63 results on '"Gudmundsdottir V"'
Search Results
2. Four groups of type 2 diabetes contribute to the etiological and clinical heterogeneity in newly diagnosed individuals: An IMI DIRECT study
- Author
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Wesolowska-Andersen A, Brorsson CA, Bizzotto R, Mari A, Tura A, Koivula R, Mahajan A, Vinuela A, Tajes JF, Sharma S, Haid M, Prehn C, Artati A, Hong MG, Musholt PB, Kurbasic A, De Masi F, Tsirigos K, Pedersen HK, Gudmundsdottir V, Thomas CE, Banasik K, Jennison C, Jones A, Kennedy G, Bell J, Thomas L, Frost G, Thomsen H, Allin K, Hansen TH, Vestergaard H, Hansen T, Rutters F, Elders P, t'Hart L, Bonnefond A, Canouil M, Brage S, Kokkola T, Heggie A, McEvoy D, Hattersley A, McDonald T, Teare H, Ridderstrale M, Walker M, Forgie I, Giordano GN, Froguel P, Pavo I, Ruetten H, Pedersen O, Dermitzakis E, Franks PW, Schwenk JM, Adamski J, Pearson E, McCarthy MI, Brunak S, and ID Consortium
- Subjects
General Economics, Econometrics and Finance - Published
- 2022
3. Heart failure risk is accurately predicted by certain serum proteins
- Author
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Emilsson, V, primary, Jonsson, BG, additional, Gudmundsdottir, V, additional, Axelsson, GT, additional, Frick, EA, additional, Jonmundsson, T, additional, Steindorsdottir, AE, additional, Launer, LJ, additional, Aspelund, T, additional, Kortekaas, KA, additional, Lindeman, JH, additional, Lamb, JR, additional, Jennings, LL, additional, and Gudnason, V, additional
- Published
- 2022
- Full Text
- View/download PDF
4. Electrical Stimulation on denervated muscle: bone structural changes and correlation between muscle contraction and bone growth
- Author
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Gargiulo, P., Vatnsdal, B., Ingvarsson, P., Knútsdóttir, S., Gudmundsdóttir, V., Yngvason, S., Helgason, T., Magjarevic, Ratko, Dössel, Olaf, editor, and Schlegel, Wolfgang C., editor
- Published
- 2010
- Full Text
- View/download PDF
5. Density Distribution of Denervated Degenerated Rectus Femoris Muscle in Electrical Stimulation treatment
- Author
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Helgason, T., Gargiulo, P., Vatnsdal, B., Yngvason, S., Gudmundsdottir, V., Knútsdóttir, S., Ingvarsson, P., Magjarevic, Ratko, editor, Dössel, Olaf, editor, and Schlegel, Wolfgang C., editor
- Published
- 2009
- Full Text
- View/download PDF
6. Reconstructing an African haploid genome from the 18th century
- Author
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Jagadeesan, A., Gunnarsdottir, E. D., Ebenesersdottir, S. S., Gudmundsdottir, V. B., Thordardottir, E. L., Einarsdottir, M. S., Jonsson, H., Dugoujon, J. M., Fortes-Lima, C., Migot Nabias, Florence, Massougbodji, A., Bellis, G., Pereira, L., Masson, G., Kong, A., Stefansson, K., and Helgason, A.
- Subjects
geographic locations - Abstract
A genome is a mosaic of chromosome fragments from ancestors who existed some arbitrary number of generations earlier. Here, we reconstruct the genome of Hans Jonatan (HJ), born in the Caribbean in 1784 to an enslaved African mother and European father. HJ migrated to Iceland in 1802, married and had two children. We genotyped 182 of his 788 descendants using single-nucleotide polymorphism (SNP) chips and whole-genome sequenced (WGS) 20 of them. Using these data, we reconstructed 38% of HJ's maternal genome and inferred that his mother was from the region spanned by Benin, Nigeria and Cameroon.
- Published
- 2018
7. Quantitative color 3-dimensional computer tomography imaging of human long-term denervated muscle
- Author
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Gargiulo, P, Kern, H, Carraro, Ugo, Ingvarsson, P, Knutsdottir, S, Gudmundsdottir, V, Yngvason, S, Vatnsdal, B, and Helgason, T.
- Published
- 2010
8. Changes in Shape and Density of Denervated Muscles: Case Reports
- Author
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Helgason, T, primary, Gargiulo, P, additional, Gudmundsdottir, V, additional, Knutsdottir, S, additional, Yngvason, S, additional, and Invarsson, P, additional
- Published
- 2013
- Full Text
- View/download PDF
9. Design of small electrodes for matrix stimulation of finger muscles
- Author
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Helgason, T., primary, Hugosdottir, R, additional, Sigthorsson, H, additional, Gudmundsdottir, V, additional, Gargiulo, P, additional, and Ingvarsson, P, additional
- Published
- 2012
- Full Text
- View/download PDF
10. Neuro-imagerie en IRM a 7T : quel potentiel clinique ?
- Author
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Hertz-Pannier, L., primary, Wiggins, C., additional, Lebon, V., additional, Roger, S., additional, Ripert, K., additional, Maison, V., additional, Allirol, L., additional, Gudmundsdottir, V., additional, Lethimonnier, F., additional, and Le Bihan, D., additional
- Published
- 2008
- Full Text
- View/download PDF
11. NR-WS-63 Neuro-imagerie en IRM a 7T : quel potentiel clinique ?
- Author
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Hertz-Pannier, L., primary, Wiggins, C., additional, Lebon, V., additional, Roger, S., additional, Ripert, K., additional, Maison, V., additional, Allirol, L., additional, Gudmundsdottir, V., additional, Lethimonnier, F., additional, and Le Bihan, D., additional
- Published
- 2008
- Full Text
- View/download PDF
12. Human gut microbes impact host serum metabolome and insulin sensitivity
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Hk, Pedersen, Gudmundsdottir V, Hb, Nielsen, Hyotylainen T, Nielsen T, Ba, Jensen, Forslund K, Hildebrand F, Prifti E, Falony G, Le Chatelier E, Levenez F, Doré J, Mattila I, Dr, Plichta, Pöhö P, Li, Hellgren, Arumugam M, Sunagawa S, and Sara Vieira-Silva
13. Genetic variation related to tolbutamide and GLP-1 stimulated insulin secretion converges functionally in protein network space: a DIRECT study
- Author
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Pedersen, H. K., Gudmundsdottir, V., Jonsson, A., Leen 't Hart, Banasik, K., Boomsma, D., Eekhof, M. M. W., Hansen, T., Pedersen, O. B., Mccarthy, M., Pearson, E., Workman, C., Gupta, R., and Brunak, S.
14. A beta cell specific protein subnetwork significantly enriched for association with GLP-1 stimulated insulin secretion: a DIRECT study
- Author
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Gudmundsdottir, V., Pedersen, H. K., Leen 't Hart, Banasik, K., Boomsma, D., Geus, E., Eekhof, M., Diamant, M., Mccarthy, M., Pearson, E., Workman, C., Gupta, R., and Brunak, S.
15. Author Correction: Serum proteomics reveal APOE-ε4-dependent and APOE-ε4-independent protein signatures in Alzheimer's disease.
- Author
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Frick EA, Emilsson V, Jonmundsson T, Steindorsdottir AE, Johnson ECB, Puerta R, Dammer EB, Shantaraman A, Cano A, Boada M, Valero S, García-González P, Gudmundsson EF, Gudjonsson A, Pitts R, Qiu X, Finkel N, Loureiro JJ, Orth AP, Seyfried NT, Levey AI, Ruiz A, Aspelund T, Jennings LL, Launer LJ, Gudmundsdottir V, and Gudnason V
- Published
- 2024
- Full Text
- View/download PDF
16. Serum proteomics reveal APOE-ε4-dependent and APOE-ε4-independent protein signatures in Alzheimer's disease.
- Author
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Frick EA, Emilsson V, Jonmundsson T, Steindorsdottir AE, Johnson ECB, Puerta R, Dammer EB, Shantaraman A, Cano A, Boada M, Valero S, García-González P, Gudmundsson EF, Gudjonsson A, Pitts R, Qiu X, Finkel N, Loureiro JJ, Orth AP, Seyfried NT, Levey AI, Ruiz A, Aspelund T, Jennings LL, Launer LJ, Gudmundsdottir V, and Gudnason V
- Subjects
- Humans, Aged, Female, Male, Aged, 80 and over, Biomarkers blood, Biomarkers cerebrospinal fluid, Prospective Studies, Iceland, Alzheimer Disease blood, Alzheimer Disease genetics, Alzheimer Disease cerebrospinal fluid, Alzheimer Disease metabolism, Proteomics methods, Apolipoprotein E4 genetics
- Abstract
A deeper understanding of the molecular processes underlying late-onset Alzheimer's disease (LOAD) could aid in biomarker and drug target discovery. Using high-throughput serum proteomics in the prospective population-based Age, Gene/Environment Susceptibility-Reykjavik Study (AGES) cohort of 5,127 older Icelandic adults (mean age, 76.6 ± 5.6 years), we identified 303 proteins associated with incident LOAD over a median follow-up of 12.8 years. Over 40% of these proteins were associated with LOAD independently of APOE-ε4 carrier status, were implicated in neuronal processes and overlapped with LOAD protein signatures in brain and cerebrospinal fluid. We identified 17 proteins whose associations with LOAD were strongly dependent on APOE-ε4 carrier status, with mostly consistent associations in cerebrospinal fluid. Remarkably, four of these proteins (TBCA, ARL2, S100A13 and IRF6) were downregulated by APOE-ε4 yet upregulated due to LOAD, a finding replicated in external cohorts and possibly reflecting a response to disease onset. These findings highlight dysregulated pathways at the preclinical stages of LOAD, including those both independent of and dependent on APOE-ε4 status., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
17. A Large-Scale Genome-Wide Study of Gene-Sleep Duration Interactions for Blood Pressure in 811,405 Individuals from Diverse Populations.
