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Genberg, M., Andrén, B., Lind, L., Hedenström, H. & Malinovschi, A. (2018). Commonly used reference values underestimate oxygen uptake in healthy, 50-year-old Swedish women.. Clinical Physiology and Functional Imaging, 38(1), 25-33.
Open this publication in new window or tab >>Commonly used reference values underestimate oxygen uptake in healthy, 50-year-old Swedish women.
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2018 (English)In: Clinical Physiology and Functional Imaging, ISSN 1475-0961, E-ISSN 1475-097X, Vol. 38, no 1, p. 25-33Article in journal (Refereed) Published
Abstract [en]

Cardiopulmonary exercise testing (CPET) is the gold standard among clinical exercise tests. It combines a conventional stress test with measurement of oxygen uptake (VO2 ) and CO2 production. No validated Swedish reference values exist, and reference values in women are generally understudied. Moreover, the importance of achieved respiratory exchange ratio (RER) and the significance of breathing reserve (BR) at peak exercise in healthy individuals are poorly understood. We compared VO2 at maximal load (peakVO2 ) and anaerobic threshold (VO2@AT ) in healthy Swedish individuals with commonly used reference values, taking gender into account. Further, we analysed maximal workload and peakVO2 with regard to peak RER and BR. In all, 181 healthy, 50-year-old individuals (91 women) performed CPET. PeakVO2 was best predicted using Jones et al. (100·5%), while SHIP reference values underestimated peakVO2 most: 112·5%. Furthermore, underestimation of peakVO2 in women was found for all studied reference values (P<0·001) and was largest for SHIP: women had 128% of predicted peakVO2 , while men had 104%. PeakVO2 was similar in subjects with peak RER of 1-1·1 and RER > 1·1 (2 328·7 versus 2 176·7 ml min(-1) , P = 0·11). Lower BR (≤30%) related to significantly higher peakVO2 (P<0·001). In conclusion, peakVO2 was best predicted by Jones. All studied reference values underestimated oxygen uptake in women. No evidence for demanding RER > 1·1 in healthy individuals was found. A lowered BR is probably a normal response to higher workloads in healthy individuals.

National Category
Cardiac and Cardiovascular Systems Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:uu:diva-312359 (URN)10.1111/cpf.12377 (DOI)000417877700005 ()27312352 (PubMedID)
Available from: 2017-01-09 Created: 2017-01-09 Last updated: 2018-01-17Bibliographically approved
Strand, R., Malmberg, F., Johansson, L., Lind, L., Sundbom, M., Ahlström, H. & Kullberg, J. (2017). A concept for holistic whole body MRI data analysis, Imiomics. PLoS ONE, 12(2), Article ID e0169966.
Open this publication in new window or tab >>A concept for holistic whole body MRI data analysis, Imiomics
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2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 2, article id e0169966Article in journal (Refereed) Published
Abstract [en]

Purpose: To present and evaluate a whole-body image analysis concept, Imiomics (imaging omics) and an image registration method that enables Imiomics analyses by deforming all image data to a common coordinate system, so that the information in each voxel can be compared between persons or within a person over time and integrated with non-imaging data.

Methods: The presented image registration method utilizes relative elasticity constraints of different tissue obtained from whole-body water-fat MRI. The registration method is evaluated by inverse consistency and Dice coefficients and the Imiomics concept is evaluated by example analyses of importance for metabolic research using non-imaging parameters where we know what to expect. The example analyses include whole body imaging atlas creation, anomaly detection, and cross-sectional and longitudinal analysis.

Results: The image registration method evaluation on 128 subjects shows low inverse consistency errors and high Dice coefficients. Also, the statistical atlas with fat content intensity values shows low standard deviation values, indicating successful deformations to the common coordinate system. The example analyses show expected associations and correlations which agree with explicit measurements, and thereby illustrate the usefulness of the proposed Imiomics concept.

Conclusions: The registration method is well-suited for Imiomics analyses, which enable analyses of relationships to non-imaging data, e.g. clinical data, in new types of holistic targeted and untargeted big-data analysis.

