Search

Your search keyword '"'t Hart, P"' showing total 1,131 results
Start Over Author "'t Hart, P"
1,131 results on '"'t Hart, P"'

5. Circulating metabolomic markers linking diabetic kidney disease and incident cardiovascular disease in type 2 diabetes: analyses from the Hong Kong Diabetes Biobank

Author

Jin, Qiao, Lau, Eric S. H., Luk, Andrea O., Tam, Claudia H. T., Ozaki, Risa, Lim, Cadmon K. P., Wu, Hongjiang, Chow, Elaine Y. K., Kong, Alice P. S., Lee, Heung Man, Fan, Baoqi, Ng, Alex C. W., Jiang, Guozhi, Lee, Ka Fai, Siu, Shing Chung, Hui, Grace, Tsang, Chiu Chi, Lau, Kam Piu, Leung, Jenny Y., Tsang, Man-wo, Cheung, Elaine Y. N., Kam, Grace, Lau, Ip Tim, Li, June K., Yeung, Vincent T. F., Lau, Emmy, Lo, Stanley, Fung, Samuel, Cheng, Yuk Lun, Chow, Chun Chung, Yu, Weichuan, Tsui, Stephen K. W., Tomlinson, Brian, Huang, Yu, Lan, Hui-yao, Szeto, Cheuk Chun, So, Wing Yee, Jenkins, Alicia J., Fung, Erik, Muilwijk, Mirthe, Blom, Marieke T., ‘t Hart, Leen M., Chan, Juliana C. N., and Ma, Ronald C. W.

Published
2024
Full Text
View/download PDF

7. NMR metabolomics-guided DNA methylation mortality predictorsResearch in context

Author

Daniele Bizzarri, Marcel J.T. Reinders, Lieke Kuiper, Marian Beekman, Joris Deelen, Joyce B.J. van Meurs, Jenny van Dongen, René Pool, Dorret I. Boomsma, Mohsen Ghanbari, Lude Franke, Pieternella E. Slagboom, Erik B. van den Akker, J.M. Geleijnse, E. Boersma, W.E. van Spil, M.M.J. van Greevenbroek, C.D.A. Stehouwer, C.J.H. van der Kallen, I.C.W. Arts, F. Rutters, J.W.J. Beulens, M. Muilwijk, P.J.M. Elders, L.M. 't Hart, M. Ghanbari, M.A. Ikram, M.G. Netea, M. Kloppenburg, Y.F.M. Ramos, N. Bomer, I. Meulenbelt, K. Stronks, M.B. Snijder, A.H. Zwinderman, B.T. Heijmans, L.H. Lumey, C. Wijmenga, J. Fu, A. Zhernakova, J. Deelen, S.P. Mooijaart, M. Beekman, P.E. Slagboom, G.L.J. Onderwater, A.M.J.M. van den Maagdenberg, G.M. Terwindt, C. Thesing, M. Bot, B.W.J.H. Penninx, S. Trompet, J.W. Jukema, N. Sattar, I.C.C. van der Horst, P. van der Harst, C. So-Osman, J.A. van Hilten, R.G.H.H. Nelissen, I.E. Höfer, F.W. Asselbergs, P. Scheltens, C.E. Teunissen, W.M. van der Flier, J. van Dongen, R. Pool, A.H.M. Willemsen, D.I. Boomsma, H.E.D. Suchiman, J.J.H. Barkey Wolf, D. Cats, H. Mei, M. Slofstra, M. Swertz, M.J.T. Reinders, and E.B. van den Akker

Subjects
DNA methylation predictors, NMR metabolomics, Ageing biomarkers, Epigenetic clock, Metabolic risk score, Epidemiology, Medicine, Medicine (General), R5-920
Abstract