- Author
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Wang H, Nagarajan P, Winkler T, Bentley A, Miller C, Kraja A, Schwander K, Lee S, Wang W, Brown M, Morrison J, Giri A, O'Connell J, Bartz T, de las Fuentes L, Gudmundsdottir V, Guo X, Harris S, Huang Z, Kals M, Kho M, Lefevre C, Luan J, Lyytikäinen LP, Mangino M, Milaneschi Y, Palmer N, Rao V, Rauramaa R, Shen B, Stadler S, Sun Q, Tang J, Thériault S, van der Graaf A, van der Most P, Wang Y, Weiss S, Westerman K, Yang Q, Yasuharu T, Zhao W, Zhu W, Altschul D, Ansari MAY, Anugu P, Argoty-Pantoja A, Arzt M, Aschard H, Attia J, Bazzano L, Breyer M, Brody J, Cade B, Chen HH, Chen YI, Chen Z, de Vries P, Dimitrov L, Do A, Du J, Dupont C, Edwards T, Evans M, Faquih T, Felix S, Fisher-Hoch S, Floyd J, Graff M, Charles Gu C, Gu D, Hairston K, Hanley A, Heid I, Heikkinen S, Highland H, Hood M, Kähönen M, Karvonen-Gutierrez C, Kawaguchi T, Kazuya S, Tanika K, Komulainen P, Levy D, Lin H, Liu P, Marques-Vidal P, McCormick J, Mei H, Meigs J, Menni C, Nam K, Nolte I, Pacheco N, Petty L, Polikowsky H, Province M, Psaty B, Raffield L, Raitakari O, Rich S, Riha R, Risch L, Risch M, Ruiz-Narvaez E, Scott R, Sitlani C, Smith J, Sofer T, Teder-Laving M, Völker U, Vollenweider P, Wang G, van Dijk KW, Wilson O, Xia R, Yao J, Young K, Zhang R, Zhu X, Below J, Böger C, Conen D, Cox S, Dörr M, Feitosa M, Fox E, Franceschini N, Gharib S, Gudnason V, Harlow S, He J, Holliday E, Kutalik Z, Lakka T, Lawlor D, Lee S, Lehtimäki T, Li C, Liu CT, Mägi R, Matsuda F, Morrison A, Penninx BWJH, Peyser P, Rotter J, Snieder H, Spector T, Wagenknecht L, Wareham N, Zonderman A, North K, Fornage M, Hung A, Manning A, Gauderman W, Chen H, Munroe P, Rao D, van Heemst D, Redline S, and Noordam R
- Abstract
Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discover 22 novel gene-sleep duration interaction loci for blood pressure, mapped to 23 genes. Investigating these genes' functional implications shed light on neurological, thyroidal, bone metabolism, and hematopoietic pathways that necessitate future investigation for blood pressure management that caters to sleep health lifestyle. Non-overlap between short sleep (12) and long sleep (10) interactions underscores the plausible nature of distinct influences of both sleep duration extremes in cardiovascular health. Several of our loci are specific towards a particular population background or sex, emphasizing the importance of addressing heterogeneity entangled in gene-environment interactions, when considering precision medicine design approaches for blood pressure management., Competing Interests: Declarations CONFLICT OF INTEREST C.L.M. has received funding from AstraZeneca not related to the current study. B.M.P. serves on the steering committee of the Yale Open Data Access Project funded by Johnson & Johnson. D.C. receives consultancy fees from Roche Diagnostics and Trimedics and speaker fees from Servier. D.A.L. has received support from Medtronic LTD and Roche Diagnostics for biomarker research not related to the current study. The remaining authors declare no competing interests.
- Published
- 2024
- Full Text
- View/download PDF
18. Proteomic analysis of Alzheimer's disease cerebrospinal fluid reveals alterations associated with APOE ε4 and atomoxetine treatment.
- Author
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Dammer EB, Shantaraman A, Ping L, Duong DM, Gerasimov ES, Ravindran SP, Gudmundsdottir V, Frick EA, Gomez GT, Walker KA, Emilsson V, Jennings LL, Gudnason V, Western D, Cruchaga C, Lah JJ, Wingo TS, Wingo AP, Seyfried NT, Levey AI, and Johnson ECB
- Subjects
- Humans, tau Proteins cerebrospinal fluid, tau Proteins metabolism, Amyloid beta-Peptides cerebrospinal fluid, Amyloid beta-Peptides metabolism, Male, Aged, Female, Biomarkers cerebrospinal fluid, Biomarkers metabolism, Alzheimer Disease cerebrospinal fluid, Alzheimer Disease drug therapy, Alzheimer Disease genetics, Proteomics methods, Apolipoprotein E4 genetics, Atomoxetine Hydrochloride therapeutic use, Atomoxetine Hydrochloride pharmacology
- Abstract
Alzheimer's disease (AD) is currently defined by the aggregation of amyloid-β (Aβ) and tau proteins in the brain. Although biofluid biomarkers are available to measure Aβ and tau pathology, few markers are available to measure the complex pathophysiology that is associated with these two cardinal neuropathologies. Here, we characterized the proteomic landscape of cerebrospinal fluid (CSF) changes associated with Aβ and tau pathology in 300 individuals using two different proteomic technologies-tandem mass tag mass spectrometry and SomaScan. Integration of both data types allowed for generation of a robust protein coexpression network consisting of 34 modules derived from 5242 protein measurements, including disease-relevant modules associated with autophagy, ubiquitination, endocytosis, and glycolysis. Three modules strongly associated with the apolipoprotein E ε4 ( APOE ε4) AD risk genotype mapped to oxidant detoxification, mitogen-associated protein kinase signaling, neddylation, and mitochondrial biology and overlapped with a previously described lipoprotein module in serum. Alterations of all three modules in blood were associated with dementia more than 20 years before diagnosis. Analysis of CSF samples from an AD phase 2 clinical trial of atomoxetine (ATX) demonstrated that abnormal elevations in the glycolysis CSF module-the network module most strongly correlated to cognitive function-were reduced by ATX treatment. Clustering of individuals based on their CSF proteomic profiles revealed heterogeneity of pathological changes not fully reflected by Aβ and tau.
- Published
- 2024
- Full Text
- View/download PDF
19. A Large-Scale Genome-Wide Study of Gene-Sleep Duration Interactions for Blood Pressure in 811,405 Individuals from Diverse Populations.
- Author
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Nagarajan P, Winkler TW, Bentley AR, Miller CL, Kraja AT, Schwander K, Lee S, Wang W, Brown MR, Morrison JL, Giri A, O'Connell JR, Bartz TM, de las Fuentes L, Gudmundsdottir V, Guo X, Harris SE, Huang Z, Kals M, Kho M, Lefevre C, Luan J, Lyytikäinen LP, Mangino M, Milaneschi Y, Palmer ND, Rao V, Rauramaa R, Shen B, Stadler S, Sun Q, Tang J, Thériault S, van der Graaf A, van der Most PJ, Wang Y, Weiss S, Westerman KE, Yang Q, Yasuharu T, Zhao W, Zhu W, Altschul D, Ansari MAY, Anugu P, Argoty-Pantoja AD, Arzt M, Aschard H, Attia JR, Bazzanno L, Breyer MA, Brody JA, Cade BE, Chen HH, Ida Chen YD, Chen Z, de Vries PS, Dimitrov LM, Do A, Du J, Dupont CT, Edwards TL, Evans MK, Faquih T, Felix SB, Fisher-Hoch SP, Floyd JS, Graff M, Gu C, Gu D, Hairston KG, Hanley AJ, Heid IM, Heikkinen S, Highland HM, Hood MM, Kähönen M, Karvonen-Gutierrez CA, Kawaguchi T, Kazuya S, Kelly TN, Komulainen P, Levy D, Lin HJ, Liu PY, Marques-Vidal P, McCormick JB, Mei H, Meigs JB, Menni C, Nam K, Nolte IM, Pacheco NL, Petty LE, Polikowsky HG, Province MA, Psaty BM, Raffield LM, Raitakari OT, Rich SS, Riha RL, Risch L, Risch M, Ruiz-Narvaez EA, Scott RJ, Sitlani CM, Smith JA, Sofer T, Teder-Laving M, Völker U, Vollenweider P, Wang G, van Dijk KW, Wilson OD, Xia R, Yao J, Young KL, Zhang R, Zhu X, Below JE, Böger CA, Conen D, Cox SR, Dörr M, Feitosa MF, Fox ER, Franceschini N, Gharib SA, Gudnason V, Harlow SD, He J, Holliday EG, Kutalik Z, Lakka TA, Lawlor DA, Lee S, Lehtimäki T, Li C, Liu CT, Mägi R, Matsuda F, Morrison AC, Penninx BW, Peyser PA, Rotter JI, Snieder H, Spector TD, Wagenknecht LE, Wareham NJ, Zonderman AB, North KE, Fornage M, Hung AM, Manning AK, Gauderman J, Chen H, Munroe PB, Rao DC, van Heemst D, Redline S, Noordam R, and Wang H
- Abstract
Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discover 22 novel gene-sleep duration interaction loci for blood pressure, mapped to genes involved in neurological, thyroidal, bone metabolism, and hematopoietic pathways. Non-overlap between short sleep (12) and long sleep (10) interactions underscores the plausibility of distinct influences of both sleep duration extremes in cardiovascular health. With several of our loci reflecting specificity towards population background or sex, our discovery sheds light on the importance of embracing granularity when addressing heterogeneity entangled in gene-environment interactions, and in therapeutic design approaches for blood pressure management., Competing Interests: Conflict of Interest/Disclosures: C.L.M. has received funding from AstraZeneca not related to the current study. B.M.P. serves on the steering committee of the Yale Open Data Access Project funded by Johnson & Johnson. D.C. receives consultancy fees from Roche Diagnostics and Trimedics and speaker fees from Servier. D.A.L. has received support from Medtronic LTD and Roche Diagnostics for biomarker research not related to the current study. The remaining authors declare no competing interests.
