| 1. |
- Graff, M., et al.
(författare)
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Genome-wide physical activity interactions in adiposity. A meta-analysis of 200,452 adults
- 2017
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Ingår i: PLoS Genet. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 13:4
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Tidskriftsartikel (refereegranskat)abstract
- Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by similar to 30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.
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| 2. |
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| 3. |
- Wang, Z., et al.
(författare)
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Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention
- 2022
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 54:9, s. 1332-1344
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Tidskriftsartikel (refereegranskat)abstract
- Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIA muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention. Multi-ancestry meta-analyses of genome-wide association studies for self-reported physical activity during leisure time, leisure screen time, sedentary commuting and sedentary behavior at work identify 99 loci associated with at least one of these traits.
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| 4. |
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| 5. |
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| 6. |
- Willems, S. M., et al.
(författare)
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Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 × 10-8) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres (ACTG1), neuronal maintenance and signal transduction (PEX14, TGFA, SYT1), or monogenic syndromes with involvement of psychomotor impairment (PEX14, LRPPRC and KANSL1). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality. © The Author(s) 2017.
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| 7. |
- Scott, Robert A, et al.
(författare)
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No interactions between previously associated 2-hour glucose gene variants and physical activity or BMI on 2-hour glucose levels
- 2012
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Ingår i: Diabetes. - Alexandria, VA : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 61:5, s. 1291-1296
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Tidskriftsartikel (refereegranskat)abstract
- Gene-lifestyle interactions have been suggested to contribute to the development of type 2 diabetes. Glucose levels 2 h after a standard 75-g glucose challenge are used to diagnose diabetes and are associated with both genetic and lifestyle factors. However, whether these factors interact to determine 2-h glucose levels is unknown. We meta-analyzed single nucleotide polymorphism (SNP) × BMI and SNP × physical activity (PA) interaction regression models for five SNPs previously associated with 2-h glucose levels from up to 22 studies comprising 54,884 individuals without diabetes. PA levels were dichotomized, with individuals below the first quintile classified as inactive (20%) and the remainder as active (80%). BMI was considered a continuous trait. Inactive individuals had higher 2-h glucose levels than active individuals (β = 0.22 mmol/L [95% CI 0.13-0.31], P = 1.63 × 10(-6)). All SNPs were associated with 2-h glucose (β = 0.06-0.12 mmol/allele, P ≤ 1.53 × 10(-7)), but no significant interactions were found with PA (P > 0.18) or BMI (P ≥ 0.04). In this large study of gene-lifestyle interaction, we observed no interactions between genetic and lifestyle factors, both of which were associated with 2-h glucose. It is perhaps unlikely that top loci from genome-wide association studies will exhibit strong subgroup-specific effects, and may not, therefore, make the best candidates for the study of interactions.
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| 8. |
- Speakman, John R., et al.
(författare)
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Total daily energy expenditure has declined over the past three decades due to declining basal expenditure, not reduced activity expenditure
- 2023
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Ingår i: Nature Metabolism. - : NATURE PORTFOLIO. - 2522-5812. ; 5:4, s. 579-588
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Obesity is caused by a prolonged positive energy balance(1,2). Whether reduced energy expenditure stemming from reduced activity levels contributes is debated(3,4). Here we show that in both sexes, total energy expenditure (TEE) adjusted for body composition and age declined since the late 1980s, while adjusted activity energy expenditure increased over time. We use the International Atomic Energy Agency Doubly Labelled Water database on energy expenditure of adults in the United States and Europe (n = 4,799) to explore patterns in total (TEE: n = 4,799), basal (BEE: n = 1,432) and physical activity energy expenditure (n = 1,432) over time. In males, adjusted BEE decreased significantly, but in females this did not reach significance. A larger dataset of basal metabolic rate (equivalent to BEE) measurements of 9,912 adults across 163 studies spanning 100 years replicates the decline in BEE in both sexes. We conclude that increasing obesity in the United States/Europe has probably not been fuelled by reduced physical activity leading to lowered TEE. We identify here a decline in adjusted BEE as a previously unrecognized factor.
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| 9. |
- Ekelund, U., et al.