Summary: Background: 1H-NMR metabolomics and DNA methylation in blood are widely known biomarkers predicting age-related physiological decline and mortality yet exert mutually independent mortality and frailty signals. Methods: Leveraging multi-omics data in four Dutch population studies (N = 5238, ∼40% of which male) we investigated whether the mortality signal captured by 1H-NMR metabolomics could guide the construction of DNA methylation-based mortality predictors. Findings: We trained DNA methylation-based surrogates for 64 metabolomic analytes and found that analytes marking inflammation, fluid balance, or HDL/VLDL metabolism could be accurately reconstructed using DNA-methylation assays. Interestingly, a previously reported multi-analyte score indicating mortality risk (MetaboHealth) could also be accurately reconstructed. Sixteen of our derived surrogates, including the MetaboHealth surrogate, showed significant associations with mortality, independent of relevant covariates. Interpretation: The addition of our metabolic analyte-derived surrogates to the well-established epigenetic clock GrimAge demonstrates that our surrogates potentially represent valuable mortality signal. Funding: BBMRI-NL, X-omics, VOILA, Medical Delta, NWO, ERC.

Published
2024
Full Text
View/download PDF

9. Distinct learning, retention, and generalization patterns in de novo learning versus motor adaptation

Author

Raphael Q. Gastrock, Bernard Marius ’t Hart, and Denise Y. P. Henriques

Subjects
Medicine, Science
Abstract

Abstract People correct for movement errors when acquiring new motor skills (de novo learning) or adapting well-known movements (motor adaptation). While de novo learning establishes new control policies, adaptation modifies existing ones, and previous work have distinguished behavioral and underlying brain mechanisms for each motor learning type. However, it is still unclear whether learning in each type interferes with the other. In study 1, we use a within-subjects design where participants train with both 30° visuomotor rotation and mirror reversal perturbations, to compare adaptation and de novo learning respectively. We find no perturbation order effects, and find no evidence for differences in learning rates and asymptotes for both perturbations. Explicit instructions also provide an advantage during early learning in both perturbations. However, mirror reversal learning shows larger inter-participant variability and slower movement initiation. Furthermore, we only observe reach aftereffects following rotation training. In study 2, we incorporate the mirror reversal in a browser-based task, to investigate under-studied de novo learning mechanisms like retention and generalization. Learning persists across three or more days, substantially transfers to the untrained hand, and to targets on both sides of the mirror axis. Our results extend insights for distinguishing motor skill acquisition from adapting well-known movements.

Published
2024
Full Text
View/download PDF

10. Micro‐diffusely abnormal white matter: An early multiple sclerosis lesion phase with intensified myelin blistering

Author

Antonio Luchicchi, Gema Muñoz‐Gonzalez, Saar T. Halperin, Eva Strijbis, Laura H. M. vanDijk, Chrisa Foutiadou, Florence Uriac, Piet M. Bouman, Maxime A. N. Schouten, Jason Plemel, Bert A. 't Hart, Jeroen J. G. Geurts, and Geert J. Schenk

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Objective Multiple sclerosis (MS) is a chronic central nervous system disease whose white matter lesion origin remains debated. Recently, we reported subtle changes in the MS normal appearing white matter (NAWM), presenting with an increase in myelin blisters and myelin protein citrullination, which may recapitulate some of the prodromal degenerative processes involved in MS pathogenesis. Here, to clarify the relevance of these changes for subsequent MS myelin degeneration we explored their prevalence in WM regions characterized by subtly reduced myelination (dubbed as micro‐diffusely abnormal white matter, mDAWM). Methods We used an in‐depth (immuno)histochemistry approach in 27 MS donors with histological presence of mDAWM and 5 controls. An antibody panel against degenerative markers was combined and the presence of myelin/axonal aberrations was analyzed and compared with the NAWM from the same cases/slices/regions. Results mDAWM‐defined areas exhibit ill‐defined borders, no signs of Wallerian degeneration, and they associate with visible veins. Remarkably, such areas present with augmented myelin blister frequency, enhanced prevalence of polar myelin phospholipids, citrullination, and degradation of myelin basic protein (MBP) when compared with the NAWM. Furthermore, enhanced reactivity of microglia/macrophages against citrullinated MBP was also observed in this tissue. Interpretation We report a new histologically defined early phase in MS lesion formation, namely mDAWM, which lacks signs of Wallerian pathology. These results support the prelesional nature of the mDAWM. We conceptualize that evolution to pathologically evident lesions comprises the previously documented imbalance of axo‐myelinic units (myelin blistering) leading to their degeneration and immune system activation by released myelin components.