- Published
- 2024
- Full Text
- View/download PDF
20. Proteomic associations with forced expiratory volume: a Mendelian randomisation study.
- Author
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Axelsson GT, Jonmundsson T, Woo Y, Frick EA, Aspelund T, Loureiro JJ, Orth AP, Jennings LL, Gudmundsson G, Emilsson V, Gudmundsdottir V, and Gudnason V
- Subjects
- Humans, Female, Pregnancy, Aged, Forced Expiratory Volume genetics, Placenta, Biomarkers, Lung, Proteomics
- Abstract
Background: A decline in forced expiratory volume (FEV1) is a hallmark of respiratory diseases that are an important cause of morbidity among the elderly. While some data exist on biomarkers that are related to FEV1, we sought to do a systematic analysis of causal relations of biomarkers with FEV1., Methods: Data from the population-based AGES-Reykjavik study were used. Serum proteomic measurements were done using 4782 DNA aptamers (SOMAmers). Data from 1479 participants with spirometric data were used to assess the association of SOMAmer measurements with FEV1 using linear regression. Bi-directional two-sample Mendelian randomisation (MR) analyses were done to assess causal relations of observationally associated SOMAmers with FEV1, using genotype and SOMAmer data from 5368 AGES-Reykjavik participants and genetic associations with FEV1 from a publicly available GWAS (n = 400,102)., Results: In observational analyses, 530 SOMAmers were associated with FEV1 after multiple testing adjustment (FDR < 0.05). The most significant were Retinoic Acid Receptor Responder 2 (RARRES2), R-Spondin 4 (RSPO4) and Alkaline Phosphatase, Placental Like 2 (ALPPL2). Of the 257 SOMAmers with genetic instruments available, eight were associated with FEV1 in MR analyses. Three were directionally consistent with the observational estimate, Thrombospondin 2 (THBS2), Endoplasmic Reticulum Oxidoreductase 1 Beta (ERO1B) and Apolipoprotein M (APOM). THBS2 was further supported by a colocalization analysis. Analyses in the reverse direction, testing whether changes in SOMAmer levels were caused by changes in FEV1, were performed but no significant associations were found after multiple testing adjustments., Conclusions: In summary, this large scale proteogenomic analyses of FEV1 reveals circulating protein markers of FEV1, as well as several proteins with potential causality to lung function., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
21. Serum proteomics reveals APOE dependent and independent protein signatures in Alzheimer's disease.
- Author
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Gudmundsdottir V, Frick E, Emilsson V, Jonmundsson T, Steindorsdottir A, Johnson ECB, Puerta R, Dammer E, Shantaraman A, Cano A, Boada M, Valero S, Garcia-Gonzalez P, Gudmundsson E, Gudjonsson A, Pitts R, Qiu X, Finkel N, Loureiro J, Orth A, Seyfried N, Levey A, Ruiz A, Aspelund T, Jennings L, Launer L, and Gudnason V
- Abstract
The current demand for early intervention, prevention, and treatment of late onset Alzheimer's disease (LOAD) warrants deeper understanding of the underlying molecular processes which could contribute to biomarker and drug target discovery. Utilizing high-throughput proteomic measurements in serum from a prospective population-based cohort of older adults (n = 5,294), we identified 303 unique proteins associated with incident LOAD (median follow-up 12.8 years). Over 40% of these proteins were associated with LOAD independently of APOE -ε 4 carrier status. These proteins were implicated in neuronal processes and overlapped with protein signatures of LOAD in brain and cerebrospinal fluid. We found 17 proteins which LOAD-association was strongly dependent on APOE -ε 4 carrier status. Most of them showed consistent associations with LOAD in cerebrospinal fluid and a third had brain-specific gene expression. Remarkably, four proteins in this group (TBCA, ARL2, S100A13 and IRF6) were downregulated by APOE -ε 4 yet upregulated as a consequence of LOAD as determined in a bi-directional Mendelian randomization analysis, reflecting a potential response to the disease onset. Accordingly, the direct association of these proteins to LOAD was reversed upon APOE -ε 4 genotype adjustment, a finding which we replicate in an external cohort (n = 719). Our findings provide an insight into the dysregulated pathways that may lead to the development and early detection of LOAD, including those both independent and dependent on APOE -ε 4 . Importantly, many of the LOAD-associated proteins we find in the circulation have been found to be expressed - and have a direct link with AD - in brain tissue. Thus, the proteins identified here, and their upstream modulating pathways, provide a new source of circulating biomarker and therapeutic target candidates for LOAD., Competing Interests: Competing interest declaration R.P., X.Q., N.F., L.L.J., A.P.O and J.J.L are employees and stockholders of Novartis. N.T.S and A.I.L are co-founders of Emtherapro. No other potential conflicts of interest relevant to this article were reported.
- Published
- 2024
- Full Text
- View/download PDF
22. Proteomic prediction of incident heart failure and its main subtypes.
- Author
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Emilsson V, Jonsson BG, Austin TR, Gudmundsdottir V, Axelsson GT, Frick EA, Jonmundsson T, Steindorsdottir AE, Loureiro J, Brody JA, Aspelund T, Launer LJ, Thorgeirsson G, Kortekaas KA, Lindeman JH, Orth AP, Lamb JR, Psaty BM, Kizer JR, Jennings LL, and Gudnason V
- Subjects
- Humans, Aged, Cohort Studies, Stroke Volume, Prospective Studies, Proteomics, Blood Proteins, Prognosis, Heart Failure diagnosis, Heart Failure epidemiology
- Abstract
Aim: To examine the ability of serum proteins in predicting future heart failure (HF) events, including HF with reduced or preserved ejection fraction (HFrEF or HFpEF), in relation to event time, and with or without considering established HF-associated clinical variables., Methods and Results: In the prospective population-based Age, Gene/Environment Susceptibility Reykjavik Study (AGES-RS), 440 individuals developed HF after their first visit with a median follow-up of 5.45 years. Among them, 167 were diagnosed with HFrEF and 188 with HFpEF. A least absolute shrinkage and selection operator regression model with non-parametric bootstrap were used to select predictors from an analysis of 4782 serum proteins, and several pre-established clinical parameters linked to HF. A subset of 8-10 distinct or overlapping serum proteins predicted different future HF outcomes, and C-statistics were used to assess discrimination, revealing proteins combined with a C-index of 0.80 for all incident HF, 0.78 and 0.80 for incident HFpEF or HFrEF, respectively. In the AGES-RS, protein panels alone encompassed the risk contained in the clinical information and improved the performance characteristics of prediction models based on N-terminal pro-B-type natriuretic peptide and clinical risk factors. Finally, the protein predictors performed particularly well close to the time of an HF event, an outcome that was replicated in the Cardiovascular Health Study., Conclusion: A small number of circulating proteins accurately predicted future HF in the AGES-RS cohort of older adults, and they alone encompass the risk information found in a collection of clinical data. Incident HF events were predicted up to 8 years, with predictor performance significantly improving for events occurring less than 1 year ahead, a finding replicated in an external cohort study., (© 2023 European Society of Cardiology.)
- Published
- 2024
- Full Text
- View/download PDF
23. Serum proteomics reveals APOE dependent and independent protein signatures in Alzheimer's disease.
- Author
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Frick EA, Emilsson V, Jonmundsson T, Steindorsdottir AE, Johnson ECB, Puerta R, Dammer EB, Shantaraman A, Cano A, Boada M, Valero S, García-González P, Gudmundsson EF, Gudjonsson A, Loureiro JJ, Orth AP, Seyfried NT, Levey AI, Ruiz A, Aspelund T, Jennings LL, Launer LJ, Gudmundsdottir V, and Gudnason V
- Abstract
The current demand for early intervention, prevention, and treatment of late onset Alzheimer's disease (LOAD) warrants deeper understanding of the underlying molecular processes which could contribute to biomarker and drug target discovery. Utilizing high-throughput proteomic measurements in serum from a prospective population-based cohort of older adults (n=5,294), we identified 303 unique proteins associated with incident LOAD (median follow-up 12.8 years). Over 40% of these proteins were associated with LOAD independently of APOE -ε 4 carrier status. These proteins were implicated in neuronal processes and overlapped with protein signatures of LOAD in brain and cerebrospinal fluid. We found 17 proteins which LOAD-association was strongly dependent on APOE -ε 4 carrier status. Most of them showed consistent associations with LOAD in cerebrospinal fluid and a third had brain-specific gene expression. Remarkably, four proteins in this group (TBCA, ARL2, S100A13 and IRF6) were downregulated by APOE -ε 4 yet upregulated as a consequence of LOAD as determined in a bi-directional Mendelian randomization analysis, reflecting a potential response to the disease onset. Accordingly, the direct association of these proteins to LOAD was reversed upon APOE -ε 4 genotype adjustment, a finding which we replicate in an external cohort (n=719). Our findings provide an insight into the dysregulated pathways that may lead to the development and early detection of LOAD, including those both independent and dependent on APOE -ε 4 . Importantly, many of the LOAD-associated proteins we find in the circulation have been found to be expressed - and have a direct link with AD - in brain tissue. Thus, the proteins identified here, and their upstream modulating pathways, provide a new source of circulating biomarker and therapeutic target candidates for LOAD., Competing Interests: Declaration of interests L.L.J., A.P.O and J.J.L are employees and stockholders of Novartis. N.T.S and A.I.L are co-founders of Emtherapro. No other potential conflicts of interest relevant to this article were reported.
- Published
- 2023
- Full Text
- View/download PDF
24. Identification of circulating proteins associated with general cognitive function among middle-aged and older adults.
- Author
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Tin A, Fohner AE, Yang Q, Brody JA, Davies G, Yao J, Liu D, Caro I, Lindbohm JV, Duggan MR, Meirelles O, Harris SE, Gudmundsdottir V, Taylor AM, Henry A, Beiser AS, Shojaie A, Coors A, Fitzpatrick AL, Langenberg C, Satizabal CL, Sitlani CM, Wheeler E, Tucker-Drob EM, Bressler J, Coresh J, Bis JC, Candia J, Jennings LL, Pietzner M, Lathrop M, Lopez OL, Redmond P, Gerszten RE, Rich SS, Heckbert SR, Austin TR, Hughes TM, Tanaka T, Emilsson V, Vasan RS, Guo X, Zhu Y, Tzourio C, Rotter JI, Walker KA, Ferrucci L, Kivimäki M, Breteler MMB, Cox SR, Debette S, Mosley TH, Gudnason VG, Launer LJ, Psaty BM, Seshadri S, and Fornage M
- Subjects
- Middle Aged, Humans, Aged, Cognition, Neurons, Biomarkers, Alzheimer Disease, Cognitive Dysfunction
- Abstract
Identifying circulating proteins associated with cognitive function may point to biomarkers and molecular process of cognitive impairment. Few studies have investigated the association between circulating proteins and cognitive function. We identify 246 protein measures quantified by the SomaScan assay as associated with cognitive function (p < 4.9E-5, n up to 7289). Of these, 45 were replicated using SomaScan data, and three were replicated using Olink data at Bonferroni-corrected significance. Enrichment analysis linked the proteins associated with general cognitive function to cell signaling pathways and synapse architecture. Mendelian randomization analysis implicated higher levels of NECTIN2, a protein mediating viral entry into neuronal cells, with higher Alzheimer's disease (AD) risk (p = 2.5E-26). Levels of 14 other protein measures were implicated as consequences of AD susceptibility (p < 2.0E-4). Proteins implicated as causes or consequences of AD susceptibility may provide new insight into the potential relationship between immunity and AD susceptibility as well as potential therapeutic targets., (© 2023. The Author(s).)
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- 2023
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25. A proteomic analysis of atrial fibrillation in a prospective longitudinal cohort (AGES-Reykjavik study).
