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Wuttke, M., Li, Y., Li, M., Sieber, K. B., Feitosa, M. F., Gorski, M., . . . Pattaro, C. (2019). A catalog of genetic loci associated with kidney function from analyses of a million individuals. Nature Genetics, 51(6), 957-972
Open this publication in new window or tab >>A catalog of genetic loci associated with kidney function from analyses of a million individuals
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2019 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 6, p. 957-972Article in journal (Refereed) Published
Abstract [en]

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-387933 (URN)10.1038/s41588-019-0407-x (DOI)000469996900008 ()31152163 (PubMedID)
Funder
AstraZenecaNovo NordiskNIH (National Institute of Health)
Note

Group Authors: Lifelines COHort Study

Available from: 2019-06-26 Created: 2019-06-26 Last updated: 2019-06-26Bibliographically approved
Sjöholm, T., Ekström, S., Strand, R., Ahlström, H., Lind, L., Malmberg, F. & Kullberg, J. (2019). A whole-body FDG PET/MR atlas for multiparametric voxel-based analysis. Scientific Reports, 9, Article ID 6158.
Open this publication in new window or tab >>A whole-body FDG PET/MR atlas for multiparametric voxel-based analysis
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 6158Article in journal (Refereed) Published
National Category
Medical Image Processing
Research subject
Computerized Image Processing
Identifiers
urn:nbn:se:uu:diva-382934 (URN)10.1038/s41598-019-42613-z (DOI)000464652400029 ()30992502 (PubMedID)
Available from: 2019-04-16 Created: 2019-05-07 Last updated: 2019-06-14Bibliographically approved
Tan, X., Titova, O. E., Lindberg, E., Elmståhl, S., Lind, L., Schiöth, H. B. & Benedict, C. (2019). Association Between Self-Reported Sleep Duration and Body Composition in Middle-Aged and Older Adults. Journal of Clinical Sleep Medicine (JCSM), 15(3), 431-435
Open this publication in new window or tab >>Association Between Self-Reported Sleep Duration and Body Composition in Middle-Aged and Older Adults
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2019 (English)In: Journal of Clinical Sleep Medicine (JCSM), ISSN 1550-9389, E-ISSN 1550-9397, Vol. 15, no 3, p. 431-435Article in journal (Refereed) Published
Abstract [en]

STUDY OBJECTIVES: The current study sought to examine whether self-reported sleep duration is linked to an adverse body composition in 19,709 adults aged 45 to 75 years.

METHODS: All variables used in the current study were derived from the Swedish EpiHealth cohort study. Habitual sleep duration was measured by questionnaires. Body composition was assessed by bioimpedance. The main outcome variables were fat mass and fat-free mass (in kg). Analysis of covariance adjusting for age, sex, fat mass in the case of fat-free mass (and vice versa), leisure time physical activity, smoking, and alcohol consumption was used to investigate the association between sleep duration and body composition.

RESULTS: Short sleep (defined as ≤ 5 hours sleep per day) and long sleep (defined as 8 or more hours of sleep per day) were associated with lower fat-free mass and higher fat mass, compared with 6 to 7 hours of sleep duration (P< .05).

CONCLUSIONS: These observations could suggest that both habitual short and long sleep may contribute to two common clinical phenotypes in middle-aged and older humans, ie, body adiposity and sarcopenia. However, the observational nature of our study does not allow for causal interpretation.