Published
2024
Full Text
View/download PDF

11. IT-assisted comprehensive geriatric assessment for residents in care homes: quasi-experimental longitudinal study

Author

David Attwood, Jim Vafidis, James Boorer, Scarlett Long, Wendy Ellis, Michelle Earley, Jillian Denovan, Gerard ’t Hart, Maria Williams, Nicholas Burdett, Melissa Lemon, and Suzy Hope

Subjects
Advanced care planning, Frailty, Care homes, Primary care, Geriatric assessment, Geriatrics, RC952-954.6
Abstract

Abstract Background Frailty interventions such as Comprehensive Geriatric Assessment (CGA) can provide significant benefits for older adults living with frailty. However, incorporating such proactive interventions into primary care remains a challenge. We developed an IT-assisted CGA (i-CGA) process, which includes advance care planning (ACP). We assessed if, in older care home residents, particularly those with severe frailty, i-CGA could improve access to advance care planning discussions and reduce unplanned hospitalisations. Method As a quality improvement project we progressively incorporated our i-CGA process into routine primary care for older care home residents, and used a quasi-experimental approach to assess its interim impact. Residents were assessed for frailty by General Practitioners. Proactive i-CGAs were completed, including consideration of traditional CGA domains, deprescribing and ACP discussions. Interim analysis was conducted at 1 year: documented completion, preferences and adherence to ACPs, unplanned hospital admissions, and mortality rates were compared for i-CGA and control (usual care) groups, 1-year post-i-CGA or post-frailty diagnosis respectively. Documented ACP preferences and place of death were compared using the Chi-Square Test. Unplanned hospital admissions and bed days were analysed using the Mann-Whitney U test. Survival was estimated using Kaplan-Meier survival curves. Results At one year, the i-CGA group comprised 196 residents (severe frailty 111, 57%); the control group 100 (severe frailty 56, 56%). ACP was documented in 100% of the i-CGA group, vs. 72% of control group, p

Published
2024
Full Text
View/download PDF

12. Teaching Crisis Management before and after the Pandemic: Personal Reflections

Author

't Hart, Paul

Abstract

This reflective contribution tells the story of a veteran public sector crisis management (CM) researcher's 35-year journey with educating students and CM practitioners. It offers preliminary insights about how the pandemic experience might -- and should -- induce a significant rethink of how educators conceptualize the nature of crises and the challenges governments and public agencies face in coping with them.

Published
2023
Full Text
View/download PDF

13. New views on the complex interplay between degeneration and autoimmunity in multiple sclerosis

Author

Peter K. Stys, Shigeki Tsutsui, Arie R. Gafson, Bert A. ‘t Hart, Shibeshih Belachew, and Jeroen J. G. Geurts

Subjects
myelin, B cell, protein misfolding, prion, Epstein–Barr virus, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Multiple sclerosis (MS) is a frequently disabling neurological disorder characterized by symptoms, clinical signs and imaging abnormalities that typically fluctuate over time, affecting any level of the CNS. Prominent lymphocytic inflammation, many genetic susceptibility variants involving immune pathways, as well as potent responses of the neuroinflammatory component to immunomodulating drugs, have led to the natural conclusion that this disease is driven by a primary autoimmune process. In this Hypothesis and Theory article, we discuss emerging data that cast doubt on this assumption. After three decades of therapeutic experience, what has become clear is that potent immune modulators are highly effective at suppressing inflammatory relapses, yet exhibit very limited effects on the later progressive phase of MS. Moreover, neuropathological examination of MS tissue indicates that degeneration, CNS atrophy, and myelin loss are most prominent in the progressive stage, when lymphocytic inflammation paradoxically wanes. Finally, emerging clinical observations such as “progression independent of relapse activity” and “silent progression,” now thought to take hold very early in the course, together argue that an underlying “cytodegenerative” process, likely targeting the myelinating unit, may in fact represent the most proximal step in a complex pathophysiological cascade exacerbated by an autoimmune inflammatory overlay. Parallels are drawn with more traditional neurodegenerative disorders, where a progressive proteopathy with prion-like propagation of toxic misfolded species is now known to play a key role. A potentially pivotal contribution of the Epstein–Barr virus and B cells in this process is also discussed.