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Jonmundsson T, Steindorsdottir AE, Austin TR, Frick EA, Axelsson GT, Launer L, Psaty BM, Loureiro J, Orth AP, Aspelund T, Emilsson V, Floyd JS, Jennings L, Gudnason V, and Gudmundsdottir V
- Subjects
- Humans, Natriuretic Peptide, Brain, Biomarkers, Prognosis, Prospective Studies, Proteomics, Risk Factors, Peptide Fragments, Oxidoreductases Acting on Sulfur Group Donors, Endosomal Sorting Complexes Required for Transport, Atrial Fibrillation diagnosis, Atrial Fibrillation epidemiology
- Abstract
Aims: Atrial fibrillation (AF) is associated with high risk of comorbidities and mortality. Our aim was to examine causal and predictive relationships between 4137 serum proteins and incident AF in the prospective population-based Age, Gene/Environment Susceptibility-Reykjavik (AGES-Reykjavik) study., Methods and Results: The study included 4765 participants, of whom 1172 developed AF. Cox proportional hazards regression models were fitted for 4137 baseline protein measurements adjusting for known risk factors. Protein associations were tested for replication in the Cardiovascular Health Study (CHS). Causal relationships were examined in a bidirectional, two-sample Mendelian randomization analysis. The time-dependent area under the receiver operating characteristic curve (AUC)-statistic was examined as protein levels and an AF-polygenic risk score (PRS) were added to clinical risk models. The proteomic signature of incident AF consisted of 76 proteins, of which 63 (83%) were novel and 29 (38%) were replicated in CHS. The signature included both N-terminal prohormone of brain natriuretic peptide (NT-proBNP)-dependent (e.g. CHST15, ATP1B1, and SVEP1) and independent components (e.g. ASPN, AKR1B, and LAMA1/LAMB1/LAMC1). Nine causal candidates were identified (TAGLN, WARS, CHST15, CHMP3, COL15A1, DUSP13, MANBA, QSOX2, and SRL). The reverse causal analysis suggested that most AF-associated proteins were affected by the genetic liability to AF. N-terminal prohormone of brain natriuretic peptide improved the prediction of incident AF events close to baseline with further improvements gained by the AF-PRS at all time points., Conclusion: The AF proteomic signature includes biologically relevant proteins, some of which may be causal. It mainly reflects an NT-proBNP-dependent consequence of the genetic liability to AF. N-terminal prohormone of brain natriuretic peptide is a promising marker for incident AF in the short term, but risk assessment incorporating a PRS may improve long-term risk assessment., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)
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- 2023
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26. Proteomic Network Analysis of Alzheimer's Disease Cerebrospinal Fluid Reveals Alterations Associated with APOE ε4 Genotype and Atomoxetine Treatment.
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Dammer EB, Shantaraman A, Ping L, Duong DM, Gerasimov ES, Ravindran SP, Gudmundsdottir V, Frick EA, Gomez GT, Walker KA, Emilsson V, Jennings LL, Gudnason V, Western D, Cruchaga C, Lah JJ, Wingo TS, Wingo AP, Seyfried NT, Levey AI, and Johnson ECB
- Abstract
Alzheimer's disease (AD) is currently defined at the research level by the aggregation of amyloid-β (Aβ) and tau proteins in brain. While biofluid biomarkers are available to measure Aβ and tau pathology, few biomarkers are available to measure the complex pathophysiology that is associated with these two cardinal neuropathologies. Here we describe the proteomic landscape of cerebrospinal fluid (CSF) changes associated with Aβ and tau pathology in 300 individuals as assessed by two different proteomic technologies-tandem mass tag (TMT) mass spectrometry and SomaScan. Harmonization and integration of both data types allowed for generation of a robust protein co-expression network consisting of 34 modules derived from 5242 protein measurements, including disease-relevant modules associated with autophagy, ubiquitination, endocytosis, and glycolysis. Three modules strongly associated with the apolipoprotein E ε4 ( APOE ε4) AD risk genotype mapped to oxidant detoxification, mitogen associated protein kinase (MAPK) signaling, neddylation, and mitochondrial biology, and overlapped with a previously described lipoprotein module in serum. Neddylation and oxidant detoxification/MAPK signaling modules had a negative association with APOE ε4 whereas the mitochondrion module had a positive association with APOE ε4. The directions of association were consistent between CSF and blood in two independent longitudinal cohorts, and altered levels of all three modules in blood were associated with dementia over 20 years prior to diagnosis. Dual-proteomic platform analysis of CSF samples from an AD phase 2 clinical trial of atomoxetine (ATX) demonstrated that abnormal elevations in the glycolysis CSF module-the network module most strongly correlated to cognitive function-were reduced by ATX treatment. Individuals who had more severe glycolytic changes at baseline responded better to ATX. Clustering of individuals based on their CSF proteomic network profiles revealed ten groups that did not cleanly stratify by Aβ and tau status, underscoring the heterogeneity of pathological changes not fully reflected by Aβ and tau. AD biofluid proteomics holds promise for the development of biomarkers that reflect diverse pathologies for use in clinical trials and precision medicine.
- Published
- 2023
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27. Proteomic associations with forced expiratory volume - a Mendelian randomisation study.
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Axelsson GT, Jonmundsson T, Woo YJ, Frick EA, Aspelund T, Loureiro JJ, Orth AP, Jennings LL, Gudmundsson G, Emilsson V, Gudmundsdottir V, and Gudnason V
- Abstract
A decline in forced expiratory volume (FEV1) is a hallmark of obstructive respiratory diseases, an important cause of morbidity among the elderly. While some data exist on biomarkers that are related to FEV1, we sought to do a systematic analysis of causal relations of biomarkers with FEV1. Data from the general population-based AGES-Reykjavik study were used. Proteomic measurements were done using 4,782 DNA aptamers (SOMAmers). Data from 1,648 participants with spirometric data were used to assess the association of SOMAmer measurements with FEV1 using linear regression. Bi-directional Mendelian randomisation (MR) analyses were done to assess causal relations of observationally associated SOMAmers with FEV1, using genotype and SOMAmer data from 5,368 AGES-Reykjavik participants and genetic associations with FEV1 from a publicly available GWAS (n = 400,102). In observational analyses, 473 SOMAmers were associated with FEV1 after multiple testing adjustment. The most significant were R-Spondin 4, Alkaline Phosphatase, Placental Like 2 and Retinoic Acid Receptor Responder 2. Of the 235 SOMAmers with genetic data, eight were associated with FEV1 in MR analyses. Three were directionally consistent with the observational estimate, Thrombospondin 2 (THBS2), Endoplasmic Reticulum Oxidoreductase 1 Beta and Apolipoprotein M. THBS2 was further supported by a colocalization analysis. Analyses in the reverse direction, testing whether changes in SOMAmer levels were caused by changes in FEV1, were performed but no significant associations were found after multiple testing adjustments. In summary, this large scale proteogenomic analyses of FEV1 reveals protein markers of FEV1, as well as several proteins with potential causality to lung function.
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- 2023
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28. Author Correction: Discovery of drug-omics associations in type 2 diabetes with generative deep-learning models.
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Allesøe RL, Lundgaard AT, Hernández Medina R, Aguayo-Orozco A, Johansen J, Nissen JN, Brorsson C, Mazzoni G, Niu L, Biel JH, Leal Rodríguez C, Brasas V, Webel H, Benros ME, Pedersen AG, Chmura PJ, Jacobsen UP, Mari A, Koivula R, Mahajan A, Vinuela A, Tajes JF, Sharma S, Haid M, Hong MG, Musholt PB, De Masi F, Vogt J, Pedersen HK, Gudmundsdottir V, Jones A, Kennedy G, Bell J, Thomas EL, Frost G, Thomsen H, Hansen E, Hansen TH, Vestergaard H, Muilwijk M, Blom MT, 't Hart LM, Pattou F, Raverdy V, Brage S, Kokkola T, Heggie A, McEvoy D, Mourby M, Kaye J, Hattersley A, McDonald T, Ridderstråle M, Walker M, Forgie I, Giordano GN, Pavo I, Ruetten H, Pedersen O, Hansen T, Dermitzakis E, Franks PW, Schwenk JM, Adamski J, McCarthy MI, Pearson E, Banasik K, Rasmussen S, and Brunak S
- Published
- 2023
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29. Identification of biomarkers for glycaemic deterioration in type 2 diabetes.
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Slieker RC, Donnelly LA, Akalestou E, Lopez-Noriega L, Melhem R, Güneş A, Abou Azar F, Efanov A, Georgiadou E, Muniangi-Muhitu H, Sheikh M, Giordano GN, Åkerlund M, Ahlqvist E, Ali A, Banasik K, Brunak S, Barovic M, Bouland GA, Burdet F, Canouil M, Dragan I, Elders PJM, Fernandez C, Festa A, Fitipaldi H, Froguel P, Gudmundsdottir V, Gudnason V, Gerl MJ, van der Heijden AA, Jennings LL, Hansen MK, Kim M, Leclerc I, Klose C, Kuznetsov D, Mansour Aly D, Mehl F, Marek D, Melander O, Niknejad A, Ottosson F, Pavo I, Duffin K, Syed SK, Shaw JL, Cabrera O, Pullen TJ, Simons K, Solimena M, Suvitaival T, Wretlind A, Rossing P, Lyssenko V, Legido Quigley C, Groop L, Thorens B, Franks PW, Lim GE, Estall J, Ibberson M, Beulens JWJ, 't Hart LM, Pearson ER, and Rutter GA
- Subjects
- Mice, Animals, Male, Blood Glucose metabolism, Insulin metabolism, Lipids, Biomarkers metabolism, Cell Adhesion Molecules metabolism, Extracellular Matrix Proteins metabolism, Diabetes Mellitus, Type 2 metabolism, Islets of Langerhans metabolism
- Abstract
We identify biomarkers for disease progression in three type 2 diabetes cohorts encompassing 2,973 individuals across three molecular classes, metabolites, lipids and proteins. Homocitrulline, isoleucine and 2-aminoadipic acid, eight triacylglycerol species, and lowered sphingomyelin 42:2;2 levels are predictive of faster progression towards insulin requirement. Of ~1,300 proteins examined in two cohorts, levels of GDF15/MIC-1, IL-18Ra, CRELD1, NogoR, FAS, and ENPP7 are associated with faster progression, whilst SMAC/DIABLO, SPOCK1 and HEMK2 predict lower progression rates. In an external replication, proteins and lipids are associated with diabetes incidence and prevalence. NogoR/RTN4R injection improved glucose tolerance in high fat-fed male mice but impaired it in male db/db mice. High NogoR levels led to islet cell apoptosis, and IL-18R antagonised inflammatory IL-18 signalling towards nuclear factor kappa-B in vitro. This comprehensive, multi-disciplinary approach thus identifies biomarkers with potential prognostic utility, provides evidence for possible disease mechanisms, and identifies potential therapeutic avenues to slow diabetes progression., (© 2023. The Author(s).)
