivity on cardiac structure and function in twin pairs discordant for physical activity for 32 years. Twelve same-sex twin pairs (five monozygotic and seven dizygotic, 50-67 years) were studied as a part of the TWINACTIVE study. Discordance in physical activity was initially determined in 1975 and it remained significant throughout the follow-up. At the end of the follow-up in 2007, resting echocardiographic and electrocardiographic measurements were performed. During the follow-up period, the active co-twins were on average 8.2 (SD 4.0) MET hours/day more active than their inactive co-twins (p < 0.001). At the end of the follow-up, resting heart rate was lower in the active than inactive co-twins [59 (SD 5) vs. 68 (SD 10) bpm, p=0.03]. The heart rate-corrected QT interval was similar between the co-twins. Also, there was a tendency for left ventricular mass per body weight to be greater and T wave amplitude in lead II to be higher in the active co-twins (18% and 15%, respectively, p=0.08 for both). Similar trends were found for both monozygotic and dizygotic twin pairs. In conclusion, the main adaptation to long- term physical activity is lowered resting heart rate, even after partially or fully controlling for genetic liability and childhood environment.
Key pointsThe main adaptation to long-term physical activity is lowering of resting heart rate, even after controlling for genetic liability.VO2peak is increased in the active co-twins compared with their inactive co-twins and accordingly, also submaximal heart rates during the clinical exercise test are lower in physically active co-twins.There is a tendency for increased LVM per body weight and heightened T wave amplitude in the active co-twins.
PMCID: PMC3761543  PMID: 24149594
Exercise; echocardiography; electrocardiography; heart rate; controlling for genetic liability; longitudinal study
18.  Physical Activity in Adolescence as a Predictor of Alcohol and Illicit Drug Use in Early Adulthood: A Longitudinal Population Based Twin Study 
We investigated prospectively whether physical activity level in adolescence predicts use of alcohol and illicit drugs in early adulthood. We studied 4240 individual twins (1870 twin pairs). We classified those who consistently reported frequent leisure physical activity at ages 16, 17 and 18½ as persistent exercisers, those exercising less than three times monthly as persistently inactive, and all others as occasional exercisers. To control for familial confounds, within-family analyses compared activity-substance use associations in co-twins discordant for baseline physical activity. Individual-based analyses showed no clear association between baseline physical activity and subsequent weekly alcohol consumption. However, weekly alcohol intoxication (OR=1.9, p = .002) and problems due to alcohol use (OR=2.0, p < .001) were more common among persistently inactive participants. After excluding those reporting weekly intoxication at baseline, the risk for alcohol intoxication remained elevated among women occasionally (OR=2.4, p = .017) or persistently (OR= 5.8, p < .001) inactive at baseline, but this association was not replicated within discordant twin pairs. Individual-based analyses showed that drug use in adulthood was more common among those persistently physically inactive in adolescence (OR=3.7, p < .001) in comparison to those persistently active. This finding was replicated within discordant twin pairs. Among those with no drug experience during adolescence, persistent inactivity (OR= 1.9, p = .007) increased risk for drug use. We conclude that persistent physical inactivity in adolescence may increase the risk of later problems due to excess alcohol use. Sedentary lifestyle predicts illicit drug use even when controlling for familial factors.