National Category
Radiology, Nuclear Medicine and Medical Imaging
Research subject
Computerized Image Processing
Identifiers
urn:nbn:se:uu:diva-316830 (URN)10.1371/journal.pone.0169966 (DOI)000395934400002 ()28241015 (PubMedID)
Available from: 2017-02-27 Created: 2017-03-07 Last updated: 2017-11-29Bibliographically approved
Ciuculete, D.-M., Bandstein, M., Benedict, C., Waeber, G., Vollenweider, P., Lind, L., . . . Mwinyi, J. (2017). A genetic risk score is significantly associated with statin therapy response in the elderly population. Clinical Genetics, 91(3), 379-385.
Open this publication in new window or tab >>A genetic risk score is significantly associated with statin therapy response in the elderly population
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2017 (English)In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 91, no 3, p. 379-385Article in journal (Refereed) Published
Abstract [en]

The ability of statins to strongly reduce low-density lipoprotein cholesterol (LDL-C) varies interindividually and is partially influenced by genetic variants. Based on a comprehensive analysis of 23 single nucleotide polymorphisms (SNPs) known to be associated with pharmacokinetics and dynamics of statins, we developed a genetic risk score to study its impact on the therapy outcome in elderly individuals under at least 5 years statin therapy. The study was performed in a population-based cohort of 1016 elderly individuals, which comprised 168 statin users investigated at age 75 and 80. Using random forest models, the major variants influencing LDL-C levels were summarized in a weighted GRS (wGRS). The wGRS was tested with lipid and glucose outcomes and validated in an independent population-based cohort including 221 statin users. Four SNPs within the APOE cluster (rs7412, rs4420638), ABCC2 (rs2002042) and CELSR/SORT1/PSRC1 (rs646776), displayed a major impact on statin efficacy. The wGRS was significantly associated with lower LDL-C at age 75 and 80. This association was replicated displaying similar results. GRS analysis is a powerful tool to evaluate the additive effects of genetic variants on statin response and to estimate the magnitude of LDL-C reduction to a considerable extent in the older population.

Keyword
pharmacogenetics, polygenetic risk score, random forest analysis, single nucleotide polymorphism, statins
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-318494 (URN)10.1111/cge.12890 (DOI)000395007600004 ()27943270 (PubMedID)
Funder
Swedish Society for Medical Research (SSMF)Swedish Research CouncilGlaxoSmithKline (GSK)
Available from: 2017-03-24 Created: 2017-03-24 Last updated: 2018-01-13Bibliographically approved
Manning, A., Highland, H. M., Gasser, J., Sim, X., Tukiainen, T., Fontanillas, P., . . . Lindgren, C. M. (2017). A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk. Diabetes, 66(7), 2019-2032.
Open this publication in new window or tab >>A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk
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2017 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 66, no 7, p. 2019-2032Article in journal (Refereed) Published
Abstract [en]

To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.

Place, publisher, year, edition, pages
AMER DIABETES ASSOC, 2017
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-328990 (URN)10.2337/db16-1329 (DOI)000403778600030 ()28341696 (PubMedID)
Available from: 2017-09-08 Created: 2017-09-08 Last updated: 2017-09-08Bibliographically approved
Dumanski, J. P., Rasi, C., Björklund, P., Davies, H., Ali, A. S., Grönberg, M., . . . Tiensuu Janson, E. (2017). A MUTYH germline mutation is associated with small intestinal neuroendocrine tumors. Endocrine-Related Cancer, 24(8), 427-443.
Open this publication in new window or tab >>A MUTYH germline mutation is associated with small intestinal neuroendocrine tumors
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2017 (English)In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 24, no 8, p. 427-443Article in journal (Refereed) Published
Abstract [en]