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- 2023
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30. Discovery of drug-omics associations in type 2 diabetes with generative deep-learning models.
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Allesøe RL, Lundgaard AT, Hernández Medina R, Aguayo-Orozco A, Johansen J, Nissen JN, Brorsson C, Mazzoni G, Niu L, Biel JH, Leal Rodríguez C, Brasas V, Webel H, Benros ME, Pedersen AG, Chmura PJ, Jacobsen UP, Mari A, Koivula R, Mahajan A, Vinuela A, Tajes JF, Sharma S, Haid M, Hong MG, Musholt PB, De Masi F, Vogt J, Pedersen HK, Gudmundsdottir V, Jones A, Kennedy G, Bell J, Thomas EL, Frost G, Thomsen H, Hansen E, Hansen TH, Vestergaard H, Muilwijk M, Blom MT, 't Hart LM, Pattou F, Raverdy V, Brage S, Kokkola T, Heggie A, McEvoy D, Mourby M, Kaye J, Hattersley A, McDonald T, Ridderstråle M, Walker M, Forgie I, Giordano GN, Pavo I, Ruetten H, Pedersen O, Hansen T, Dermitzakis E, Franks PW, Schwenk JM, Adamski J, McCarthy MI, Pearson E, Banasik K, Rasmussen S, and Brunak S
- Subjects
- Humans, Algorithms, Deep Learning, Diabetes Mellitus, Type 2 drug therapy, Diabetes Mellitus, Type 2 genetics
- Abstract
The application of multiple omics technologies in biomedical cohorts has the potential to reveal patient-level disease characteristics and individualized response to treatment. However, the scale and heterogeneous nature of multi-modal data makes integration and inference a non-trivial task. We developed a deep-learning-based framework, multi-omics variational autoencoders (MOVE), to integrate such data and applied it to a cohort of 789 people with newly diagnosed type 2 diabetes with deep multi-omics phenotyping from the DIRECT consortium. Using in silico perturbations, we identified drug-omics associations across the multi-modal datasets for the 20 most prevalent drugs given to people with type 2 diabetes with substantially higher sensitivity than univariate statistical tests. From these, we among others, identified novel associations between metformin and the gut microbiota as well as opposite molecular responses for the two statins, simvastatin and atorvastatin. We used the associations to quantify drug-drug similarities, assess the degree of polypharmacy and conclude that drug effects are distributed across the multi-omics modalities., (© 2023. The Author(s).)
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- 2023
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31. Metabolic and proteomic signatures of type 2 diabetes subtypes in an Arab population.
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Zaghlool SB, Halama A, Stephan N, Gudmundsdottir V, Gudnason V, Jennings LL, Thangam M, Ahlqvist E, Malik RA, Albagha OME, Abou-Samra AB, and Suhre K
- Subjects
- Humans, Proteomics, Arabs, Insulin, Diabetes Mellitus, Type 2 genetics, Diabetes Mellitus, Type 2 metabolism, Diabetes Mellitus, Type 1
- Abstract
Type 2 diabetes (T2D) has a heterogeneous etiology influencing its progression, treatment, and complications. A data driven cluster analysis in European individuals with T2D previously identified four subtypes: severe insulin deficient (SIDD), severe insulin resistant (SIRD), mild obesity-related (MOD), and mild age-related (MARD) diabetes. Here, the clustering approach was applied to individuals with T2D from the Qatar Biobank and validated in an independent set. Cluster-specific signatures of circulating metabolites and proteins were established, revealing subtype-specific molecular mechanisms, including activation of the complement system with features of autoimmune diabetes and reduced 1,5-anhydroglucitol in SIDD, impaired insulin signaling in SIRD, and elevated leptin and fatty acid binding protein levels in MOD. The MARD cluster was the healthiest with metabolomic and proteomic profiles most similar to the controls. We have translated the T2D subtypes to an Arab population and identified distinct molecular signatures to further our understanding of the etiology of these subtypes., (© 2022. The Author(s).)
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- 2022
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32. Meals, Microbiota and Mental Health in Children and Adolescents (MMM-Study): A protocol for an observational longitudinal case-control study.
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Asbjornsdottir B, Lauth B, Fasano A, Thorsdottir I, Karlsdottir I, Gudmundsson LS, Gottfredsson M, Smarason O, Sigurdardottir S, Halldorsson TI, Marteinsson VT, Gudmundsdottir V, and Birgisdottir BE
- Subjects
- Adolescent, Case-Control Studies, Child, Humans, Meals, Observational Studies as Topic, RNA, Ribosomal, 16S genetics, Gastrointestinal Microbiome genetics, Mental Health
- Abstract
Recent studies indicate that the interplay between diet, intestinal microbiota composition, and intestinal permeability can impact mental health. More than 10% of children and adolescents in Iceland suffer from mental disorders, and rates of psychotropics use are very high. The aim of this novel observational longitudinal case-control study, "Meals, Microbiota and Mental Health in Children and Adolescents (MMM-Study)" is to contribute to the promotion of treatment options for children and adolescents diagnosed with mental disorders through identification of patterns that may affect the symptoms. All children and adolescents, 5-15 years referred to the outpatient clinic of the Child and Adolescent Psychiatry Department at The National University Hospital in Reykjavik, Iceland, for one year (n≈150) will be invited to participate. There are two control groups, i.e., sex-matched children from the same postal area (n≈150) and same parent siblings (full siblings) in the same household close in age +/- 3 years (n<150). A three-day food diary, rating scales for mental health, and multiple questionnaires will be completed. Biosamples (fecal-, urine-, saliva-, blood samples, and buccal swab) will be collected and used for 16S rRNA gene amplicon sequencing of the oral and gut microbiome, measurements of serum factors, quantification of urine metabolites and host genotype, respectively. For longitudinal follow-up, data collection will be repeated after three years in the same groups. Integrative analysis of diet, gut microbiota, intestinal permeability, serum metabolites, and mental health will be conducted applying bioinformatics and systems biology approaches. Extensive population-based data of this quality has not been collected before, with collection repeated in three years' time, contributing to the high scientific value. The MMM-study follows the "Strengthening the Reporting of Observational Studies in Epidemiology" (STROBE) guidelines. Approval has been obtained from the Icelandic National Bioethics Committee, and the study is registered with Clinicaltrials.gov. The study will contribute to an improved understanding of the links between diet, gut microbiota and mental health in children through good quality study design by collecting information on multiple components, and a longitudinal approach. Furthermore, the study creates knowledge on possibilities for targeted and more personalized dietary and lifestyle interventions in subgroups. Trial registration numbers: VSN-19-225 & NCT04330703., Competing Interests: The authors have declared that no competing intrests exist.
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- 2022
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33. The Proteomic Profile of Interstitial Lung Abnormalities.
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Axelsson GT, Gudmundsson G, Pratte KA, Aspelund T, Putman RK, Sanders JL, Gudmundsson EF, Hatabu H, Gudmundsdottir V, Gudjonsson A, Hino T, Hida T, Hobbs BD, Cho MH, Silverman EK, Bowler RP, Launer LJ, Jennings LL, Hunninghake GM, Emilsson V, and Gudnason V
- Subjects
- Genetic Predisposition to Disease, Humans, Lung, Prospective Studies, Proteomics, Tomography, X-Ray Computed, Lung Diseases, Interstitial epidemiology, Lung Diseases, Interstitial genetics, Respiratory System Abnormalities
- Abstract
Rationale: Knowledge on biomarkers of interstitial lung disease is incomplete. Interstitial lung abnormalities (ILAs) are radiologic changes that may present in its early stages. Objectives: To uncover blood proteins associated with ILAs using large-scale proteomics methods. Methods: Data from two prospective cohort studies, the AGES-Reykjavik (Age, Gene/Environment Susceptibility-Reykjavik) study ( N = 5,259) for biomarker discovery and the COPDGene (Genetic Epidemiology of COPD) study ( N = 4,899) for replication, were used. Blood proteins were measured using DNA aptamers, targeting more than 4,700 protein analytes. The association of proteins with ILAs and ILA progression was assessed with regression modeling, as were associations with genetic risk factors. Adaptive Least Absolute Shrinkage and Selection Operator models were applied to bootstrap data samples to discover sets of proteins predictive of ILAs and their progression. Measurements and Main Results: Of 287 associations, SFTPB (surfactant protein B) (odds ratio [OR], 3.71 [95% confidence interval (CI), 3.20-4.30]; P = 4.28 × 10
-67 ), SCGB3A1 (Secretoglobin family 3A member 1) (OR, 2.43 [95% CI, 2.13-2.77]; P = 8.01 × 10-40 ), and WFDC2 (WAP four-disulfide core domain protein 2) (OR, 2.42 [95% CI, 2.11-2.78]; P = 4.01 × 10-36 ) were most significantly associated with ILA in AGES-Reykjavik and were replicated in COPDGene. In AGES-Reykjavik, concentrations of SFTPB were associated with the rs35705950 MUC5B (mucin 5B) promoter polymorphism, and SFTPB and WFDC2 had the strongest associations with ILA progression. Multivariate models of ILAs in AGES-Reykjavik, ILAs in COPDGene, and ILA progression in AGES-Reykjavik had validated areas under the receiver operating characteristic curve of 0.880, 0.826, and 0.824, respectively. Conclusions: Novel, replicated associations of ILA, its progression, and genetic risk factors with numerous blood proteins are demonstrated as well as machine-learning-based models with favorable predictive potential. Several proteins are revealed as potential markers of early fibrotic lung disease.- Published
- 2022
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34. A proteogenomic signature of age-related macular degeneration in blood.
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Emilsson V, Gudmundsson EF, Jonmundsson T, Jonsson BG, Twarog M, Gudmundsdottir V, Li Z, Finkel N, Poor S, Liu X, Esterberg R, Zhang Y, Jose S, Huang CL, Liao SM, Loureiro J, Zhang Q, Grosskreutz CL, Nguyen AA, Huang Q, Leehy B, Pitts R, Aspelund T, Lamb JR, Jonasson F, Launer LJ, Cotch MF, Jennings LL, Gudnason V, and Walshe TE
- Subjects
- Aged, Genetic Loci, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Risk Factors, Macular Degeneration genetics, Macular Degeneration metabolism, Proteogenomics
- Abstract
Age-related macular degeneration (AMD) is one of the most common causes of visual impairment in the elderly, with a complex and still poorly understood etiology. Whole-genome association studies have discovered 34 genomic regions associated with AMD. However, the genes and cognate proteins that mediate the risk, are largely unknown. In the current study, we integrate levels of 4782 human serum proteins with all genetic risk loci for AMD in a large population-based study of the elderly, revealing many proteins and pathways linked to the disease. Serum proteins are also found to reflect AMD severity independent of genetics and predict progression from early to advanced AMD after five years in this population. A two-sample Mendelian randomization study identifies several proteins that are causally related to the disease and are directionally consistent with the observational estimates. In this work, we present a robust and unique framework for elucidating the pathobiology of AMD., (© 2022. The Author(s).)
