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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
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
Radiology, Nuclear Medicine and Medical Imaging
Research subject
Computerized Image Processing
Identifiers
urn:nbn:se:uu:diva-393367 (URN)10.1038/s41598-019-42613-z (DOI)
Available from: 2019-04-16 Created: 2019-09-20 Last updated: 2019-09-20Bibliographically 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
Lind, P. M., Salihovic, S., Stubleski, J., Karrman, A. & Lind, L. (2019). Association of Exposure to Persistent Organic Pollutants With Mortality Risk: An Analysis of Data From the Prospective Investigation of Vasculature in Uppsala Seniors (PIVUS) Study. JAMA NETWORK OPEN, 2(4), Article ID e193070.
Open this publication in new window or tab >>Association of Exposure to Persistent Organic Pollutants With Mortality Risk: An Analysis of Data From the Prospective Investigation of Vasculature in Uppsala Seniors (PIVUS) Study
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2019 (English)In: JAMA NETWORK OPEN, ISSN 2574-3805, Vol. 2, no 4, article id e193070Article in journal (Refereed) Published
Abstract [en]

IMPORTANCE It has been suggested that persistent organic pollutants (POPs) are harmful to human health.

OBJECTIVE To investigate if POP levels in plasma are associated with future mortality.

DESIGN, SETTING, AND PARTICIPANTS Cohort study using data from the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, collected between May 2001 and June 2004 when participants reached age 70 years. Participants were followed up for 5 years after the first examination. Mortality was tracked from age 70 to 80 years. Data analysis was conducted in January and February 2018.

EXPOSURES Eighteen POPs identified by the Stockholm Convention, including polychlorinated biphenyls (PCBs), organochlorine pesticides, and a brominated flame retardant, were measured in plasma levels by gas chromatography-mass spectrometry.

MAIN OUTCOMES AND MEASURES All-cause mortality.

RESULTS The study sample initially included 992 individuals (497 [50.1%] men) aged 70 years, who were examined between 2001 and 2004. At the second examination 5 years later, 814 individuals (82.1%; 412 [50.7%] women) completed follow-up. During a follow-up period of 10.0 years, 158 deaths occurred. When updated information on POP levels at ages 70 and 75 years was associated with all-cause mortality using Cox proportional hazard analyses, a significant association was found between hexa-chloro-through octa-chloro-substituted (highly chlorinated) PCBs and all-cause mortality (except PCB 194). The most significant association was observed for PCB 206 (hazard ratio [HR] for 1-SD higher natural log-transformed circulating PCB 206 levels, 1.55; 95% CI, 1.26-1.91; P < .001). Following adjustment for hypertension, diabetes, smoking, body mass index, and cardiovascular disease at baseline, most associations were no longer statistically significant, but PCBs 206, 189, 170, and 209 were still significantly associated with all-cause mortality (PCB 206: adjusted HR, 1.47; 95% CI, 1.19-1.81; PCB 189: adjusted HR, 1.29; 95% CI, 1.08-1.55; PCB 170: adjusted HR, 1.24; 95% CI, 1.02-1.52; PCB 209: adjusted HR, 1.29; 95% CI, 1.04-1.60). In a secondary analysis, these associations were mainly because of death from cardiovascular diseases rather than noncardiovascular diseases. Three organochlorine pesticides, including dichlorodiphenyldichloroethylene, and the brominated flame retardant diphenyl ether 47 were also evaluated but did not show any significant associations with all-cause mortality.

CONCLUSIONS AND RELEVANCE Higher levels of highly chlorinated PCBs were associated with an increased mortality risk, especially from cardiovascular diseases. These results suggest that public health actions should be undertaken to minimize exposure to highly chlorinated PCBs.