Keywords
body fat, elderly, fat-free mass, middle-aged, sleep
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-379286 (URN)10.5664/jcsm.7668 (DOI)000461417900009 ()30853046 (PubMedID)
Funder
Swedish Research CouncilNovo Nordisk, NNF14OC0009349Swedish Research Council, 2015-03100Ernfors FoundationÅke Wiberg Foundation, M17-0088Åke Wiberg Foundation, M18-0169Fredrik och Ingrid Thurings Stiftelse, 2017-00313Fredrik och Ingrid Thurings Stiftelse, 2018-00365
Available from: 2019-03-14 Created: 2019-03-14 Last updated: 2019-04-04Bibliographically approved
Marklund, M., Wu, J. H. Y., Imamura, F., Del Gobbo, L. C., Fretts, A., de Goede, J., . . . Risérus, U. (2019). Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality: An Individual-Level Pooled Analysis of 30 Cohort Studies. Circulation, 139(21), 2422-2436
Open this publication in new window or tab >>Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality: An Individual-Level Pooled Analysis of 30 Cohort Studies
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2019 (English)In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 139, no 21, p. 2422-2436Article in journal (Refereed) Published
Abstract [en]

Background:

Global dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies.

Methods:

We performed harmonized, de novo, individual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available).

Results:

In 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15198 incident cardiovascular events occurred among 68659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95% CI, 0.88-0.99), 0.78 (0.70-0.85), and 0.88 (0.79-0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94; 0.88-1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes; in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92; 0.86-0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships.

Conclusions:

In pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention.

Keywords
arachidonic acid, biomarkers, cardiovascular diseases, diet, epidemiology, linoleic acid, primary prevention
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-387592 (URN)10.1161/CIRCULATIONAHA.118.038908 (DOI)000469018300011 ()30971107 (PubMedID)
Available from: 2019-06-26 Created: 2019-06-26 Last updated: 2019-06-26Bibliographically approved
Lind, L., Elmstahl, S. & Ingelsson, E. (2019). Cardiometabolic Proteins Associated with Metabolic Syndrome. Metabolic Syndrome and Related Disorders
Open this publication in new window or tab >>Cardiometabolic Proteins Associated with Metabolic Syndrome
2019 (English)In: Metabolic Syndrome and Related Disorders, ISSN 1540-4196, E-ISSN 1557-8518Article in journal (Refereed) Epub ahead of print
Abstract [en]

Background: Although metabolic syndrome (MetS) was described in the late 80s, the molecular mechanisms underlying clustering of risk factors in certain individuals are not fully understood. The present study used targeted proteomics to establish cardiometabolic proteins related to all MetS components, thereby providing new hypotheses regarding pathways involved in the pathogenesis of MetS.

Methods: In the EpiHealth study, 249 cardiometabolic proteins were measured by proximity extension assay (PEA) and related to the five MetS components [consensus-modified National Cholesterol Education Program (NCEP) criteria] in 2,444 participants aged 45-75 years (50% women).

Results: Thirty-one proteins were associated with systolic blood pressure following adjustment for age and sex (P < 0.000040, taking multiple testing into account). The corresponding number of proteins significantly associated with fasting glucose, waist circumference, high-density lipoprotein cholesterol, and serum triglycerides were 58, 132, 127, and 148. Twenty-two proteins were significantly related to all 5 MetS components, and of those, 20 were with MetS as a binary outcome (n = 600, 24% of the sample) following adjustment for age, sex, fat mass, and lifestyle factors (alcohol intake, smoking, education, and exercise habits).

Conclusion: Using targeted proteomics, we identified 20 proteins reflecting a range of pathways, such as immunomodulation at different levels; regulation of adipocyte differentiation; lipid, carbohydrate, and amino acid metabolism; or insulin-like growth factor signaling, to be strongly associated with MetS independently of fat mass and lifestyle factors. Whether some of these proteins are causally involved in the pathogenesis of clustering of multiple risk factors in the same individual remains to be investigated.