(författare)
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Physical activity reduces the risk of incident type 2 diabetes in general and in abdominally lean and obese men and women : the EPIC-InterAct Study
- 2012
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 55:7, s. 1944-1952
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Tidskriftsartikel (refereegranskat)abstract
- We examined the independent and combined associations of physical activity and obesity with incident type 2 diabetes in men and women. The InterAct case-cohort study consists of 12,403 incident type 2 diabetes cases and a randomly selected subcohort of 16,154 individuals, drawn from a total cohort of 340,234 participants with 3.99 million person-years of follow-up. Physical activity was assessed by a four-category index. Obesity was measured by BMI and waist circumference (WC). Associations between physical activity, obesity and case-ascertained incident type 2 diabetes were analysed by Cox regression after adjusting for educational level, smoking status, alcohol consumption and energy intake. In combined analyses, individuals were stratified according to physical activity level, BMI and WC. A one-category difference in physical activity (equivalent to approximately 460 and 365 kJ/day in men and women, respectively) was independently associated with a 13% (HR 0.87, 95% CI 0.80, 0.94) and 7% (HR 0.93, 95% CI 0.89, 0.98) relative reduction in the risk of type 2 diabetes in men and women, respectively. Lower levels of physical activity were associated with an increased risk of diabetes across all strata of BMI. Comparing inactive with active individuals, the HRs were 1.44 (95% CI 1.11, 1.87) and 1.38 (95% CI 1.17, 1.62) in abdominally lean and obese inactive men, respectively, and 1.57 (95% CI 1.19, 2.07) and 1.19 (95% CI 1.01, 1.39) in abdominally lean and obese inactive women, respectively. Physical activity is associated with a reduction in the risk of developing type 2 diabetes across BMI categories in men and women, as well as in abdominally lean and obese men and women.
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| 10. |
- Garcia, L, et al.
(författare)
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Non-occupational physical activity and risk of cardiovascular disease, cancer and mortality outcomes: a dose-response meta-analysis of large prospective studies
- 2023
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Ingår i: British journal of sports medicine. - : BMJ. - 1473-0480 .- 0306-3674. ; 57:15, s. 979-
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Tidskriftsartikel (refereegranskat)abstract
- To estimate the dose–response associations between non-occupational physical activity and several chronic disease and mortality outcomes in the general adult population.DesignSystematic review and cohort-level dose-response meta-analysis.Data sourcesPubMed, Scopus, Web of Science and reference lists of published studies.Eligibility criteriaProspective cohort studies with (1) general population samples >10 000 adults, (2) ≥3 physical activity categories, and (3) risk measures and CIs for all-cause mortality or incident total cardiovascular disease, coronary heart disease, stroke, heart failure, total cancer and site-specific cancers (head and neck, myeloid leukaemia, myeloma, gastric cardia, lung, liver, endometrium, colon, breast, bladder, rectum, oesophagus, prostate, kidney).Results196 articles were included, covering 94 cohorts with >30 million participants. The evidence base was largest for all-cause mortality (50 separate results; 163 415 543 person-years, 811 616 events), and incidence of cardiovascular disease (37 results; 28 884 209 person-years, 74 757 events) and cancer (31 results; 35 500 867 person-years, 185 870 events). In general, higher activity levels were associated with lower risk of all outcomes. Differences in risk were greater between 0 and 8.75 marginal metabolic equivalent of task-hours per week (mMET-hours/week) (equivalent to the recommended 150 min/week of moderate-to-vigorous aerobic physical activity), with smaller marginal differences in risk above this level to 17.5 mMET-hours/week, beyond which additional differences were small and uncertain. Associations were stronger for all-cause (relative risk (RR) at 8.75 mMET-hours/week: 0.69, 95% CI 0.65 to 0.73) and cardiovascular disease (RR at 8.75 mMET-hours/week: 0.71, 95% CI 0.66 to 0.77) mortality than for cancer mortality (RR at 8.75 mMET-hours/week: 0.85, 95% CI 0.81 to 0.89). If all insufficiently active individuals had achieved 8.75 mMET-hours/week, 15.7% (95% CI 13.1 to 18.2) of all premature deaths would have been averted.ConclusionsInverse non-linear dose–response associations suggest substantial protection against a range of chronic disease outcomes from small increases in non-occupational physical activity in inactive adults.PROSPERO registration numberCRD42018095481.