The genetics behind predisposition to small intestinal neuroendocrine tumors (SI-NETs) is largely unknown, but there is growing awareness of a familial form of the disease. We aimed to identify germline mutations involved in the carcinogenesis of SI-NETs. The strategy included next-generation sequencing of exome- and/or whole-genome of blood DNA, and in selected cases, tumor DNA, from 24 patients from 15 families with the history of SI-NETs. We identified seven candidate mutations in six genes that were further studied using 215 sporadic SI-NET patients. The result was compared with the frequency of the candidate mutations in three control cohorts with a total of 35,688 subjects. A heterozygous variant causing an amino acid substitution p.(Gly396Asp) in the MutY DNA glycosylase gene (MUTYH) was significantly enriched in SI-NET patients (minor allele frequencies 0.013 and 0.003 for patients and controls respectively) and resulted in odds ratio of 5.09 (95% confidence interval 1.56-14.74; P value = 0.0038). We also found a statistically significant difference in age at diagnosis between familial and sporadic SI-NETs. MUTYH is involved in the protection of DNA from mutations caused by oxidative stress. The inactivation of this gene leads to specific increase of G:C- > T:A transversions in DNA sequence and has been shown to cause various cancers in humans and experimental animals. Our results suggest that p.(Gly396Asp) in MUTYH, and potentially other mutations in additional members of the same DNA excision-repair pathway (such as the OGG1 gene) might be involved in driving the tumorigenesis leading to familial and sporadic SI-NETs.

Keyword
DNA excision-repair pathway, cancer predisposition, familial cancer, oxidative stress, small intestinal carcinoid
National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-328686 (URN)10.1530/ERC-17-0196 (DOI)000406493000011 ()28634180 (PubMedID)
Available from: 2017-08-29 Created: 2017-08-29 Last updated: 2017-11-06Bibliographically approved
Roos, V., Elmstahl, S., Ingelsson, E., Sundström, J., Ärnlöv, J. & Lind, L. (2017). Alterations in Multiple Lifestyle Factors in Subjects with the Metabolic Syndrome Independently of Obesity. Metabolic Syndrome and Related Disorders, 15(3), 118-123.
Open this publication in new window or tab >>Alterations in Multiple Lifestyle Factors in Subjects with the Metabolic Syndrome Independently of Obesity
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2017 (English)In: Metabolic Syndrome and Related Disorders, ISSN 1540-4196, E-ISSN 1557-8518, Vol. 15, no 3, p. 118-123Article in journal (Refereed) Published
Abstract [en]

Background: Many lifestyle factors have been associated with the metabolic syndrome (MetS). However, most of these studies have not considered the potential impact of obesity and have often only investigated one lifestyle factor at the time. We aimed to investigate the interplay between body mass index (BMI) and MetS with respect to multiple lifestyle factors. Methods: BMI and MetS [National Cholesterol Education Program (NCEP)/Adult Treatment Panel III criteria] were assessed in a sample of 18,880 subjects aged 45-75 years from the population-based EpiHealth study. Participants were categorized into six groups according to BMI category (normal weight/BMI <25 kg/m(2), overweight/BMI 25-30 kg/m(2), and obesity/BMI > 30 kg/m(2)) and MetS status (+/-, NCEP criteria). A wide range of lifestyle factors related to physical activity, smoking, alcohol, sleep quality, working conditions, quality of life and stress, and eating patterns were assessed using a questionnaire. Results: Prevalent MetS (23% in the sample) was associated with less physical activity (P < 0.0001), more TV watching (P < 0.0001), more years of smoking (P < 0.0001), lower education level (P = 0.007), and experiencing a poor general quality of life (P < 0.0001). These lifestyle factors were all associated with MetS, independently of each other and independently of BMI. Similar results were generated when number of MetS components and presence/absence of individual MetS components were used as outcomes. Conclusions: This cross-sectional study identified alterations in a number of lifestyle factors associated with MetS independently of each other and independently of BMI. Future longitudinal studies are needed to assess causal and temporal relationships between lifestyle factors and MetS development.