Place, publisher, year, edition, pages
MARY ANN LIEBERT, INC, 2019
Keywords
metabolic syndrome, proteomics, epidemiology
National Category
Other Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-380437 (URN)10.1089/met.2018.0123 (DOI)000461504000001 ()30883260 (PubMedID)
Available from: 2019-03-28 Created: 2019-03-28 Last updated: 2019-03-28Bibliographically approved
Lind, L. & Sundström, J. (2019). Change in left ventricular geometry over 10 years in the elderly and risk of incident cardiovascular disease. Journal of Hypertension, 37(2), 325-330
Open this publication in new window or tab >>Change in left ventricular geometry over 10 years in the elderly and risk of incident cardiovascular disease
2019 (English)In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 37, no 2, p. 325-330Article in journal (Refereed) Published
Abstract [en]

Objective: Left ventricular hypertrophy (LVH) is related to a poor prognosis. We aimed to determine how left ventricular (LV) geometry changes over time, and how this relates to future cardiovascular disease.

Methods: In the Prospective Study of the Vasculature in Uppsala Seniors study, 1016 individuals were investigated with echocardiography at age 70. This was repeated after 5 and 10 years. Incident cardiovascular disease (myocardial infarction, stroke, and heart failure, n = 163) was recorded over 10 years.

Results: LV mass index (LVMI) and LV end-diastolic diameter (LVEDD) progressively increased over 10 years, while LV thickness declined (P< 0.0001 for all). Adjusting for traditional cardiovascular risk factors, LVMI at baseline, but not LVEDD, was significantly associated with incident cardiovascular disease [hazard ratio (HR) 1.02, 95% confidence interval 1.003-1.03, P = 0.019]. When adding the change in LVMI, or change in LVEDD, between ages 70 and 75 years to the models and using the time between 75 and 80 as follow-up (in total 82 incident cases), neither the change in LVMI nor the change in LVEDD were significant. Using updated information on LV geometric groups, an increased risk was seen for concentric LVH as compared with the normal group following adjustment for traditional risk factors (HR 2.29, P = 0.0014, 95% confidence interval 1.38-3.82). Eccentric LVH and concentric remodeling were not associated with a statistically significant increased risk of cardiovascular disease.

Conclusion: In elderly individuals without myocardial infarction, a progressive dilatation of the LV was seen over 10 years. However, the LV dilation seen over time in this age group was not associated with a major increase in risk of future cardiovascular disease.

Keywords
cardiovascular risk, epidemiology, left ventricular geometry
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-383890 (URN)10.1097/HJH.0000000000001897 (DOI)000467336700013 ()30113528 (PubMedID)
Available from: 2019-05-28 Created: 2019-05-28 Last updated: 2019-05-28Bibliographically approved
Dörr, M., Hamburg, N. M., Müller, C., Smith, N. L., Gustafsson, S., Lehtimäki, T., . . . Schnabel, R. B. (2019). Common Genetic Variation in Relation to Brachial Vascular Dimensions and Flow-Mediated Vasodilation [Letter to the editor]. CIRCULATION-GENOMIC AND PRECISION MEDICINE, 12(2), Article ID e002409.
Open this publication in new window or tab >>Common Genetic Variation in Relation to Brachial Vascular Dimensions and Flow-Mediated Vasodilation
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2019 (English)In: CIRCULATION-GENOMIC AND PRECISION MEDICINE, ISSN 2574-8300, Vol. 12, no 2, article id e002409Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS, 2019
Keywords
brachial artery, dilation, epidemiology, genetics, genome-wide association study, insulin-like growth factor binding protein 3
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-379085 (URN)10.1161/CIRCGEN.118.002409 (DOI)000458995600002 ()30779634 (PubMedID)
Funder
EU, European Research Council, 648131EU, European Research Council, 742927
Available from: 2019-03-12 Created: 2019-03-12 Last updated: 2019-03-12Bibliographically approved
Karasik, D., Zillikens, M. C., Hsu, Y.-H., Aghdassi, A., Akesson, K., Amin, N., . . . Ohlsson, C. (2019). Disentangling the genetics of lean mass. American Journal of Clinical Nutrition, 109(2), 276-287
Open this publication in new window or tab >>Disentangling the genetics of lean mass
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2019 (English)In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 109, no 2, p. 276-287Article in journal (Refereed) Published
Abstract [en]

Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass. Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci. Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age(2), and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms). Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LMwere termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection. Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.