Published
2024
Full Text
View/download PDF

15. A translational repression reporter assay for the analysis of RNA-binding protein consensus sites

Author

Jessica Nowacki, Mateo Malenica, Stefan Schmeing, Damian Schiller, Benjamin Buchmuller, Gulshan Amrahova, and Peter ‘t Hart

Subjects
translation, rna-binding proteins, protein-rna interactions, binding studies, translational repression assay, Genetics, QH426-470
Abstract

RNA-binding proteins are essential regulators of RNA processing and function. Translational repression assays can be used to study how they interact with specific RNA sequences by insertion of such a consensus sequence into the 5’ untranslated region of a reporter mRNA and measuring reporter protein translation. The straightforward set-up of these translational repression assays avoids the need for the isolation of the protein or the RNA providing speed, robustness and a low-cost method. Here, we report the optimization of the assay to function with linear RNA sequences instead of the previously reported hairpin type sequences to allow the study of a wider variety of RNA-binding proteins. Multiplication of a consensus sequence strongly improves the signal allowing analysis by both fluorescence intensity measurements and flow cytometry.

Published
2023
Full Text
View/download PDF

16. Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits

Author

Brown, Andrew A., Fernandez-Tajes, Juan J., Hong, Mun-gwan, Brorsson, Caroline A., Koivula, Robert W., Davtian, David, Dupuis, Théo, Sartori, Ambra, Michalettou, Theodora-Dafni, Forgie, Ian M., Adam, Jonathan, Allin, Kristine H., Caiazzo, Robert, Cederberg, Henna, De Masi, Federico, Elders, Petra J. M., Giordano, Giuseppe N., Haid, Mark, Hansen, Torben, Hansen, Tue H., Hattersley, Andrew T., Heggie, Alison J., Howald, Cédric, Jones, Angus G., Kokkola, Tarja, Laakso, Markku, Mahajan, Anubha, Mari, Andrea, McDonald, Timothy J., McEvoy, Donna, Mourby, Miranda, Musholt, Petra B., Nilsson, Birgitte, Pattou, Francois, Penet, Deborah, Raverdy, Violeta, Ridderstråle, Martin, Romano, Luciana, Rutters, Femke, Sharma, Sapna, Teare, Harriet, ‘t Hart, Leen, Tsirigos, Konstantinos D., Vangipurapu, Jagadish, Vestergaard, Henrik, Brunak, Søren, Franks, Paul W., Frost, Gary, Grallert, Harald, Jablonka, Bernd, McCarthy, Mark I., Pavo, Imre, Pedersen, Oluf, Ruetten, Hartmut, Walker, Mark, Adamski, Jerzy, Schwenk, Jochen M., Pearson, Ewan R., Dermitzakis, Emmanouil T., and Viñuela, Ana