Place, publisher, year, edition, pages
AMER MEDICAL ASSOC, 2019
National Category
Occupational Health and Environmental Health
Identifiers
urn:nbn:se:uu:diva-392891 (URN)10.1001/jamanetworkopen.2019.3070 (DOI)000476798700069 ()31026035 (PubMedID)
Funder
Swedish Research Council Formas, 2004-2007
Available from: 2019-09-24 Created: 2019-09-24 Last updated: 2019-09-24Bibliographically approved
Yang, W.-Y., Melgarejo, J. D., Thijs, L., Zhang, Z.-Y., Boggia, J., Wei, F.-F., . . . Melgarejo, J. D. (2019). Association of Office and Ambulatory Blood Pressure With Mortality and Cardiovascular Outcomes. Journal of the American Medical Association (JAMA), 322(5), 409-420
Open this publication in new window or tab >>Association of Office and Ambulatory Blood Pressure With Mortality and Cardiovascular Outcomes
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2019 (English)In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 322, no 5, p. 409-420Article in journal (Refereed) Published
Abstract [en]

ImportanceBlood pressure (BP) is a known risk factor for overall mortality and cardiovascular (CV)-specific fatal and nonfatal outcomes. It is uncertain which BP index is most strongly associated with these outcomes. ObjectiveTo evaluate the association of BP indexes with death and a composite CV event. Design, Setting, and ParticipantsLongitudinal population-based cohort study of 11135 adults from Europe, Asia, and South America with baseline observations collected from May 1988 to May 2010 (last follow-ups, August 2006-October 2016). ExposuresBlood pressure measured by an observer or an automated office machine; measured for 24 hours, during the day or the night; and the dipping ratio (nighttime divided by daytime readings). Main Outcomes and MeasuresMultivariable-adjusted hazard ratios (HRs) expressed the risk of death or a CV event associated with BP increments of 20/10 mm Hg. Cardiovascular events included CV mortality combined with nonfatal coronary events, heart failure, and stroke. Improvement in model performance was assessed by the change in the area under the curve (AUC). ResultsAmong 11135 participants (median age, 54.7 years, 49.3% women), 2836 participants died (18.5 per 1000 person-years) and 2049 (13.4 per 1000 person-years) experienced a CV event over a median of 13.8 years of follow-up. Both end points were significantly associated with all single systolic BP indexes (P<.001). For nighttime systolic BP level, the HR for total mortality was 1.23 (95% CI, 1.17-1.28) and for CV events, 1.36 (95% CI, 1.30-1.43). For the 24-hour systolic BP level, the HR for total mortality was 1.22 (95% CI, 1.16-1.28) and for CV events, 1.45 (95% CI, 1.37-1.54). With adjustment for any of the other systolic BP indexes, the associations of nighttime and 24-hour systolic BP with the primary outcomes remained statistically significant (HRs ranging from 1.17 [95% CI, 1.10-1.25] to 1.87 [95% CI, 1.62-2.16]). Base models that included single systolic BP indexes yielded an AUC of 0.83 for mortality and 0.84 for the CV outcomes. Adding 24-hour or nighttime systolic BP to base models that included other BP indexes resulted in incremental improvements in the AUC of 0.0013 to 0.0027 for mortality and 0.0031 to 0.0075 for the composite CV outcome. Adding any systolic BP index to models already including nighttime or 24-hour systolic BP did not significantly improve model performance. These findings were consistent for diastolic BP. Conclusions and RelevanceIn this population-based cohort study, higher 24-hour and nighttime blood pressure measurements were significantly associated with greater risks of death and a composite CV outcome, even after adjusting for other office-based or ambulatory blood pressure measurements. Thus, 24-hour and nighttime blood pressure may be considered optimal measurements for estimating CV risk, although statistically, model improvement compared with other blood pressure indexes was small.

Place, publisher, year, edition, pages
AMER MEDICAL ASSOC, 2019
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-393617 (URN)10.1001/jama.2019.9811 (DOI)000480293200013 ()31386134 (PubMedID)
Funder
EU, European Research Council, 713601-uPROPHETEU, European Research Council, 2011-294713-EPLORE
Available from: 2019-09-26 Created: 2019-09-26 Last updated: 2019-09-26Bibliographically 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
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-2335-8542

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