Keyword
metabolic syndrome, obesity, lifestyle factors, MHO
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:uu:diva-321438 (URN)10.1089/met.2016.0120 (DOI)000397585500003 ()28339343 (PubMedID)
Available from: 2017-05-09 Created: 2017-05-09 Last updated: 2017-05-09Bibliographically approved
Scott, R. A., Scott, L. J., Maegi, R., Marullo, L., Gaulton, K. J., Kaakinen, M., . . . Prokopenko, I. (2017). An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans. Diabetes, 66(11), 2888-2902.
Open this publication in new window or tab >>An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans
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2017 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 66, no 11, p. 2888-2902Article in journal (Refereed) Published
Abstract [en]

To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 x 10(-8)), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.

Place, publisher, year, edition, pages
AMER DIABETES ASSOC, 2017
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-340702 (URN)10.2337/db16-1253 (DOI)000413559100018 ()28566273 (PubMedID)
Funder
NIH (National Institute of Health), HHSN268200625226C
Available from: 2018-02-20 Created: 2018-02-20 Last updated: 2018-02-20Bibliographically approved
Mendelson, M. M., Marioni, R. E., Joehanes, R., Liu, C., Hedman, Å. K., Aslibekyan, S., . . . Deary, L. J. (2017). Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease: A Mendelian Randomization Approach. PLoS Medicine, 14(1), Article ID e1002215.
Open this publication in new window or tab >>Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease: A Mendelian Randomization Approach
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2017 (English)In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 14, no 1, article id e1002215Article in journal (Refereed) Published
Abstract [en]

Background The link between DNA methylation, obesity, and adiposity-related diseases in the general population remains uncertain. Methods and Findings We conducted an association study of body mass index (BMI) and differential methylation for over 400,000 CpGs assayed by microarray in whole-blood-derived DNA from 3,743 participants in the Framingham Heart Study and the Lothian Birth Cohorts, with independent replication in three external cohorts of 4,055 participants. We examined variations in whole blood gene expression and conducted Mendelian randomization analyses to investigate the functional and clinical relevance of the findings. We identified novel and previously reported BMI-related differential methylation at 83 CpGs that replicated across cohorts; BMI-related differential methylation was associated with concurrent changes in the expression of genes in lipid metabolism pathways. Genetic instrumental variable analysis of alterations in methylation at one of the 83 replicated CpGs, cg11024682 (intronic to sterol regulatory element binding transcription factor 1 [SREBF1]), demonstrated links to BMI, adiposity-related traits, and coronary artery disease. Independent genetic instruments for expression of SREBF1 supported the findings linking methylation to adiposity and cardiometabolic disease. Methylation at a substantial proportion (16 of 83) of the identified loci was found to be secondary to differences in BMI. However, the cross-sectional nature of the data limits definitive causal determination. Conclusions We present robust associations of BMI with differential DNA methylation at numerous loci in blood cells. BMI-related DNA methylation and gene expression provide mechanistic insights into the relationship between DNA methylation, obesity, and adiposity-related diseases.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2017
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-319336 (URN)10.1371/journal.pmed.10022151 (DOI)000395719900011 ()
Available from: 2017-04-03 Created: 2017-04-03 Last updated: 2017-11-29Bibliographically approved
Lind, L., Elmstahl, S. & Ärnlöv, J. (2017). Change in Body Weight from Age 20 Years Is a Powerful Determinant of the Metabolic Syndrome. Metabolic Syndrome and Related Disorders, 15(3), 112-117.
Open this publication in new window or tab >>Change in Body Weight from Age 20 Years Is a Powerful Determinant of the Metabolic Syndrome
2017 (English)In: Metabolic Syndrome and Related Disorders, ISSN 1540-4196, E-ISSN 1557-8518, Vol. 15, no 3, p. 112-117Article in journal (Refereed) Published
Abstract [en]

