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Schoffelen, P. F. M., den Hoed, M., van Breda, E. & Plasqui, G. (2019). Test-retest variability of VO2max using total-capture indirect calorimetry reveals linear relationship of VO2 and Power. Scandinavian Journal of Medicine and Science in Sports, 29(2), 213-222
Open this publication in new window or tab >>Test-retest variability of VO2max using total-capture indirect calorimetry reveals linear relationship of VO2 and Power
2019 (English)In: Scandinavian Journal of Medicine and Science in Sports, ISSN 0905-7188, E-ISSN 1600-0838, Vol. 29, no 2, p. 213-222Article in journal (Refereed) Published
Abstract [en]

This study aimed to analyze the intra-individual variation in VO2max of human subjects using total-capture and free-flow indirect calorimetry. Twenty-seven men (27 ± 5 year; VO2max 49-79 mL•kg-1 •min-1) performed two maximal exertion tests (CPETs) on a cycle ergometer, separated by a 7 ± 2 day interval. VO2 and VCO2 were assessed using an indirect calorimeter (Omnical) with total capture of exhalation in a free-flow airstream. Thirteen subjects performed a third maximal exertion test using a breath-by-breath calorimeter (Oxycon Pro). On-site validation was deemed a requirement. For the Omnical, the mean within-subject CV for VO2max was 1.2 ± 0.9% (0.0%-4.4%) and for ergometer workload P max 1.3 ± 1.3% (0%-4.6%). VO2max values with the Oxycon Pro were significantly lower in comparison with Omnical (P< t 0.001; t test) with mean 3570 vs 4061 and difference SD 361 mL • min-1. Validation results for the Omnical with methanol combustion were -0.05 ± 0.70% (mean ± SD; n = 31) at the 225 mL • min-1 VO2 level and -0.23 ± 0.80% (n = 31) at the 150 mL • min-1 VCO2 level. Results using gas infusion were 0.04 ± 0.75% (n = 34) and -0.99 ± 1.05% (n = 24) over the respective 500-6000 mL • min-1 VO2 and VCO2 ranges. Validation results for the Oxycon Pro in breath-by-breath mode were - 2.2 ± 1.6% (n = 12) for VO2 and 5.7 ± 3.3% (n = 12) for VCO2 over the 1000-4000 mL •min-1 range. On a Visual analog scale, participants reported improved breathing using the free-flow indirect calorimetry (score 7.6 ± 1.2 vs 5.1 ± 2.7, P = 0.008). We conclude that total capturing free-flow indirect calorimetry is suitable for measuring VO2 even with the highest range. VO2max was linear with the incline in P max over the full range.

Keywords
breath-by-breath, exercise testing, gas exchange, intra-individual variability, validation
National Category
Sport and Fitness Sciences
Identifiers
urn:nbn:se:uu:diva-375802 (URN)10.1111/sms.13324 (DOI)000456093700007 ()30341979 (PubMedID)
Available from: 2019-02-13 Created: 2019-02-13 Last updated: 2019-02-13Bibliographically approved
Lightfoot, J. T., De Geus, E. J. C., Booth, F. W., Bray, M. S., den Hoed, M., Kaprio, J., . . . Bouchard, C. (2018). Biological/Genetic Regulation of Physical Activity Level: Consensus From Genbiopac. Medicine & Science in Sports & Exercise, 50(4), 863-873
Open this publication in new window or tab >>Biological/Genetic Regulation of Physical Activity Level: Consensus From Genbiopac
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2018 (English)In: Medicine & Science in Sports & Exercise, ISSN 0195-9131, E-ISSN 1530-0315, Vol. 50, no 4, p. 863-873Article, review/survey (Refereed) Published
Abstract [en]

Purpose: Physical activity unquestionably maintains and improves health; however, physical activity levels globally are low and not rising despite all the resources devoted to this goal. Attention in both the research literature and the public policy domain has focused on social-behavioral factors; however, a growing body of literature suggests that biological determinants play a significant role in regulating physical activity levels. For instance, physical activity level, measured in various manners, has a genetic component in both humans and nonhuman animal models. This consensus article, developed as a result of an American College of Sports Medicine-sponsored round table, provides a brief review of the theoretical concepts and existing literature that supports a significant role of genetic and other biological factors in the regulation of physical activity.

Conclusions: Future research on physical activity regulation should incorporate genetics and other biological determinants of physical activity instead of a sole reliance on social and other environmental determinants.