doi:10.1375/twin.12.3.261
PMCID: PMC2723718  PMID: 19456218
longitudinal; twin study; physical activity; alcohol use; illicit drugs
19.  Gender Differences in Sport Injury Risk and Types of Inju-Ries: A Retrospective Twelve-Month Study on Cross-Country Skiers, Swimmers, Long-Distance Runners and Soccer Players 
This twelve months survey compared injury risk and injury types by genders (312 females, 262 males) in 15- to 35-year-old cross-country skiers, swimmers, long- distance runners and soccer players. More male than female athletes reported at least one acute injury (44% vs. 35%, p < 0.05), and more male than female runners reported at least one overuse injury (69% vs. 51%, p < 0.05). When the incidence of acute and overuse injuries both separately and combined was calculated per 1000 training hours, per 1000 competition hours and all exposure hours combined we found no gender differences in either of these comparisons. After adjustment for sport event males were at increased risk for posterior thigh overuse injuries compared to females (relative risk (RR) 5.8, 95% confidence interval (CI) 1.3 to 26.4, p < 0.05) while females were at increased risk for overuse injuries in the ankle compared to males (RR 3.1, 95% CI 1.0 to 9.3, p < 0.05). After adjustment for exposure time (injuries/1000 exposure hours) significance of the difference between the sexes in overuse injury to the ankle persisted (female 0.11 vs. male 0.02 injuries/1000 exposure hours, p < 0.05). Six athletes had an anterior cruciate ligament (ACL) injury, of whom four were female soccer players. After combining all reported acute and overuse ankle and knee injuries, the proportion of athletes with such injury was higher in the female compared to male soccer players (75% and 54% respectively; p < 0.05), but no difference was found in such injuries when calculated per 1000 exposure hours. In conclusion, we found some gender differences in sport-related injuries, but most of these differences seemed to be explained at least in part by differences in the amount of training.
Key pointsOnly a few sport injury studies have compared in-jury rates between the sexesOverall gender-related risk for acute and overuse injuries in top-level athletes between the sexes was smallSome gender differences in the specific anatomical locations of injuries as well as in specific injuries in sports were foundSome of these differences seem to be explained by the differences in the amount of training
PMCID: PMC3763291  PMID: 24150009
Male; female; athletic injuries; acute injury; over-use injury
20.  Trait-specific tracking and determinants of body composition: a 7-year follow-up study of pubertal growth in girls 
BMC Medicine  2009;7:5.
Background
Understanding how bone (BM), lean (LM) and fat mass (FM) develop through childhood, puberty and adolescence is vital since it holds key information regarding current and future health. Our study aimed to determine how BM, LM and FM track from prepuberty to early adulthood in girls and what factors are associated with intra- and inter-individual variation in these three tissues.
Methods
The study was a 7-year longitudinal cohort study. BM, LM and FM measured using dual-energy X-ray absorptiometry, self-reported dietary information, leisure time physical activity (LTPA) and other factors were assessed one to eight times in 396 girls aged 10 to 13 years (baseline), and in 255 mothers once.
Results
The location of a girl's BM, LM and FM in the lower, middle or upper part of the sample distribution was established before puberty and tracked in its percentile of origin over 7 years (r = 0.72 for BM, r = 0.61 for LM, and r = 0.65 for FM all p < 0.001 first vs. last measurements' ranking). Seventy-three percent of those in the lowest quartile for BM and 69% for LM, and 79% of those in the highest quartile for FM at baseline remained in their quartile at 7-year follow-up. Heritability was estimated to contribute 69% of the total variance of the BM, 50% of the LM, and 57% of the FM. Besides body size, diet index (explaining 9% of variance), breast feeding duration (6%) and mother's BM (9%) predicted high BM. Diet index and high LTPA predicted high LM (24% and 14%, respectively), and low FM (25% and 12%, respectively), and low level of parental education predicted high FM (4%).
Conclusion
Individual levels of BM, LM and FM are established before puberty and track in a trait-specific manner until early adulthood. Girls who are prone to develop low BM and LM and high FM in adulthood can be identified in prepuberty. The developments of three components of body composition are inter-related during growth. BM was the most heritable trait while LM the most environmentally modifiable. Diet and physical activity played an important role in increasing LM and preventing the accumulation of excessive FM.
doi:10.1186/1741-7015-7-5
PMCID: PMC2639618  PMID: 19171028
21.  Physical inactivity and obesity: A vicious circle 
Obesity (Silver Spring, Md.)  2008;16(2):409-414.
Objective
Physical activity (PA) begins to decline in adolescence with concomitant increase in weight. We hypothesized that a vicious circle may arise between decreasing physical activity and weight gain from adolescence to early adulthood.