Place, publisher, year, edition, pages
Oxford University Press, 2019
Keywords
body composition, skeletal muscle, body fat, meta-analysis of genome-wide association studies, metabolic profile
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-380499 (URN)10.1093/ajcn/nqy272 (DOI)000460615600007 ()30721968 (PubMedID)
Available from: 2019-04-23 Created: 2019-04-23 Last updated: 2019-04-23Bibliographically approved
Wagner-Golbs, A., Neuber, S., Kamlage, B., Christiansen, N., Bethan, B., Rennefahrt, U., . . . Lind, L. (2019). Effects of Long-Term Storage at -80 degrees C on the Human Plasma Metabolome. Metabolites, 9(5), Article ID 99.
Open this publication in new window or tab >>Effects of Long-Term Storage at -80 degrees C on the Human Plasma Metabolome
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2019 (English)In: Metabolites, ISSN 2218-1989, E-ISSN 2218-1989, Vol. 9, no 5, article id 99Article in journal (Refereed) Published
Abstract [en]

High-quality biological samples are required for the favorable outcome of research studies, and valid data sets are crucial for successful biomarker identification. Prolonged storage of biospecimens may have an artificial effect on compound levels. In order to investigate the potential effects of long-term storage on the metabolome, human ethylenediaminetetraacetic acid (EDTA) plasma samples stored for up to 16 years were analyzed by gas and liquid chromatography-tandem mass spectrometry-based metabolomics. Only 2% of 231 tested plasma metabolites were altered in the first seven years of storage. However, upon longer storage periods of up to 16 years and more time differences of few years significantly affected up to 26% of the investigated metabolites when analyzed within subject age groups. Ontology classes that were most affected included complex lipids, fatty acids, energy metabolism molecules, and amino acids. In conclusion, the human plasma metabolome is adequately stable to long-term storage at -80 degrees C for up to seven years but significant changes occur upon longer storage. However, other biospecimens may display different sensitivities to long-term storage. Therefore, in retrospective studies on EDTA plasma samples, analysis is best performed within the first seven years of storage.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
biomarker, long-term stability, storage, plasma, metabolomics, mass spectrometry
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-390538 (URN)10.3390/metabo9050099 (DOI)000472660600019 ()31108909 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, GA 306031
Available from: 2019-08-12 Created: 2019-08-12 Last updated: 2019-08-12Bibliographically approved
Spracklen, C. N., Karaderi, T., Yaghootkar, H., Schurmann, C., Fine, R. S., Kutalik, Z., . . . Mohlke, K. L. (2019). Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology. American Journal of Human Genetics, 105(1), 15-28
Open this publication in new window or tab >>Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology
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2019 (English)In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 105, no 1, p. 15-28Article in journal (Refereed) Published
Abstract [en]

Circulating levels of adiponectin, an adipocyte-secreted protein associated with cardiovascular and metabolic risk, are highly heritable. To gain insights into the biology that regulates adiponectin levels, we performed an exome array meta-analysis of 265,780 genetic variants in 67,739 individuals of European, Hispanic, African American, and East Asian ancestry. We identified 20 loci associated with adiponectin, including 11 that had been reported previously (p < 2 x 10(-7)). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r(2) > .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p < 1 x 10(-4)) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.

Place, publisher, year, edition, pages
CELL PRESS, 2019
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-391019 (URN)10.1016/j.ajhg.2019.05.002 (DOI)000473723000003 ()31178129 (PubMedID)
Funder
EU, European Research Council, 323195: GLUCOSEGENES-FP7-IDEAS-ERCNovo Nordisk, NNF17OC0027594Novo Nordisk, NNF14CC0001Academy of Finland, 285380Wellcome trust, WT083442AIA
Available from: 2019-08-20 Created: 2019-08-20 Last updated: 2019-08-20Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-2335-8542

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