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| 11. |
- Thomassen, Mads, et al.
(författare)
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Clinical, splicing, and functional analysis to classify BRCA2 exon 3 variants : Application of a points-based ACMG/AMP approach
- 2022
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 43:12, s. 1921-1944
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Tidskriftsartikel (refereegranskat)abstract
- Skipping of BRCA2 exon 3 (∆E3) is a naturally occurring splicing event, complicating clinical classification of variants that may alter ∆E3 expression. This study used multiple evidence types to assess pathogenicity of 85 variants in/near BRCA2 exon 3. Bioinformatically predicted spliceogenic variants underwent mRNA splicing analysis using minigenes and/or patient samples. ∆E3 was measured using quantitative analysis. A mouse embryonic stem cell (mESC) based assay was used to determine the impact of 18 variants on mRNA splicing and protein function. For each variant, population frequency, bioinformatic predictions, clinical data, and existing mRNA splicing and functional results were collated. Variant class was assigned using a gene-specific adaptation of ACMG/AMP guidelines, following a recently proposed points-based system. mRNA and mESC analysis combined identified six variants with transcript and/or functional profiles interpreted as loss of function. Cryptic splice site use for acceptor site variants generated a transcript encoding a shorter protein that retains activity. Overall, 69/85 (81%) variants were classified using the points-based approach. Our analysis shows the value of applying gene-specific ACMG/AMP guidelines using a points-based approach and highlights the consideration of cryptic splice site usage to appropriately assign PVS1 code strength.
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| 12. |
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| 13. |
- Brito, Ema C, 1961-, et al.
(författare)
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PPARGC1A sequence variation and cardiovascular risk-factor levels : a study of the main genetic effects and gene x environment interactions in children from the European youth heart study
- 2009
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 52:4, s. 609-613
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: The PPARGC1A gene coactivates multiple nuclear transcription factors involved in cellular energy metabolism and vascular stasis. In the present study, we genotyped 35 tagging polymorphisms to capture all common PPARGC1A nucleotide sequence variations and tested for association with metabolic and cardiovascular traits in 2,101 Danish and Estonian boys and girls from the European Youth Heart Study, a multicentre school-based cross-sectional cohort study. METHODS: Fasting plasma glucose concentrations, anthropometric variables and blood pressure were measured. Habitual physical activity and aerobic fitness were objectively assessed using uniaxial accelerometry and a maximal aerobic exercise stress test on a bicycle ergometer, respectively. RESULTS: In adjusted models, nominally significant associations were observed for BMI (rs10018239, p = 0.039), waist circumference (rs7656250, p = 0.012; rs8192678 [Gly482Ser], p = 0.015; rs3755863, p = 0.02; rs10018239, beta = -0.01 cm per minor allele copy, p = 0.043), systolic blood pressure (rs2970869, p = 0.018) and fasting glucose concentrations (rs11724368, p = 0.045). Stronger associations were observed for aerobic fitness (rs7656250, p = 0.005; rs13117172, p = 0.008) and fasting glucose concentrations (rs7657071, p = 0.002). None remained significant after correcting for the number of statistical comparisons. We proceeded by testing for gene x physical activity interactions for the polymorphisms that showed nominal evidence of association in the main effect models. None of these tests was statistically significant. CONCLUSIONS/INTERPRETATION: Variants at PPARGC1A may influence several metabolic traits in this European paediatric cohort. However, variation at PPARGC1A is unlikely to have a major impact on cardiovascular or metabolic health in these children.
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| 14. |
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| 15. |
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| 16. |
- Franks, Paul, et al.
(författare)
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Physical activity energy expenditure may mediate the relationship between plasma leptin levels and worsening insulin resistance independently of adiposity.