Keywords
Animal, Biology, Genetics, Genomics, Human, Physical Activity, Spontaneous Activity, Voluntary Physical Activity
National Category
Sport and Fitness Sciences
Identifiers
urn:nbn:se:uu:diva-387467 (URN)10.1249/MSS.0000000000001499 (DOI)000427796400028 ()29166322 (PubMedID)
Funder
Swedish Research Council, 2015-03657Swedish Heart Lung Foundation
Available from: 2019-06-25 Created: 2019-06-25 Last updated: 2019-06-25Bibliographically approved
Malik, R., Chauhan, G., Traylor, M., Sargurupremraj, M., Okada, Y., Mishra, A., . . . Dichgans, M. (2018). Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. Nature Genetics, 50(4), 524-537
Open this publication in new window or tab >>Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes
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2018 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 50, no 4, p. 524-537Article in journal (Refereed) Published
Abstract [en]

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke sub-types. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-352708 (URN)10.1038/s41588-018-0058-3 (DOI)000429529300013 ()29531354 (PubMedID)
Available from: 2018-06-07 Created: 2018-06-07 Last updated: 2018-06-07Bibliographically approved
van Setten, J., Brody, J. A., Jamshidi, Y., Swenson, B. R., Butler, A. M., Campbell, H., . . . Sotoodehnia, N. (2018). PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity. Nature Communications, 9, Article ID 2904.
Open this publication in new window or tab >>PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity
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2018 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 2904Article in journal (Refereed) Published
Abstract [en]

Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genomewide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are overrepresented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of similar to 105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ionchannel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-387268 (URN)10.1038/s41467-018-04766-9 (DOI)000439687600002 ()30046033 (PubMedID)
Funder
AstraZeneca
Available from: 2019-06-26 Created: 2019-06-26 Last updated: 2019-06-26Bibliographically approved
Kramer, I. F., Snijders, T., Smeets, J. S. J., Leenders, M., van Kranenburg, J., den Hoed, M., . . . van Loon, L. J. C. (2017). Extensive Type II Muscle Fiber Atrophy in Elderly Female Hip Fracture Patients. The journals of gerontology. Series A, Biological sciences and medical sciences, 72(10), 1369-1375
Open this publication in new window or tab >>Extensive Type II Muscle Fiber Atrophy in Elderly Female Hip Fracture Patients
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2017 (English)In: The journals of gerontology. Series A, Biological sciences and medical sciences, ISSN 1079-5006, E-ISSN 1758-535X, Vol. 72, no 10, p. 1369-1375Article in journal (Refereed) Published
Abstract [en]

Background: Sarcopenia, or the loss of muscle mass and strength, is known to increase the risk for falls and (hip) fractures in older people. The objective of this study was to assess the skeletal muscle fiber characteristics in elderly female hip fracture patients.

Method: Percutaneous needle biopsies were collected from the vastus lateralis muscle in 15 healthy young women (20 +/- 0.4 years), 15 healthy elderly women (79 +/- 1.7 years), and 15 elderly women with a fall-related hip fracture (82 +/- 1.5 years). Immunohistochemical analyses were performed to assess Type I and Type II muscle fiber size, and myonuclear and satellite cell content.

Results: Type II muscle fiber size was significantly different between all groups (p <.05), with smaller Type II muscle fibers in the hip fracture patients (2,609 +/- 185 mu m(2)) compared with healthy elderly group (3,723 +/- 322 mu m(2)) and the largest Type II muscle fibers in the healthy young group (4,755 +/- 335 mu m(2)). Furthermore, Type I muscle fiber size was significantly lower in the hip fracture patients (4,684 +/- 211 mu m(2)) compared with the healthy elderly group (5,842 +/- 316 mu m(2), p =.02). The number of myonuclei per Type II muscle fiber was significantly lower in the healthy elderly and hip fracture group compared with the healthy young group (p =.011 and p =.002, respectively). Muscle fiber satellite cell content did not differ between groups.

Conclusion: Elderly female hip fracture patients show extensive Type II muscle fiber atrophy when compared with healthy young or agematched healthy elderly controls. Type II muscle fiber atrophy is an important hallmark of sarcopenia and may predispose to falls and (hip) fractures in the older population.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS INC, 2017
Keywords
Falls, Hip fracture, Muscle, Sarcopenia
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-335135 (URN)10.1093/gerona/glw253 (DOI)000410071900009 ()28329045 (PubMedID)
Available from: 2017-12-04 Created: 2017-12-04 Last updated: 2017-12-04Bibliographically approved
Nolte, I. M., Munoz, M. L., Tragante, V., Amare, A. T., Jansen, R., Vaez, A., . . . de Geus, E. J. C. (2017). Genetic loci associated with heart rate variability and their effects on cardiac disease risk. Nature Communications, 8, Article ID 15805.
Open this publication in new window or tab >>Genetic loci associated with heart rate variability and their effects on cardiac disease risk
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2017 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 15805Article in journal (Refereed) Published
Abstract [en]

Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74 < r(g) < -0.55) and blood pressure (-0.35 < r(g) < -0.20). These findings provide clinically relevant biological insight into heritable variation in vagal heart rhythm regulation, with a key role for genetic variants (GNG11, RGS6) that influence G-protein heterotrimer action in GIRK-channel induced pacemaker membrane hyperpolarization.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2017
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-329672 (URN)10.1038/ncomms15805 (DOI)000403216600001 ()28613276 (PubMedID)
Available from: 2017-09-19 Created: 2017-09-19 Last updated: 2019-03-11Bibliographically approved
Graff, M., Scott, R. A., Justice, A. E., Young, K. L., Feitosa, M. F., Barata, L., . . . Kilpeläinen, T. O. (2017). Genome-wide physical activity interactions in adiposity: A meta-analysis of 200,452 adults.. PLoS Genetics, 13(4), Article ID e1006528.
Open this publication in new window or tab >>Genome-wide physical activity interactions in adiposity: A meta-analysis of 200,452 adults.
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2017 (English)In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 4, article id e1006528Article in journal (Refereed) Published
Abstract [en]

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 ~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.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2017
Keywords
BODY-MASS INDEX; REACTIVE PROTEIN-LEVELS; GENE-EXPRESSION; IDENTICAL-TWINS; ADIPOCYTE DIFFERENTIATION; ASSOCIATION METAANALYSIS; ACTIVITY QUESTIONNAIRES; FAT DISTRIBUTION; BINDING PROTEIN; FOOD-INTAKE
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-321624 (URN)10.1371/journal.pgen.1006528 (DOI)000402549200002 ()28448500 (PubMedID)
Available from: 2017-05-09 Created: 2017-05-09 Last updated: 2018-07-06Bibliographically approved
Strawbridge, R. J., Silveira, A., den Hoed, M., Gustafsson, S., Luan, J., Rybin, D., . . . Hamsten, A. (2017). Identification of a novel proinsulin-associated SNP and demonstration that proinsulin is unlikely to be a causal factor in subclinical vascular remodelling using Mendelian randomisation. Atherosclerosis, 266, 196-204
Open this publication in new window or tab >>Identification of a novel proinsulin-associated SNP and demonstration that proinsulin is unlikely to be a causal factor in subclinical vascular remodelling using Mendelian randomisation
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2017 (English)In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 266, p. 196-204Article in journal (Refereed) Published
Abstract [en]

Background and aims: Increased proinsulin relative to insulin levels have been associated with subclinical atherosclerosis (measured by carotid intima-media thickness (cIMT)) and are predictive of future cardiovascular disease (CVD), independently of established risk factors. The mechanisms linking proinsulin to atherosclerosis and CVD are unclear. A genome-wide meta-analysis has identified nine loci associated with circulating proinsulin levels. Using proinsulin-associated SNPs, we set out to use a Mendelian randomisation approach to test the hypothesis that proinsulin plays a causal role in subclinical vascular remodelling.

Methods: We studied the high CVD-risk IMPROVE cohort (n = 3345), which has detailed biochemical phenotyping and repeated, state-of-the-art, high-resolution carotid ultrasound examinations. Genotyping was performed using Illumina Cardio-Metabo and Immuno arrays, which include reported proinsulin-associated loci. Participants with type 2 diabetes (n = 904) were omitted from the analysis. Linear regression was used to identify proinsulin-associated genetic variants.

Results: We identified a proinsulin locus on chromosome 15 (rs8029765) and replicated it in data from 20,003 additional individuals. An 11-SNP score, including the previously identified and the chromosome 15 proinsulin-associated loci, was significantly and negatively associated with baseline IMTmean and IMTmax (the primary cIMT phenotypes) but not with progression measures. However, MR-Eggers refuted any significant effect of the proinsulin-associated 11-SNP score, and a non-pleiotropic SNP score of three variants (including rs8029765) demonstrated no effect on baseline or progression cIMT measures.

Conclusions: We identified a novel proinsulin-associated locus and demonstrated that whilst proinsulin levels are associated with cIMT measures, proinsulin per se is unlikely to have a causative effect on cIMT.