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- 2022
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35. Proteomic Analysis Identifies Circulating Proteins Associated With Plasma Amyloid-β and Incident Dementia.
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Tin A, Sullivan KJ, Walker KA, Bressler J, Talluri R, Yu B, Simino J, Gudmundsdottir V, Emilsson V, Jennings LL, Launer L, Mei H, Boerwinkle E, Windham BG, Gottesman R, Gudnason V, Coresh J, Fornage M, and Mosley TH
- Abstract
Background: Plasma amyloid-β (Aβ) (Aβ
42 , Aβ40 , and Aβ42 /Aβ40 ), biomarkers of the Alzheimer's form of dementia, are under consideration for clinical use. The associations of these peptides with circulating proteins may identify novel plasma biomarkers of dementia and inform peripheral factors influencing the levels of these peptides., Methods: We analyzed the association of these 3 plasma Aβ measures with 4638 circulating proteins among a subset of the participants of the Atherosclerosis Risk in Communities (ARIC) study (midlife: n = 1955; late life: n = 2082), related the Aβ-associated proteins with incident dementia in the overall ARIC cohort (midlife: n = 11,069, late life: n = 4110) with external replication in the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study ( n = 4973), estimated the proportion of Aβ variance explained, and conducted enrichment analyses to characterize the proteins associated with the plasma Aβ peptides., Results: At midlife, of the 296 Aβ-associated proteins, 8 were associated with incident dementia from midlife and late life in the ARIC study, and NPPB, IBSP, and THBS2 were replicated in the AGES-Reykjavik Study. At late life, of the 34 Aβ-associated proteins, none were associated with incident dementia at midlife, and kidney function explained 10%, 12%, and 0.2% of the variance of Aβ42 , Aβ40 , and Aβ42 /Aβ40 , respectively. Aβ42-associated proteins at midlife were found to be enriched in the liver, and those at late life were found to be enriched in the spleen., Conclusions: This study identifies circulating proteins associated with plasma Aβ levels and incident dementia and informs peripheral factors associated with plasma Aβ levels., (© 2022 The Authors.)- Published
- 2022
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36. Type 2 Diabetes Partitioned Polygenic Scores Associate With Disease Outcomes in 454,193 Individuals Across 13 Cohorts.
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DiCorpo D, LeClair J, Cole JB, Sarnowski C, Ahmadizar F, Bielak LF, Blokstra A, Bottinger EP, Chaker L, Chen YI, Chen Y, de Vries PS, Faquih T, Ghanbari M, Gudmundsdottir V, Guo X, Hasbani NR, Ibi D, Ikram MA, Kavousi M, Leonard HL, Leong A, Mercader JM, Morrison AC, Nadkarni GN, Nalls MA, Noordam R, Preuss M, Smith JA, Trompet S, Vissink P, Yao J, Zhao W, Boerwinkle E, Goodarzi MO, Gudnason V, Jukema JW, Kardia SLR, Loos RJF, Liu CT, Manning AK, Mook-Kanamori D, Pankow JS, Picavet HSJ, Sattar N, Simonsick EM, Verschuren WMM, Willems van Dijk K, Florez JC, Rotter JI, Meigs JB, Dupuis J, and Udler MS
- Subjects
- Alleles, Cross-Sectional Studies, Genetic Loci, Humans, Obesity genetics, Diabetes Mellitus, Type 2 genetics, Pharmaceutical Preparations metabolism
- Abstract
Objective: Type 2 diabetes (T2D) has heterogeneous patient clinical characteristics and outcomes. In previous work, we investigated the genetic basis of this heterogeneity by clustering 94 T2D genetic loci using their associations with 47 diabetes-related traits and identified five clusters, termed β-cell, proinsulin, obesity, lipodystrophy, and liver/lipid. The relationship between these clusters and individual-level metabolic disease outcomes has not been assessed., Research Design and Methods: Here we constructed individual-level partitioned polygenic scores (pPS) for these five clusters in 12 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (n = 454,193) and tested for cross-sectional association with T2D-related outcomes, including blood pressure, renal function, insulin use, age at T2D diagnosis, and coronary artery disease (CAD)., Results: Despite all clusters containing T2D risk-increasing alleles, they had differential associations with metabolic outcomes. Increased obesity and lipodystrophy cluster pPS, which had opposite directions of association with measures of adiposity, were both significantly associated with increased blood pressure and hypertension. The lipodystrophy and liver/lipid cluster pPS were each associated with CAD, with increasing and decreasing effects, respectively. An increased liver/lipid cluster pPS was also significantly associated with reduced renal function. The liver/lipid cluster includes known loci linked to liver lipid metabolism (e.g., GCKR, PNPLA3, and TM6SF2), and these findings suggest that cardiovascular disease risk and renal function may be impacted by these loci through their shared disease pathway., Conclusions: Our findings support that genetically driven pathways leading to T2D also predispose differentially to clinical outcomes., (© 2022 by the American Diabetes Association.)
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- 2022
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37. A genome-wide association study of serum proteins reveals shared loci with common diseases.
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Gudjonsson A, Gudmundsdottir V, Axelsson GT, Gudmundsson EF, Jonsson BG, Launer LJ, Lamb JR, Jennings LL, Aspelund T, Emilsson V, and Gudnason V
- Subjects
- Aged, Aged, 80 and over, Cohort Studies, Disease classification, Female, Humans, Iceland, Male, Blood Proteins genetics, Disease genetics, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study methods, Polymorphism, Single Nucleotide, Quantitative Trait Loci
- Abstract
With the growing number of genetic association studies, the genotype-phenotype atlas has become increasingly more complex, yet the functional consequences of most disease associated alleles is not understood. The measurement of protein level variation in solid tissues and biofluids integrated with genetic variants offers a path to deeper functional insights. Here we present a large-scale proteogenomic study in 5,368 individuals, revealing 4,035 independent associations between genetic variants and 2,091 serum proteins, of which 36% are previously unreported. The majority of both cis- and trans-acting genetic signals are unique for a single protein, although our results also highlight numerous highly pleiotropic genetic effects on protein levels and demonstrate that a protein's genetic association profile reflects certain characteristics of the protein, including its location in protein networks, tissue specificity and intolerance to loss of function mutations. Integrating protein measurements with deep phenotyping of the cohort, we observe substantial enrichment of phenotype associations for serum proteins regulated by established GWAS loci, and offer new insights into the interplay between genetics, serum protein levels and complex disease., (© 2022. The Author(s).)
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- 2022
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38. Coding and regulatory variants are associated with serum protein levels and disease.
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Emilsson V, Gudmundsdottir V, Gudjonsson A, Jonmundsson T, Jonsson BG, Karim MA, Ilkov M, Staley JR, Gudmundsson EF, Launer LJ, Lindeman JH, Morton NM, Aspelund T, Lamb JR, Jennings LL, and Gudnason V
- Subjects
- Aged, Disease classification, Female, Humans, Iceland, Male, Blood Proteins genetics, Disease genetics, Exome genetics, Genetic Predisposition to Disease, Genotype, Polymorphism, Single Nucleotide, Proteome metabolism
- Abstract
Circulating proteins can be used to diagnose and predict disease-related outcomes. A deep serum proteome survey recently revealed close associations between serum protein networks and common disease. In the current study, 54,469 low-frequency and common exome-array variants were compared to 4782 protein measurements in the serum of 5343 individuals from the AGES Reykjavik cohort. This analysis identifies a large number of serum proteins with genetic signatures overlapping those of many diseases. More specifically, using a study-wide significance threshold, we find that 2021 independent exome array variants are associated with serum levels of 1942 proteins. These variants reside in genetic loci shared by hundreds of complex disease traits, highlighting serum proteins' emerging role as biomarkers and potential causative agents of a wide range of diseases., (© 2022. The Author(s).)
- Published
- 2022
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39. Multiethnic Genome-Wide Association Study of Subclinical Atherosclerosis in Individuals With Type 2 Diabetes.
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Lu Y, Dimitrov L, Chen SH, Bielak LF, Bis JC, Feitosa MF, Lu L, Kavousi M, Raffield LM, Smith AV, Wang L, Weiss S, Yao J, Zhu J, Gudmundsson EF, Gudmundsdottir V, Bos D, Ghanbari M, Ikram MA, Hwang SJ, Taylor KD, Budoff MJ, Gíslason GK, O'Donnell CJ, An P, Franceschini N, Freedman BI, Fu YP, Guo X, Heiss G, Kardia SLR, Wilson JG, Langefeld CD, Schminke U, Uitterlinden AG, Lange LA, Peyser PA, Gudnason VG, Psaty BM, Rotter JI, Bowden DW, and Ng MCY
- Subjects
- Genome-Wide Association Study, Humans, Atherosclerosis genetics, Black People genetics, Diabetes Complications genetics, Diabetes Mellitus, Type 2 genetics, Genetic Loci, Genetic Predisposition to Disease, White People genetics
- Abstract
Background: Coronary artery calcification (CAC) and carotid artery intima-media thickness (cIMT) are measures of subclinical atherosclerosis in asymptomatic individuals and strong risk factors for cardiovascular disease. Type 2 diabetes (T2D) is an independent cardiovascular disease risk factor that accelerates atherosclerosis., Methods: We performed meta-analyses of genome-wide association studies in up to 2500 T2D individuals of European ancestry (EA) and 1590 T2D individuals of African ancestry with or without exclusion of prevalent cardiovascular disease, for CAC measured by cardiac computed tomography, and 3608 individuals of EA and 838 individuals of African ancestry with T2D for cIMT measured by ultrasonography within the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium., Results: We replicated 2 loci (rs9369640 and rs9349379 near PHACTR1 and rs10757278 near CDKN2B ) for CAC and one locus for cIMT (rs7412 and rs445925 near APOE-APOC1 ) that were previously reported in the general EA populations. We identified one novel CAC locus (rs8000449 near CSNK1A1L/LINC00547/POSTN at 13q13.3) at P =2.0×10
-8 in EA. No additional loci were identified with the meta-analyses of EA and African ancestry. The expression quantitative trait loci analysis with nearby expressed genes derived from arterial wall and metabolic tissues from the Genotype-Tissue Expression project pinpoints POSTN , encoding a matricellular protein involved in bone formation and bone matrix organization, as the potential candidate gene at this locus. In addition, we found significant associations ( P <3.1×10-4 ) for 3 previously reported coronary artery disease loci for these subclinical atherosclerotic phenotypes (rs2891168 near CDKN2B-AS1 and rs11170820 near FLJ12825 for CAC, and rs7412 near APOE for cIMT)., Conclusions: Our results provide potential biological mechanisms that could link CAC and cIMT to increased cardiovascular disease risk in individuals with T2D.- Published
- 2021
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40. It's in Our Blood: A Glimpse of Personalized Medicine.