- 2007
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Ingår i: J Appl Physiol. - : American Physiological Society. - 8750-7587. ; 102:5, s. 1921-6
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Tidskriftsartikel (refereegranskat)abstract
- Leptin regulates a constellation of neuroendocrine processes that control energy homeostasis. The infusion of leptin in rodents lacking endogenous leptin promotes physical activity energy expenditure (PAEE) and improves insulin signaling, whereas hyperleptinemia is associated with physical inactivity and insulin resistance (IR). We tested whether baseline leptin levels predict changes in PAEE and IR over time, independent of obesity. We also assessed whether the relationship between leptin and change in IR is mediated by PAEE. The population consisted of 288 nondiabetic UK Caucasian adults (mean age: 49.4 yr; SD: 0.7 yr), in whom leptin, insulin, glucose, PAEE (via heart rate monitoring with individual calibration by indirect calorimetry), and anthropometric characteristics had been measured at baseline and 5 yr later. In linear regression models, baseline leptin levels inversely predicted follow-up PAEE ( P = 0.033). On average, individuals with low leptin levels (below sex-specific median) increased their daily activity 35% more during the 5-yr follow-up period than those with above-median leptin levels. Baseline leptin level also predicted worsening IR (fasting, 30-min, and 2-h insulins, and homeostasis model assessment-IR; all P < 0.01). Associations were independent of potential confounders, such as adiposity, age, and sex. Including baseline PAEE as a cofactor in the leptin-insulin models reduced the strength (1–4% reduction) and significance of the associations, suggesting that PAEE mediates the leptin-insulin relationships. Hyperleptinemia predicts a relative decline in PAEE and worsening insulin resistance, possibly via shared molecular pathways.
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| 17. |
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| 18. |
- Goharian, T S, et al.
(författare)
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Examining the causal association of fasting glucose with blood pressure in healthy children and adolescents: a Mendelian randomization study employing common genetic variants of fasting glucose.
- 2015
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Ingår i: Journal of Human Hypertension. - : Springer Science and Business Media LLC. - 1476-5527 .- 0950-9240. ; 29:3, s. 179-184
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the study was to determine whether genetically raised fasting glucose (FG) levels are associated with blood pressure (BP) in healthy children and adolescents. We used 11 common genetic variants of FG discovered in genome-wide association studies (GWAS), including the rs560887 single-nucleotide polymorphism (SNP) located in the G6PC2 locus found to be robustly associated with FG in children and adolescents, as an instrument to associate FG with resting BP in 1506 children and adolescents from the European Youth Heart Study (EYHS). Rs560887 was associated with increased FG levels corresponding to an increase of 0.08 mmol l(-1) (P=2.4 × 10(-8)). FG was associated with BP, independent of other important determinants of BP in conventional multivariable analysis (systolic BP z-score: 0.32 s.d. per increase in mmol l(-1) (95% confidence interval (CI) 0.20-0.44, P=1.9 × 10(-7)), diastolic BP z-score: 0.13 s.d. per increase in mmol l(-1) (95% CI 0.04-0.21, P=3.2 × 10(-3)). This association was not supported by the Mendelian randomization approach, neither from instrumenting FG from all 11 variants nor from the rs560887, where non-significant associations of glucose with BP were observed. The results of this study could not support a causal association between FG and BP in healthy children and adolescents; however, it is possible that rs560887 has pleiotropic effects on unknown factors with a BP lowering effect or that these results were due to a lack of statistical power.Journal of Human Hypertension advance online publication, 31 July 2014; doi:10.1038/jhh.2014.63.
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| 19. |
- Guo, X. L., et al.
(författare)
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Calculations with spectroscopic accuracy for the ground configuration (3d(9)) forbidden transition in Co-like ions
- 2016
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Ingår i: Physical Review A (Atomic, Molecular and Optical Physics). - 1050-2947. ; 93:1
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Tidskriftsartikel (refereegranskat)abstract
- We present systematic and large-scale calculations for the fine-structure energy splitting and transition rate between the 3d(9) D-2(3/2,5/2) levels of Co-like ions with 28 <= Z <= 100. Two different fully relativistic approaches are used, based on the multiconfiguration Dirac-Hartree-Fock (MCDHF) theory and the relativistic many-body-perturbation theory (RMBPT). Especially the former gives results of similar accuracy as experiments for a large range of ions. Our calculations are therefore accurate enough to probe Breit and quantum-electro-dynamic effects. To obtain spectroscopic accuracy, we show that it is important to include deep core-valence correlation, down to and including the n = 2 shell. We estimate that the uncertainties of our wavelengths are within the uncertainty of experiments, i.e., 0.02%. We also show that the frequently used flexible atomic code has an inaccurate treatment of the self-energy (SE) contribution and of the M1-transition properties for lower-Z ions. After correcting for the SE calculation, the resulting RMBPT transition energies are in good agreement with the MCDHF ones, especially for the high-Z end of the Co-like sequence.