Research Methods and Procedures
PA and self-perceived physical fitness assessed in adolescence (16-18 years) were used to predict the development of obesity (BMI≥30 kg/m2) and abdominal obesity (waist≥88 cm in females and ≥102 cm in males) at age 25 in 4240 twin individuals (90% of twins born in Finland 1975-1979). Ten 25-year-old monozygotic (MZ) twin pairs discordant for obesity (16 kg weight difference) were then carefully evaluated for current PA (triaxial accelerometer), total energy expenditure (TEE, doubly labeled water), and basal metabolic rate (BMR, indirect calorimetry).
Results
Physical inactivity in adolescence strongly predicted the risk of obesity (OR 3.9, 95%CI 1.4-10.9) and abdominal obesity (4.8, 1.9-12.0) at age 25, even after adjusting for baseline and current BMI. Poor physical fitness in adolescence also increased the risk of overall (5.1, 2.0-12.7) and abdominal obesity (3.2, 1.5-6.7) in adulthood. Physical inactivity was both causative and secondary to the development of obesity discordance in the MZ pairs. TEE did not differ between the MZ co-twins. PA levels were lower whereas BMR was higher in the obese co-twins.
Discussion
Physical inactivity in adolescence strongly and independently predicts total and especially abdominal obesity in young adulthood, favoring the development of a self-perpetuating vicious circle of obesity and physical inactivity. Physical (in)activity should be a major target of obesity prevention in the young.
doi:10.1038/oby.2007.72
PMCID: PMC2249563  PMID: 18239652
longitudinal; twin studies; body mass index; waist circumference; energy expenditure
22.  Knee arthroscopy and exercise versus exercise only for chronic patellofemoral pain syndrome: a randomized controlled trial 
BMC Medicine  2007;5:38.
Background
Arthroscopy is often used to treat patients with chronic patellofemoral pain syndrome (PFPS). As there is a lack of evidence, we conducted a randomized controlled trial to study the efficacy of arthroscopy in patients with chronic PFPS.
Methods
A total of 56 patients with chronic PFPS were randomized into two treatment groups: an arthroscopy group (N = 28), treated with knee arthroscopy and an 8-week home exercise program, and a control group (N = 28), treated with the 8-week home exercise program only. The arthroscopy included finding-specific surgical procedures according to current recommendations. The primary outcome was the Kujala score on patellofemoral pain and function at 9 months following randomization. Secondary outcomes were visual analog scales (VASs) to assess activity-related symptoms. We also estimated the direct healthcare costs.
Results
Both groups showed marked improvement during the follow-up. The mean improvement in the Kujala score was 12.9 (95% confidence interval (CI) 8.2–17.6) in the arthroscopy group and 11.4 (95% CI 6.9–15.8) in the control group. However, there was no difference between the groups in mean improvement in the Kujala score (group difference 1.1 (95% CI -7.4 - 5.2)) or in any of the VAS scores. Total direct healthcare costs in the arthroscopy group were estimated to exceed on average those of the control group by €901 per patient (p < 0.001).
Conclusion
In this controlled trial involving patients with chronic PFPS, the outcome when arthroscopy was used in addition to a home exercise program was no better than when the home exercise program was used alone.
Trial registration
Current Controlled Trials ISRCTN 41800323
doi:10.1186/1741-7015-5-38
PMCID: PMC2249589  PMID: 18078506
23.  Physical activity in adolescence and smoking in young adulthood: a prospective twin cohort study 
Addiction (Abingdon, England)  2007;102(7):1151-1157.
Aims
To control for familial confounds, we studied the association between adolescent physical activity and later smoking in twin siblings discordant for their baseline physical activity.
Design and measurements
In this prospective population-based twin study, we asked whether persistent physical activity/inactivity in adolescence (assessed at 16, 17 and 18.5 years) predicted questionnaire-reported daily smoking at ages 22–27. Twins who, on the three baseline questionnaires, consistently reported frequent leisure physical activity (more than three times weekly) were classified as persistent exercisers, those who exercised less than three times monthly were called persistently inactive, others were occasional exercisers.
Setting
Finland
Participants
4240 individuals, including 1870 twin pairs.