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Lamb JR, Jennings LL, Gudmundsdottir V, Gudnason V, and Emilsson V
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- Disease Susceptibility, Genomics methods, Humans, Organ Specificity, Blood Proteins metabolism, Precision Medicine methods, Proteome, Proteomics methods
- Abstract
Recent advances in protein profiling technology has facilitated simultaneous measurement of thousands of proteins in large population studies, exposing the depth and complexity of the plasma and serum proteomes. This revealed that proteins in circulation were organized into regulatory modules under genetic control and closely associated with current and future common diseases. Unlike networks in solid tissues, serum protein networks comprise members synthesized across different tissues of the body. Genetic analysis reveals that this cross-tissue regulation of the serum proteome participates in systemic homeostasis and mirrors the global disease state of individuals. Here, we discuss how application of this information in routine clinical evaluations may transform the future practice of medicine., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2021
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41. Serum levels of ACE2 are higher in patients with obesity and diabetes.
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Emilsson V, Gudmundsson EF, Aspelund T, Jonsson BG, Gudjonsson A, Launer LJ, Lamb JR, Gudmundsdottir V, Jennings LL, and Gudnason V
- Abstract
Objective: As severity of outcome in COVID-19 is disproportionately higher among individuals with obesity, smokers, patients with hypertension, kidney disease, chronic pulmonary disease, coronary heart disease (CHD), and/or type 2 diabetes (T2D), serum levels of ACE2, the cellular entry point for the coronavirus SARS-CoV-2, were examined in these high-risk groups., Methods: Associations of ACE2 levels to smokers and patients with hypertension, T2D, obesity, CHD, or COPD were investigated in a single center population-based study of 5457 Icelanders from the Age, Gene/Environment Susceptibility Reykjavík Study (AGES-RS) of the elderly (mean age 75 ± 6 years), using multiple linear regression analysis., Results: Serum levels of ACE2 were higher in smokers and individuals with T2D and/or obesity while they were unaffected in the other patient groups., Conclusion: ACE2 levels are higher in some patient groups with comorbidities linked to COVID-19 including obesity and T2D and as such may have an emerging role as a circulating biomarker for severity of outcome in the disease., Competing Interests: John R. Lamb and Lori L. Jennings was and is, respectively, employee and stockholder of Novartis. All other authors declare they have no competing interests., (© 2020 The Authors. Obesity Science & Practice published by World Obesity and The Obesity Society and John Wiley & Sons Ltd.)
- Published
- 2020
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42. Whole blood co-expression modules associate with metabolic traits and type 2 diabetes: an IMI-DIRECT study.
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Gudmundsdottir V, Pedersen HK, Mazzoni G, Allin KH, Artati A, Beulens JW, Banasik K, Brorsson C, Cederberg H, Chabanova E, De Masi F, Elders PJ, Forgie I, Giordano GN, Grallert H, Gupta R, Haid M, Hansen T, Hansen TH, Hattersley AT, Heggie A, Hong MG, Jones AG, Koivula R, Kokkola T, Laakso M, Løngreen P, Mahajan A, Mari A, McDonald TJ, McEvoy D, Musholt PB, Pavo I, Prehn C, Ruetten H, Ridderstråle M, Rutters F, Sharma S, Slieker RC, Syed A, Tajes JF, Thomas CE, Thomsen HS, Vangipurapu J, Vestergaard H, Viñuela A, Wesolowska-Andersen A, Walker M, Adamski J, Schwenk JM, McCarthy MI, Pearson E, Dermitzakis E, Franks PW, Pedersen O, and Brunak S
- Subjects
- Cohort Studies, Gene Expression Regulation, Genome-Wide Association Study, Humans, Insulin, Insulin Resistance, Leukocytes, Diabetes Mellitus, Type 2 genetics, Diabetes Mellitus, Type 2 metabolism, Phenotype, Transcriptome
- Abstract
Background: The rising prevalence of type 2 diabetes (T2D) poses a major global challenge. It remains unresolved to what extent transcriptomic signatures of metabolic dysregulation and T2D can be observed in easily accessible tissues such as blood. Additionally, large-scale human studies are required to further our understanding of the putative inflammatory component of insulin resistance and T2D. Here we used transcriptomics data from individuals with (n = 789) and without (n = 2127) T2D from the IMI-DIRECT cohorts to describe the co-expression structure of whole blood that mainly reflects processes and cell types of the immune system, and how it relates to metabolically relevant clinical traits and T2D., Methods: Clusters of co-expressed genes were identified in the non-diabetic IMI-DIRECT cohort and evaluated with regard to stability, as well as preservation and rewiring in the cohort of individuals with T2D. We performed functional and immune cell signature enrichment analyses, and a genome-wide association study to describe the genetic regulation of the modules. Phenotypic and trans-omics associations of the transcriptomic modules were investigated across both IMI-DIRECT cohorts., Results: We identified 55 whole blood co-expression modules, some of which clustered in larger super-modules. We identified a large number of associations between these transcriptomic modules and measures of insulin action and glucose tolerance. Some of the metabolically linked modules reflect neutrophil-lymphocyte ratio in blood while others are independent of white blood cell estimates, including a module of genes encoding neutrophil granule proteins with antibacterial properties for which the strongest associations with clinical traits and T2D status were observed. Through the integration of genetic and multi-omics data, we provide a holistic view of the regulation and molecular context of whole blood transcriptomic modules. We furthermore identified an overlap between genetic signals for T2D and co-expression modules involved in type II interferon signaling., Conclusions: Our results offer a large-scale map of whole blood transcriptomic modules in the context of metabolic disease and point to novel biological candidates for future studies related to T2D.
- Published
- 2020
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43. Circulating Protein Signatures and Causal Candidates for Type 2 Diabetes.
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Gudmundsdottir V, Zaghlool SB, Emilsson V, Aspelund T, Ilkov M, Gudmundsson EF, Jonsson SM, Zilhão NR, Lamb JR, Suhre K, Jennings LL, and Gudnason V
- Subjects
- Aged, Aged, 80 and over, Case-Control Studies, Diabetes Mellitus, Type 2 blood, Female, Genetic Predisposition to Disease genetics, Genotype, Humans, Male, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide genetics, Diabetes Mellitus, Type 2 genetics
- Abstract
The increasing prevalence of type 2 diabetes poses a major challenge to societies worldwide. Blood-based factors like serum proteins are in contact with every organ in the body to mediate global homeostasis and may thus directly regulate complex processes such as aging and the development of common chronic diseases. We applied a data-driven proteomics approach, measuring serum levels of 4,137 proteins in 5,438 elderly Icelanders, and identified 536 proteins associated with prevalent and/or incident type 2 diabetes. We validated a subset of the observed associations in an independent case-control study of type 2 diabetes. These protein associations provide novel biological insights into the molecular mechanisms that are dysregulated prior to and following the onset of type 2 diabetes and can be detected in serum. A bidirectional two-sample Mendelian randomization analysis indicated that serum changes of at least 23 proteins are downstream of the disease or its genetic liability, while 15 proteins were supported as having a causal role in type 2 diabetes., (© 2020 by the American Diabetes Association.)
- Published
- 2020
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44. ACE2 levels are altered in comorbidities linked to severe outcome in COVID-19.
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Emilsson V, Gudmundsson EF, Aspelund T, Jonsson BG, Gudjonsson A, Launer LJ, Lamb JR, Gudmundsdottir V, Jennings LL, and Gudnason V
- Abstract
Aims: Severity of outcome in COVID-19 is disproportionately higher among the obese, males, smokers, those suffering from hypertension, kidney disease, coronary heart disease (CHD) and/or type 2 diabetes (T2D). We examined if serum levels of ACE2, the cellular entry point for the coronavirus SARS-CoV-2, were altered in these high-risk groups., Methods: Associations of serum ACE2 levels to hypertension, T2D, obesity, CHD, smokers and males in a single center population-based study of 5457 Icelanders from the Age, Gene/Environment Susceptibility Reykjavik Study (AGES-RS) of the elderly (mean age 75+/-6 years)., Results: Smokers, males, and individuals with T2D or obesity have altered serum levels of ACE2 that may influence productive infection of SARS-CoV-2 in these high-risk groups., Conclusion: ACE2 levels are upregulated in some patient groups with comorbidities linked to COVID-19 and as such may have an emerging role as a circulating biomarker for severity of outcome in COVID-19.
- Published
- 2020
- Full Text
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45. Antihypertensive medication uses and serum ACE2 levels: ACEIs/ARBs treatment does not raise serum levels of ACE2.
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Emilsson V, Gudmundsson EF, Aspelund T, Jonsson BG, Gudjonsson A, Launer LJ, Jennings LL, Gudmundsdottir V, and Gudnason V
- Abstract
Importance: Recent reports have shown that hypertension is the most common comorbidity associated with mortality in the current coronavirus disease 2019 (COVID-19). This has been related to the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) as animal studies indicate that these medications increase levels of ACE2, the cellular entry point for the coronavirus SARS-CoV-2. This has prompted clinicians to recommend discontinuing ACEIs and ARBs., Objective: To examine the effect of ACEIs or ARBs treatment on serum levels of ACE2 and other key enzymes in the renin-angiotensin system (RAS)., Design Setting and Participants: A single center population-based study of 5457 Icelanders from the Age, Gene/Environment Susceptibility Reykjavik Study (AGES-RS) of the elderly (mean age 75±6 years) stratified by ACEIs (N = 699) or ARBs (N = 753) treatment., Main Outcomes and Measures: The AGES-RS study population was stratified by ACEIs and ARBs medication use and compared for age, body mass index (BMI) (kg/m
2 ), hypertension and type 2 diabetes (T2D) as well as serum levels of renin, ACE and ACE2., Results: While renin and ACE levels were significantly raised in serum of individuals on ACEIs or ARBs treatments, the ACE2 levels remained unaffected., Conclusions and Relevance: Treatment with ACEIs or ARBs does not raise ACE2 levels in serum. Therefore, the present study does not support the proposed discontinuation of these medications among patients affected with COVID-19.- Published
- 2020
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46. Comparison of Spasticity in Spinal Cord Injury and Stroke Patients Using Reflex Period in Pendulum Test.