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| 20. |
- Koivula, Robert W., et al.
(författare)
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The role of physical activity in metabolic homeostasis before and after the onset of type 2 diabetes : an IMI DIRECT study
- 2020
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Ingår i: Diabetologia. - : Springer Nature. - 0012-186X .- 1432-0428. ; 63:4, s. 744-756
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: It is well established that physical activity, abdominal ectopic fat and glycaemic regulation are related but the underlying structure of these relationships is unclear. The previously proposed twin-cycle hypothesis (TC) provides a mechanistic basis for impairment in glycaemic control through the interactions of substrate availability, substrate metabolism and abdominal ectopic fat accumulation. Here, we hypothesise that the effect of physical activity in glucose regulation is mediated by the twin-cycle. We aimed to examine this notion in the Innovative Medicines Initiative Diabetes Research on Patient Stratification (IMI DIRECT) Consortium cohorts comprised of participants with normal or impaired glucose regulation (cohort 1: N ≤ 920) or with recently diagnosed type 2 diabetes (cohort 2: N ≤ 435). Methods: We defined a structural equation model that describes the TC and fitted this within the IMI DIRECT dataset. A second model, twin-cycle plus physical activity (TC-PA), to assess the extent to which the effects of physical activity in glycaemic regulation are mediated by components in the twin-cycle, was also fitted. Beta cell function, insulin sensitivity and glycaemic control were modelled from frequently sampled 75 g OGTTs (fsOGTTs) and mixed-meal tolerance tests (MMTTs) in participants without and with diabetes, respectively. Abdominal fat distribution was assessed using MRI, and physical activity through wrist-worn triaxial accelerometry. Results are presented as standardised beta coefficients, SE and p values, respectively. Results: The TC and TC-PA models showed better fit than null models (TC: χ2 = 242, p = 0.004 and χ2 = 63, p = 0.001 in cohort 1 and 2, respectively; TC-PA: χ2 = 180, p = 0.041 and χ2 = 60, p = 0.008 in cohort 1 and 2, respectively). The association of physical activity with glycaemic control was primarily mediated by variables in the liver fat cycle. Conclusions/interpretation: These analyses partially support the mechanisms proposed in the twin-cycle model and highlight mechanistic pathways through which insulin sensitivity and liver fat mediate the association between physical activity and glycaemic control.
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| 21. |
- Olsen, Rikke K J, et al.
(författare)
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ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency.
- 2007
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 130:Pt 8, s. 2045-54
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Tidskriftsartikel (refereegranskat)abstract
- Multiple acyl-CoA dehydrogenation deficiency (MADD) is a disorder of fatty acid, amino acid and choline metabolism that can result from defects in two flavoproteins, electron transfer flavoprotein (ETF) or ETF: ubiquinone oxidoreductase (ETF:QO). Some patients respond to pharmacological doses of riboflavin. It is unknown whether these patients have defects in the flavoproteins themselves or defects in the formation of the cofactor, FAD, from riboflavin. We report 15 patients from 11 pedigrees. All the index cases presented with encephalopathy or muscle weakness or a combination of these symptoms; several had previously suffered cyclical vomiting. Urine organic acid and plasma acyl-carnitine profiles indicated MADD. Clinical and biochemical parameters were either totally or partly corrected after riboflavin treatment. All patients had mutations in the gene for ETF:QO. In one patient, we show that the ETF:QO mutations are associated with a riboflavin-sensitive impairment of ETF:QO activity. This patient also had partial deficiencies of flavin-dependent acyl-CoA dehydrogenases and respiratory chain complexes, most of which were restored to control levels after riboflavin treatment. Low activities of mitochondrial flavoproteins or respiratory chain complexes have been reported previously in two of our patients with ETF:QO mutations. We postulate that riboflavin-responsive MADD may result from defects of ETF:QO combined with general mitochondrial dysfunction. This is the largest collection of riboflavin-responsive MADD patients ever reported, and the first demonstration of the molecular genetic basis for the disorder.