Published
2023
Full Text
View/download PDF

18. Identification of biomarkers for glycaemic deterioration in type 2 diabetes

Author

Slieker, Roderick C., Donnelly, Louise A., Akalestou, Elina, Lopez-Noriega, Livia, Melhem, Rana, Güneş, Ayşim, Abou Azar, Frederic, Efanov, Alexander, Georgiadou, Eleni, Muniangi-Muhitu, Hermine, Sheikh, Mahsa, Giordano, Giuseppe N., Åkerlund, Mikael, Ahlqvist, Emma, Ali, Ashfaq, Banasik, Karina, Brunak, Søren, Barovic, Marko, Bouland, Gerard A., Burdet, Frédéric, Canouil, Mickaël, Dragan, Iulian, Elders, Petra J. M., Fernandez, Celine, Festa, Andreas, Fitipaldi, Hugo, Froguel, Phillippe, Gudmundsdottir, Valborg, Gudnason, Vilmundur, Gerl, Mathias J., van der Heijden, Amber A., Jennings, Lori L., Hansen, Michael K., Kim, Min, Leclerc, Isabelle, Klose, Christian, Kuznetsov, Dmitry, Mansour Aly, Dina, Mehl, Florence, Marek, Diana, Melander, Olle, Niknejad, Anne, Ottosson, Filip, Pavo, Imre, Duffin, Kevin, Syed, Samreen K., Shaw, Janice L., Cabrera, Over, Pullen, Timothy J., Simons, Kai, Solimena, Michele, Suvitaival, Tommi, Wretlind, Asger, Rossing, Peter, Lyssenko, Valeriya, Legido Quigley, Cristina, Groop, Leif, Thorens, Bernard, Franks, Paul W., Lim, Gareth E., Estall, Jennifer, Ibberson, Mark, Beulens, Joline W. J., ’t Hart, Leen M, Pearson, Ewan R., and Rutter, Guy A.

Published
2023
Full Text
View/download PDF

20. Peroperative administration of tranexamic acid in Roux-en-Y and one-anastomosis gastric bypass to reduce haemorrhage in patients with morbid obesity: protocol for randomised controlled trial (PATRY trial)

Author

Erwin Birnie, Eric J Hazebroek, Cornelis Verhoef, Jan A Apers, Martin Dunkelgrun, Marc J van Det, Judith W H 't Hart, Bo J Noordman, Evert-Jan G Boerma, Jeannine Palsgraaf-Huisbrink, Hans F Zengerink, Steve M M de Castro, and Barbara S Langenhoff

Subjects
Medicine
Abstract

Introduction By implementation of Enhanced Recovery After Bariatric Surgery protocols and day-care surgery, early discharge poses a challenge if excessive bleeding occurs after bariatric surgery. Tranexamic acid (TXA) has demonstrated efficacy in other surgical fields and in bariatric pilot studies. This trial aims to assess the efficacy of peroperative administration of TXA in reducing haemorrhage in patients undergoing gastric bypass surgery.Method and analysis This is a multicentre, phase III, double-blind randomised controlled trial in six high-volume bariatric centres in the Netherlands. A total of 1524 eligible patients, aged 18 years or older, undergoing primary gastric bypass surgery (either Roux-en-Y gastric bypass or one-anastomosis gastric bypass) will be randomised between TXA and placebo (1:1, variable block, stratified for centre, day-care/overnight stay and type of surgery) after obtaining informed consent (2.5% less haemorrhage, power 80%, 2-sided-α 0.05 and 10% dropout). Exclusion criteria are pregnancy, amedical history of acute bleeding (without cause), venous thrombotic events (VTEs), epilepsy, anticoagulant use and iatrogenic bleeding during surgery (aside from staple line). The primary outcome is postoperative haemorrhage requiring intervention within 30 days postoperatively. Secondary outcome measures are staple line reinforcement, blood loss, duration of surgery, postoperative haemoglobin, vital parameters, minor and major complications, side effects of TXA (nausea, hypotension and VTE), length of hospital stay and directly made costs.Ethics and dissemination Written informed consent will be obtained from all participants. The protocol has been approved by the Medical Research Ethics Committees United, Nieuwegein, on 7 February 2023 (registration number: R22.102). Results will be disseminated through peer-reviewed publications and conferences.Trial registration number NCT05464394

Published
2024
Full Text
View/download PDF

21. Multi-omics subgroups associated with glycaemic deterioration in type 2 diabetes: an IMI-RHAPSODY Study

Author

Shiying Li, Iulian Dragan, Van Du T. Tran, Chun Ho Fung, Dmitry Kuznetsov, Michael K. Hansen, Joline W. J. Beulens, Leen M. ‘t Hart, Roderick C. Slieker, Louise A. Donnelly, Mathias J. Gerl, Christian Klose, Florence Mehl, Kai Simons, Petra J. M. Elders, Ewan R. Pearson, Guy A. Rutter, and Mark Ibberson