Keywords
Proinsulin, Atherosclerosis, Intima-media-thickness, Single nucleotide polymorphisms, Genetic variants, Mendelian randomisation
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-341363 (URN)10.1016/j.atherosclerosis.2017.09.031 (DOI)000414069700027 ()29040868 (PubMedID)
Funder
Swedish Research Council, 8691 09533 2012-1397 2015-03657Swedish Heart Lung Foundation, 20120197 20140543EU, European Research CouncilKnut and Alice Wallenberg FoundationSwedish Foundation for Strategic Research Stockholm County Council, 592229EU, FP7, Seventh Framework Programme, IMI/115006Swedish National Infrastructure for Computing (SNIC), b2011036
Available from: 2018-02-08 Created: 2018-02-08 Last updated: 2018-02-08Bibliographically approved
Deleskog, A., den Hoed, M., Tettamanti, G., Carlsson, S., Ljung, R., Feychting, M. & Brooke, H. L. (2017). Maternal diabetes and incidence of childhood cancer: a nationwide cohort study and exploratory genetic analysis. Clinical Epidemiology, 9, 633-642
Open this publication in new window or tab >>Maternal diabetes and incidence of childhood cancer: a nationwide cohort study and exploratory genetic analysis
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2017 (English)In: Clinical Epidemiology, ISSN 1179-1349, E-ISSN 1179-1349, Vol. 9, p. 633-642Article in journal (Refereed) Published
Abstract [en]

Background: The etiology of childhood cancer is not well understood, but may be linked to prenatal and perinatal factors, such as maternal diabetes. However, this association has not been examined in depth. We aimed to determine if maternal diabetes is associated with risk of childhood brain tumor (CBT), leukemia (all types combined and acute lymphoblastic leukemia [ALL] separately), and lymphoma.

Methods: All children born in Sweden between 1973 and 2014 (n= 4,239,965) were followed from birth until first cancer diagnosis, age 15 years, or December 31, 2015. Data on maternal diabetes, childhood cancer, and covariates were obtained from nationwide health registers. Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were calculated using Cox regression adjusted for potential confounders/mediators. Additionally, we performed an exploratory analysis using results from published genome-wide association studies and functional annotation.

Results: Maternal diabetes was associated with lower risk of CBT (adjusted IRR [95% CI]: 0.56 [0.35-0.91]) and higher risk of leukemia (adjusted IRR: 1.47 [1.13-1.92] for all leukemia combined and 1.64 [1.23-2.18] for ALL). These associations were similar for both maternal type 1 diabetes and gestational diabetes. Associations of five previously identified genetic loci were compatible with a causal effect of diabetes traits on neuroblastoma and common Hodgkin's lymphoma.

Conclusion: Children whose mother had diabetes had lower risk of CBT and higher risk of leukemia, compared with children whose mother did not have diabetes. Our results are compatible with a role of prenatal and perinatal glycemic environment in childhood cancer etiology.

Keywords
neoplasm, childhood, diabetes, fetal growth, perinatal environment
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:uu:diva-344542 (URN)10.2147/CLEP.S147188 (DOI)000417736800001 ()29238226 (PubMedID)
Funder
Forte, Swedish Research Council for Health, Working Life and Welfare, 2015-01228Swedish Research Council, 2015-03657Swedish Heart Lung Foundation, 20140543NIH (National Institute of Health), R01DK106236; R01DK107786
Available from: 2018-03-07 Created: 2018-03-07 Last updated: 2018-03-07Bibliographically approved
Barban, N., Jansen, R., de Vlaming, R., Vaez, A., Mandemakers, J. J., Tropf, F. C., . . . Mills, M. C. (2016). Genome-wide analysis identifies 12 loci influencing human reproductive behavior. Nature Genetics, 48(12), 1462-1472
Open this publication in new window or tab >>Genome-wide analysis identifies 12 loci influencing human reproductive behavior
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2016 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 48, no 12, p. 1462-1472Article in journal (Refereed) Published
Abstract [en]

The genetic architecture of human reproductive behavior age at first birth (AFB) and number of children ever born (NEB) has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-311496 (URN)10.1038/ng.3698 (DOI)000389011100006 ()27798627 (PubMedID)
Funder
EU, European Research Council, 615603 320116 647648 EdGeWellcome trustSwedish Research Council, 2015-03657 421-2013-1061 537-2014-371Swedish Heart Lung Foundation, 20140543Ragnar Söderbergs stiftelseNIH (National Institute of Health), P01-AG005842 P01-AG005842-20S2 P30-AG012810 T32-AG000186-23 R01-AG042568-02
Note

Marcel den Hoed is shared last author

Available from: 2016-12-28 Created: 2016-12-28 Last updated: 2018-01-13
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ORCID iD: ORCID iD iconorcid.org/0000-0001-8081-428X

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