Background: Higher body weight is a well-known determinant of the metabolic syndrome (MetS) and its components. It is however less well studied how the change in weight from age 20 years to middle age or old age affects MetS development. Methods: In the community-based EpiHealth (n = 19,000, age range 45 to 75 years, 56% females) and PIVUS (n = 1000, all aged 70 years, 50% females) studies, the participants were asked about their body weight at age 20 years. Data were collected to determine MetS prevalence (NCEP ATP III criteria). Results: In EpiHealth, the probability of having MetS increased fairly linearly with increasing weight from age 20 in the obese [odds ratios (OR) 1.04 per kg change in weight, 95% confidence interval (CI) 1.03-1.05, P < 0.0001], as well as in the overweight (OR 1.15, 95% CI 1.14-1.17, P < 0.0001) and normal-weight (OR 1.18, 95% CI 1.14-1.21, P < 0.0001), subjects after adjustment for age, sex, body mass index (BMI) at age 20, alcohol intake, smoking, education, and exercise habits. Also in the PIVUS study, the change in weight over 50 years was related to prevalent MetS (OR 1.08 per kg change in weight, 95% CI 1.06-1.10, P < 0.0001). In both studies, self-reported BMI at age 20 was related to prevalent MetS. Conclusion: Self-reported weight gain from age 20 was strongly and independently associated with prevalent MetS both in middle age or old age. Interestingly, this relationship was not restricted only to obese subjects. Our data provide additional support for the importance of maintaining a stable weight throughout life.

Keyword
metabolic syndrome, obesity, body weight, longitudinal, epidemiology
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:uu:diva-321437 (URN)10.1089/met.2016.0121 (DOI)000397585500002 ()28339342 (PubMedID)
Available from: 2017-05-09 Created: 2017-05-09 Last updated: 2017-05-09Bibliographically approved
Steubl, D., Kumar, S. V., Tato, M., Mulay, S. R., Larsson, A., Lind, L., . . . Anders, H.-J. (2017). Circulating cathepsin-S levels correlate with GFR decline and sTNFR1 and sTNFR2 levels in mice and humans. Scientific Reports, 7, Article ID 43538.
Open this publication in new window or tab >>Circulating cathepsin-S levels correlate with GFR decline and sTNFR1 and sTNFR2 levels in mice and humans
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 43538Article in journal (Refereed) Published
Abstract [en]

Cardiovascular complications determine morbidity/mortality in chronic kidney disease (CKD). We hypothesized that progressive CKD drives the release of cathepsin-S (Cat-S), a cysteine protease that promotes endothelial dysfunction and cardiovascular complications. Therefore, Cat-S, soluble tumor-necrosis-factor receptor (sTNFR) 1/2 and glomerular filtration rate (GFR) were measured in a CKD mouse model, a German CKD-cohort (MCKD, n = 421) and two Swedish community-based cohorts (ULSAM, n = 764 and PIVUS, n = 804). Association between Cat-S and sTNFR1/2/GFR was assessed using multivariable linear regression. In the mouse model, Cat-S and sTNFR1/2 concentrations were increased following the progressive decline of GFR, showing a strong correlation between Cat-S and GFR (r = -0.746, p < 0.001) and Cat-S and sTNFR1/sTNFR2 (r = 0.837/0.916, p < 0.001, respectively). In the human cohorts, an increase of one standard deviation of estimated GFR was associated with a decrease of 1.008 ng/ml (95%-confidence interval (95%-CI) -1.576-(-0.439), p < 0.001) in Cat-S levels in MCKD; in ULSAM and PIVUS, results were similar. In all three cohorts, Cat-S and sTNFR1/sTNFR2 levels were associated in multivariable linear regression (p < 0.001). In conclusion, as GFR declines Cat-S and markers of inflammation-related endothelial dysfunction increase. The present data indicating that Cat-S activity increases with CKD progression suggest that Cat-S might be a therapeutic target to prevent cardiovascular complications in CKD.

National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-316474 (URN)10.1038/srep43538 (DOI)000394936800001 ()28240259 (PubMedID)
Funder
EU, Horizon 2020, 668036, 634869Swedish Research CouncilSwedish Heart Lung FoundationMarianne and Marcus Wallenberg Foundation
Available from: 2017-03-01 Created: 2017-03-01 Last updated: 2017-11-29Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-2335-8542

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