Subjects
multi-omics, type 2 diabetes, glycaemic deterioration, metabolic syndrome, lipidomics, proteomics, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

IntroductionType 2 diabetes (T2D) onset, progression and outcomes differ substantially between individuals. Multi-omics analyses may allow a deeper understanding of these differences and ultimately facilitate personalised treatments. Here, in an unsupervised “bottom-up” approach, we attempt to group T2D patients based solely on -omics data generated from plasma.MethodsCirculating plasma lipidomic and proteomic data from two independent clinical cohorts, Hoorn Diabetes Care System (DCS) and Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS), were analysed using Similarity Network Fusion. The resulting patient network was analysed with Logistic and Cox regression modelling to explore relationships between plasma -omic profiles and clinical characteristics.ResultsFrom a total of 1,134 subjects in the two cohorts, levels of 180 circulating plasma lipids and 1195 proteins were used to separate patients into two subgroups. These differed in terms of glycaemic deterioration (Hazard Ratio=0.56;0.73), insulin sensitivity and secretion (C-peptide, p=3.7e-11;2.5e-06, DCS and GoDARTS, respectively; Homeostatic model assessment 2 (HOMA2)-B; -IR; -S, p=0.0008;4.2e-11;1.1e-09, only in DCS). The main molecular signatures separating the two groups included triacylglycerols, sphingomyelin, testican-1 and interleukin 18 receptor.ConclusionsUsing an unsupervised network-based fusion method on plasma lipidomics and proteomics data from two independent cohorts, we were able to identify two subgroups of T2D patients differing in terms of disease severity. The molecular signatures identified within these subgroups provide insights into disease mechanisms and possibly new prognostic markers for T2D.

Published
2024
Full Text
View/download PDF

22. Long-term effect of sleeve gastrectomy vs Roux-en-Y gastric bypass in people living with severe obesity: a phase III multicentre randomised controlled trial (SleeveBypass)Research in context

Author

L Ulas Biter, Judith WH. ‘t Hart, Bo J. Noordman, J Frans Smulders, Simon Nienhuijs, Martin Dunkelgrün, Johannes F. Zengerink, Erwin Birnie, Irene AM. Friskes, Guido HH. Mannaerts, and Jan A. Apers

Subjects
Roux-en-Y gastric bypass, Sleeve gastrectomy, Weight loss, GERD, Complications, Long-term follow-up, Public aspects of medicine, RA1-1270
Abstract

Summary: Background: Sleeve gastrectomy is the most performed metabolic surgical procedure worldwide. However, conflicting results offer no clear evidence about its long-term clinical comparability to Roux-en-Y gastric bypass. This study aims to determine their equivalent long-term weight loss effects. Methods: This randomised open-label controlled trial was conducted from 2012 until 2017 in two Dutch bariatric hospitals with a 5-year follow-up (last follow-up July 29th, 2022). Out of 4045 patients, 628 were eligible for metabolic surgery and were randomly assigned to sleeve gastrectomy or Roux-en-Y gastric bypass (intention-to-treat). The primary endpoint was weight loss, expressed by percentage excess body mass index (BMI) loss. The predefined clinically relevant equivalence margin was −13% to 13%. Secondary endpoints included percentage total kilograms weight loss, obesity-related comorbidities, quality of life, morbidity, and mortality. This trial is registered with Dutch Trial Register NTR4741: https://onderzoekmetmensen.nl/nl/trial/25900. Findings: 628 patients were randomised between sleeve gastrectomy (n = 312) and Roux-en-Y gastric bypass (n = 316) (mean age 43 [standard deviation (SD), 11] years; mean BMI 43.5 [SD, 4.7]; 81.8% women). Excess BMI loss at 5 years was 58.8% [95% CI, 55%–63%] after sleeve gastrectomy and 67.1% [95% CI, 63%–71%] after Roux-en-Y gastric bypass (difference 8.3% [95% CI, −12.5% to −4.0%]). This was within the predefined margin (P