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| 22. |
- Ridgway, C. L., et al.
(författare)
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Fat-free mass mediates the association between birth weight and aerobic fitness in youth
- 2011
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Ingår i: International Journal of Pediatric Obesity. - : Informa UK Limited. - 1747-7166 .- 1747-7174. ; 6:2-2, s. E590-E596
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To investigate whether birth weight acts as a biological determinant of later aerobic fitness, and whether fat-free mass may mediate this association. Methods. The European Youth Heart Study (EYHS) is a population-based cohort of two age groups (9 and 15 years) from Denmark, Portugal, Estonia and Norway. Children with parentally reported birth weight >1.5 kg were included (n = 2 749). Data were collected on weight, height, and skinfold measures to estimate fat mass and fat-free mass. Aerobic fitness (peak power, watts) was assessed using a maximal, progressive cycle ergometer test. Physical activity was collected in a subset (n = 1 505) using a hip-worn accelerometer and defined as total activity counts/wear time, all children with >600 minutes/day for >= 3 days of wear were included. Results. Lower birth weight was associated with lower aerobic fitness, after adjusting for sex, age group, country, sexual maturity and socio-economic status (beta = 5.4; 95% CI: 3.5, 7.3 W per 1 kg increase in birth weight, p < 0.001). When fat-free mass was introduced as a covariate in the model, the association between birth weight and aerobic fitness was almost completely attenuated (p = 0.7). Birth weight was also significantly associated with fat-free mass (beta = 1.4; 95% CI: 1.1, 1.8, p < 0.001) and fat-free mass was significantly associated with aerobic fitness (beta = 3.6; 95% CI: 3.4, 3.7, p < 0.001). Further adjustment for physical activity did not alter the findings. Conclusion. Birth weight may have long-term influences on fat-free mass and differences in fat-free mass mediate the observed association between birth weight and aerobic fitness.
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| 23. |
- Svedman, F. C., et al.
(författare)
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Plasma Thymidine Kinase Activity as a Novel Biomarker in Metastatic Melanoma Patients Treated with Immune Checkpoint Inhibitors
- 2022
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 14:3
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Tidskriftsartikel (refereegranskat)abstract
- Background. Immune checkpoint inhibitors (ICI) are effective in fractions of patients with disseminated melanoma. This study is the first to analyze the plasma activity of thymidine kinase (TK), an enzyme involved in DNA synthesis and repair, as a biomarker in melanoma patients. Meth-ods. Plasma samples were collected prior to treatment start in patients with unresectable metastatic cutaneous melanoma, treated with ICI (anti-CTLA-4 and/or anti-PD-1). Plasma TK activity (TKa) levels were determined using the DiviTum TKa ELISA assay. TKa levels were correlated with patients’ baseline characteristics, response rate (RR), progression-free survival (PFS), and overall survival (OS). Results. In the 90 study patients, the median TKa level was 42 Du/L (range <20–1787 Du/L). A significantly higher plasma TKa was found in patients with ECOG performance status ≥1 (p = 0.003), M1c-d disease (p = 0.015), and elevated lactate dehydrogenase levels (p < 0.001). The RR was 63.2% and 30.3% in those with low or high TKa, respectively (p = 0.022). The median PFS was 19.9 and 12.6 months in patients with low or high TKa, respectively (hazard ratio (HR) 1.83 (95% CI, 1.08–3.08), p = 0.024). The median OS was >60 months and 18.5 months in patients with low or high TKa, respectively (HR: 2.25 (95% CI, 1.25–4.05), p = 0.011. Conclusions. High pretreatment plasma TKa levels were significantly associated with worse baseline characteristics and poor response and survival in ICI-treated melanoma patients. TKa is hence a novel and interesting plasma biomarker in melanoma and should be further studied to define its role as a prognostic and predictive marker in this disease. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.