Findings
In analyses of individual twins, compared to persistent activity, persistent physical inactivity predicted increased risk of daily smoking (age-and sex-adjusted odds ratio 5.53, 95% confidence interval 3.88 to 7.88, P < 0.001). The risk remained elevated even after excluding all those who had smoked 50 cigarettes or more lifetime at baseline and adjusted for educational level in adolescence. In within-pair analyses compared to the active members of discordant twin pairs, the physically inactive co-twins had increased risk of future daily smoking (sex-adjusted odds ratio 3.39, 95% confidence interval 1.56 to 7.39, P = 0.002).
Conclusions
Persistent physical inactivity in adolescence relates to adult smoking, even after familial factors are taken into account.
doi:10.1111/j.1360-0443.2007.01858.x
PMCID: PMC1905863  PMID: 17567404
exercise; physical activity; smoking; twins
24.  Genetic Influences on Exercise Participation in 37.051 Twin Pairs from Seven Countries 
PLoS ONE  2006;1(1):e22.
Background
A sedentary lifestyle remains a major threat to health in contemporary societies. To get more insight in the relative contribution of genetic and environmental influences on individual differences in exercise participation, twin samples from seven countries participating in the GenomEUtwin project were used.
Methodology
Self-reported data on leisure time exercise behavior from Australia, Denmark, Finland, Norway, the Netherlands, Sweden and United Kingdom were used to create a comparable index of exercise participation in each country (60 minutes weekly at a minimum intensity of four metabolic equivalents).
Principal Findings
Modest geographical variation in exercise participation was revealed in 85,198 subjects, aged 19–40 years. Modeling of monozygotic and dizygotic twin resemblance showed that genetic effects play an important role in explaining individual differences in exercise participation in each country. Shared environmental effects played no role except for Norwegian males. Heritability of exercise participation in males and females was similar and ranged from 48% to 71% (excluding Norwegian males).
Conclusions
Genetic variation is important in individual exercise behavior and may involve genes influencing the acute mood effects of exercise, high exercise ability, high weight loss ability, and personality. This collaborative study suggests that attempts to find genes influencing exercise participation can pool exercise data across multiple countries and different instruments.
doi:10.1371/journal.pone.0000022
PMCID: PMC1762341  PMID: 17183649
25.  Muscle fiber-type distribution predicts weight gain and unfavorable left ventricular geometry: a 19 year follow-up study 
Background
Skeletal muscle consists of type-I (slow-twitch) and type-II (fast-twitch) fibers, with proportions highly variable between individuals and mostly determined by genetic factors. Cross-sectional studies have associated low percentage of type-I fibers (type-I%) with many cardiovascular risk factors.
Methods
We investigated whether baseline type-I% predicts left ventricular (LV) structure and function at 19-year follow-up, and if so, which are the strongest mediating factors. At baseline in 1984 muscle fiber-type distribution (by actomyosin ATPase staining) was studied in 63 healthy men (aged 32–58 years). The follow-up in 2003 included echocardiography, measurement of obesity related variables, physical activity and blood pressure.
Results
In the 40 men not using cardiovascular drugs at follow-up, low type-I% predicted higher heart rate, blood pressure, and LV fractional shortening suggesting increased sympathetic tone. Low type-I% predicted smaller LV chamber diameters (P ≤ 0.009) and greater relative wall thickness (P = 0.034) without increase in LV mass (concentric remodeling). This was explained by the association of type-I% with obesity related variables. Type-I% was an independent predictor of follow-up body fat percentage, waist/hip ratio, weight gain in adulthood, and physical activity (in all P ≤ 0.001). After including these risk factors in the regression models, weight gain was the strongest predictor of LV geometry explaining 64% of the variation in LV end-diastolic diameter, 72% in end-systolic diameter, and 53% in relative wall thickness.
Conclusion
Low type-I% predicts obesity and weight gain especially in the mid-abdomen, and consequently unfavourable LV geometry indicating increased cardiovascular risk.
doi:10.1186/1471-2261-6-2
PMCID: PMC1382267  PMID: 16403232

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