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Kristinsdottir K, Magnusdottir G, Chenery B, Gudmundsdottir V, Gudfinnsdottir HK, Karason H, Ludvigsdottir GK, and Helgason T
- Abstract
Spasticity is a motor impairment present in patients with both stroke and spinal cord injury. In this research, the results from the Wartenberg pendulum test, performed on stroke and spinal cord injury patients using goniometers and electromyogram recordings of the quadriceps, were reviewed and a new parameter to quantify spasticity was extracted. The Reflex Period (RP) of the pendulum test was defined as the time span from 50% of the maximum velocity of the leg swing to the activation of muscle contraction in the quadriceps, determined from the EMG. The results suggest that the reflex period in stroke patients is generally shorter than in those suffering from spinal cord injury., Competing Interests: Conflict of interest The authors declare they have no conflicts of interest.We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
- Published
- 2020
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47. A computational framework to integrate high-throughput '-omics' datasets for the identification of potential mechanistic links.
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Pedersen HK, Forslund SK, Gudmundsdottir V, Petersen AØ, Hildebrand F, Hyötyläinen T, Nielsen T, Hansen T, Bork P, Ehrlich SD, Brunak S, Oresic M, Pedersen O, and Nielsen HB
- Subjects
- Humans, Metabolomics methods, Phenotype, Software, Workflow, Computational Biology methods, Gastrointestinal Microbiome, Metabolome, Serum metabolism
- Abstract
We recently presented a three-pronged association study that integrated human intestinal microbiome data derived from shotgun-based sequencing with untargeted serum metabolome data and measures of host physiology. Metabolome and microbiome data are high dimensional, posing a major challenge for data integration. Here, we present a step-by-step computational protocol that details and discusses the dimensionality-reduction techniques used and methods for subsequent integration and interpretation of such heterogeneous types of data. Dimensionality reduction was achieved through a combination of data normalization approaches, binning of co-abundant genes and metabolites, and integration of prior biological knowledge. The use of prior knowledge to overcome functional redundancy across microbiome species is one central advance of our method over available alternative approaches. Applying this framework, other investigators can integrate various '-omics' readouts with variables of host physiology or any other phenotype of interest (e.g., connecting host and microbiome readouts to disease severity or treatment outcome in a clinical cohort) in a three-pronged association analysis to identify potential mechanistic links to be tested in experimental settings. Although we originally developed the framework for a human metabolome-microbiome study, it is generalizable to other organisms and environmental metagenomes, as well as to studies including other -omics domains such as transcriptomics and proteomics. The provided R code runs in ~1 h on a standard PC.
- Published
- 2018
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48. Co-regulatory networks of human serum proteins link genetics to disease.
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Emilsson V, Ilkov M, Lamb JR, Finkel N, Gudmundsson EF, Pitts R, Hoover H, Gudmundsdottir V, Horman SR, Aspelund T, Shu L, Trifonov V, Sigurdsson S, Manolescu A, Zhu J, Olafsson Ö, Jakobsdottir J, Lesley SA, To J, Zhang J, Harris TB, Launer LJ, Zhang B, Eiriksdottir G, Yang X, Orth AP, Jennings LL, and Gudnason V
- Subjects
- Aptamers, Nucleotide, Genetic Predisposition to Disease, Genetic Variation, Humans, Iceland, Metabolic Networks and Pathways, Blood Proteins analysis, Blood Proteins genetics, Cardiovascular Diseases genetics, Metabolic Diseases genetics, Proteome analysis, Proteome genetics, Proteomics methods
- Abstract
Proteins circulating in the blood are critical for age-related disease processes; however, the serum proteome has remained largely unexplored. To this end, 4137 proteins covering most predicted extracellular proteins were measured in the serum of 5457 Icelanders over 65 years of age. Pairwise correlation between proteins as they varied across individuals revealed 27 different network modules of serum proteins, many of which were associated with cardiovascular and metabolic disease states, as well as overall survival. The protein modules were controlled by cis- and trans-acting genetic variants, which in many cases were also associated with complex disease. This revealed co-regulated groups of circulating proteins that incorporated regulatory control between tissues and demonstrated close relationships to past, current, and future disease states., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2018
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49. Integrative network analysis highlights biological processes underlying GLP-1 stimulated insulin secretion: A DIRECT study.
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Gudmundsdottir V, Pedersen HK, Allebrandt KV, Brorsson C, van Leeuwen N, Banasik K, Mahajan A, Groves CJ, van de Bunt M, Dawed AY, Fritsche A, Staiger H, Simonis-Bik AMC, Deelen J, Kramer MHH, Dietrich A, Hübschle T, Willemsen G, Häring HU, de Geus EJC, Boomsma DI, Eekhoff EMW, Ferrer J, McCarthy MI, Pearson ER, Gupta R, Brunak S, and 't Hart LM
- Subjects
- Animals, Humans, Insulin Secretion, Mice, Glucagon-Like Peptide 1 metabolism, Insulin metabolism
- Abstract
Glucagon-like peptide 1 (GLP-1) stimulated insulin secretion has a considerable heritable component as estimated from twin studies, yet few genetic variants influencing this phenotype have been identified. We performed the first genome-wide association study (GWAS) of GLP-1 stimulated insulin secretion in non-diabetic individuals from the Netherlands Twin register (n = 126). This GWAS was enhanced using a tissue-specific protein-protein interaction network approach. We identified a beta-cell protein-protein interaction module that was significantly enriched for low gene scores based on the GWAS P-values and found support at the network level in an independent cohort from Tübingen, Germany (n = 100). Additionally, a polygenic risk score based on SNPs prioritized from the network was associated (P < 0.05) with glucose-stimulated insulin secretion phenotypes in up to 5,318 individuals in MAGIC cohorts. The network contains both known and novel genes in the context of insulin secretion and is enriched for members of the focal adhesion, extracellular-matrix receptor interaction, actin cytoskeleton regulation, Rap1 and PI3K-Akt signaling pathways. Adipose tissue is, like the beta-cell, one of the target tissues of GLP-1 and we thus hypothesized that similar networks might be functional in both tissues. In order to verify peripheral effects of GLP-1 stimulation, we compared the transcriptome profiling of ob/ob mice treated with liraglutide, a clinically used GLP-1 receptor agonist, versus baseline controls. Some of the upstream regulators of differentially expressed genes in the white adipose tissue of ob/ob mice were also detected in the human beta-cell network of genes associated with GLP-1 stimulated insulin secretion. The findings provide biological insight into the mechanisms through which the effects of GLP-1 may be modulated and highlight a potential role of the beta-cell expressed genes RYR2, GDI2, KIAA0232, COL4A1 and COL4A2 in GLP-1 stimulated insulin secretion.
- Published
- 2018
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50. Metabolite ratios as potential biomarkers for type 2 diabetes: a DIRECT study.
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Molnos S, Wahl S, Haid M, Eekhoff EMW, Pool R, Floegel A, Deelen J, Much D, Prehn C, Breier M, Draisma HH, van Leeuwen N, Simonis-Bik AMC, Jonsson A, Willemsen G, Bernigau W, Wang-Sattler R, Suhre K, Peters A, Thorand B, Herder C, Rathmann W, Roden M, Gieger C, Kramer MHH, van Heemst D, Pedersen HK, Gudmundsdottir V, Schulze MB, Pischon T, de Geus EJC, Boeing H, Boomsma DI, Ziegler AG, Slagboom PE, Hummel S, Beekman M, Grallert H, Brunak S, McCarthy MI, Gupta R, Pearson ER, Adamski J, and 't Hart LM
- Subjects
- Arginine metabolism, Blood Glucose metabolism, Female, Glucagon-Like Peptide 1 metabolism, Glucose metabolism, Glucose Tolerance Test, Humans, Insulin metabolism, Male, Risk Factors, Biomarkers blood, Biomarkers metabolism, Diabetes Mellitus, Type 2 blood, Diabetes Mellitus, Type 2 metabolism
- Abstract
Aims/hypothesis: Circulating metabolites have been shown to reflect metabolic changes during the development of type 2 diabetes. In this study we examined the association of metabolite levels and pairwise metabolite ratios with insulin responses after glucose, glucagon-like peptide-1 (GLP-1) and arginine stimulation. We then investigated if the identified metabolite ratios were associated with measures of OGTT-derived beta cell function and with prevalent and incident type 2 diabetes., Methods: We measured the levels of 188 metabolites in plasma samples from 130 healthy members of twin families (from the Netherlands Twin Register) at five time points during a modified 3 h hyperglycaemic clamp with glucose, GLP-1 and arginine stimulation. We validated our results in cohorts with OGTT data (n = 340) and epidemiological case-control studies of prevalent (n = 4925) and incident (n = 4277) diabetes. The data were analysed using regression models with adjustment for potential confounders., Results: There were dynamic changes in metabolite levels in response to the different secretagogues. Furthermore, several fasting pairwise metabolite ratios were associated with one or multiple clamp-derived measures of insulin secretion (all p < 9.2 × 10
-7 ). These associations were significantly stronger compared with the individual metabolite components. One of the ratios, valine to phosphatidylcholine acyl-alkyl C32:2 (PC ae C32:2), in addition showed a directionally consistent positive association with OGTT-derived measures of insulin secretion and resistance (p ≤ 5.4 × 10-3 ) and prevalent type 2 diabetes (ORVal_PC ae C32:2 2.64 [β 0.97 ± 0.09], p = 1.0 × 10-27 ). Furthermore, Val_PC ae C32:2 predicted incident diabetes independent of established risk factors in two epidemiological cohort studies (HRVal_PC ae C32:2 1.57 [β 0.45 ± 0.06]; p = 1.3 × 10-15 ), leading to modest improvements in the receiver operating characteristics when added to a model containing a set of established risk factors in both cohorts (increases from 0.780 to 0.801 and from 0.862 to 0.865 respectively, when added to the model containing traditional risk factors + glucose)., Conclusions/interpretation: In this study we have shown that the Val_PC ae C32:2 metabolite ratio is associated with an increased risk of type 2 diabetes and measures of insulin secretion and resistance. The observed effects were stronger than that of the individual metabolites and independent of known risk factors.- Published
- 2018
- Full Text
- View/download PDF
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