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| 24. |
- Tobin, N. P., et al.
(författare)
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Molecular subtype and tumor characteristics of breast cancer metastases as assessed by gene expression significantly influence patient post-relapse survival
- 2015
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Ingår i: Annals of Oncology. - : Elsevier BV. - 1569-8041 .- 0923-7534. ; 26:1, s. 81-88
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Tidskriftsartikel (refereegranskat)abstract
- We and others have recently shown that tumor characteristics are altered throughout tumor progression. These findings emphasize the need for re-examination of tumor characteristics at relapse and have led to recommendations from ESMO and the Swedish Breast Cancer group. Here, we aim to determine whether tumor characteristics and molecular subtypes in breast cancer metastases confer clinically relevant prognostic information for patients. The translational aspect of the Swedish multicenter randomized trial called TEX included 111 patients with at least one biopsy from a morphologically confirmed locoregional or distant breast cancer metastasis diagnosed from December 2002 until June 2007. All patients had detailed clinical information, complete follow-up, and metastasis gene expression information (Affymetrix array GPL10379). We assessed the previously published gene expression modules describing biological processes [proliferation, apoptosis, human epidermal receptor 2 (HER2) and estrogen (ER) signaling, tumor invasion, immune response, and angiogenesis] and pathways (Ras, MAPK, PTEN, AKT-MTOR, PI3KCA, IGF1, Src, Myc, E2F3, and beta-catenin) and the intrinsic subtypes (PAM50). Furthermore, by contrasting genes expressed in the metastases in relation to survival, we derived a poor metastasis survival signature. A significant reduction in post-relapse breast cancer-specific survival was associated with low-ER receptor signaling and apoptosis gene module scores, and high AKT-MTOR, Ras, and beta-catenin module scores. Similarly, intrinsic subtyping of the metastases provided statistically significant post-relapse survival information with the worst survival outcome in the basal-like [hazard ratio (HR) 3.7; 95% confidence interval (CI) 1.3-10.9] and HER2-enriched (HR 4.4; 95% CI 1.5-12.8) subtypes compared with the luminal A subtype. Overall, 25% of the metastases were basal-like, 32% HER2-enriched, 10% luminal A, 28% luminal B, and 5% normal-like. We show that tumor characteristics and molecular subtypes of breast cancer metastases significantly influence post-relapse patient survival, emphasizing that molecular investigations at relapse provide prognostic and clinically relevant information.
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| 25. |
- Watts, Eleanor L., et al.
(författare)
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Observational and genetic associations between cardiorespiratory fitness and cancer : a UK Biobank and international consortia study
- 2024
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Ingår i: British Journal of Cancer. - : Springer Nature. - 0007-0920 .- 1532-1827. ; 130, s. 114-124
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Tidskriftsartikel (refereegranskat)abstract
- Background: The association of fitness with cancer risk is not clear.Methods: We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of lung, colorectal, endometrial, breast, and prostate cancer in a subset of UK Biobank participants who completed a submaximal fitness test in 2009-12 (N = 72,572). We also investigated relationships using two-sample Mendelian randomisation (MR), odds ratios (ORs) were estimated using the inverse-variance weighted method.Results: After a median of 11 years of follow-up, 4290 cancers of interest were diagnosed. A 3.5 ml O2⋅min−1⋅kg−1 total-body mass increase in fitness (equivalent to 1 metabolic equivalent of task (MET), approximately 0.5 standard deviation (SD)) was associated with lower risks of endometrial (HR = 0.81, 95% CI: 0.73–0.89), colorectal (0.94, 0.90–0.99), and breast cancer (0.96, 0.92–0.99). In MR analyses, a 0.5 SD increase in genetically predicted O2⋅min−1⋅kg−1 fat-free mass was associated with a lower risk of breast cancer (OR = 0.92, 95% CI: 0.86–0.98). After adjusting for adiposity, both the observational and genetic associations were attenuated.Discussion: Higher fitness levels may reduce risks of endometrial, colorectal, and breast cancer, though relationships with adiposity are complex and may mediate these relationships. Increasing fitness, including via changes in body composition, may be an effective strategy for cancer prevention.
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