Published
2024
Full Text
View/download PDF

24. Identifying and Interpreting Government Successes: An Assessment Tool for Classroom Use

Author

Douglas, Scott, 't Hart, Paul, and Van Erp, Judith

Abstract

Journalists, politicians, watchdog institutions, and public administration scholars devote considerable energy to identifying and dissecting failures in government. Studies and case-studies of policy, organizational, and institutional failures in the public sector figure prominently in public administration curriculums and classrooms. Such a focus on failures provides students with cautionary tales and theoretical tools for understanding how things can go badly wrong. However, students are provided with less insights and tools when it comes to identifying and understanding instances of success. To address this imbalance, this article offers students a framework to systematically identify, comprehensively assess and carefully interpret instances of successful public governance. The three-stage design of the funnel introduces students to relevant debates and literatures about meaningful public outcomes, the prudent use of public power, and the ability to sustain performance over time. The articles also discuss how this framework can be used effectively in classroom settings, helping teachers to stimulate reflection on the key challenges of assessing and learning from successes.

Published
2022
Full Text
View/download PDF

26. Discovery of drug–omics associations in type 2 diabetes with generative deep-learning models

Author

Allesøe, Rosa Lundbye, Lundgaard, Agnete Troen, Hernández Medina, Ricardo, Aguayo-Orozco, Alejandro, Johansen, Joachim, Nissen, Jakob Nybo, Brorsson, Caroline, Mazzoni, Gianluca, Niu, Lili, Biel, Jorge Hernansanz, Leal Rodríguez, Cristina, Brasas, Valentas, Webel, Henry, Benros, Michael Eriksen, Pedersen, Anders Gorm, Chmura, Piotr Jaroslaw, Jacobsen, Ulrik Plesner, Mari, Andrea, Koivula, Robert, Mahajan, Anubha, Vinuela, Ana, Tajes, Juan Fernandez, Sharma, Sapna, Haid, Mark, Hong, Mun-Gwan, Musholt, Petra B., De Masi, Federico, Vogt, Josef, Pedersen, Helle Krogh, Gudmundsdottir, Valborg, Jones, Angus, Kennedy, Gwen, Bell, Jimmy, Thomas, E. Louise, Frost, Gary, Thomsen, Henrik, Hansen, Elizaveta, Hansen, Tue Haldor, Vestergaard, Henrik, Muilwijk, Mirthe, Blom, Marieke T., ‘t Hart, Leen M., Pattou, Francois, Raverdy, Violeta, Brage, Soren, Kokkola, Tarja, Heggie, Alison, McEvoy, Donna, Mourby, Miranda, Kaye, Jane, Hattersley, Andrew, McDonald, Timothy, Ridderstråle, Martin, Walker, Mark, Forgie, Ian, Giordano, Giuseppe N., Pavo, Imre, Ruetten, Hartmut, Pedersen, Oluf, Hansen, Torben, Dermitzakis, Emmanouil, Franks, Paul W., Schwenk, Jochen M., Adamski, Jerzy, McCarthy, Mark I., Pearson, Ewan, Banasik, Karina, Rasmussen, Simon, and Brunak, Søren

Published
2023
Full Text
View/download PDF

27. Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits

Author

Andrew A. Brown, Juan J. Fernandez-Tajes, Mun-gwan Hong, Caroline A. Brorsson, Robert W. Koivula, David Davtian, Théo Dupuis, Ambra Sartori, Theodora-Dafni Michalettou, Ian M. Forgie, Jonathan Adam, Kristine H. Allin, Robert Caiazzo, Henna Cederberg, Federico De Masi, Petra J. M. Elders, Giuseppe N. Giordano, Mark Haid, Torben Hansen, Tue H. Hansen, Andrew T. Hattersley, Alison J. Heggie, Cédric Howald, Angus G. Jones, Tarja Kokkola, Markku Laakso, Anubha Mahajan, Andrea Mari, Timothy J. McDonald, Donna McEvoy, Miranda Mourby, Petra B. Musholt, Birgitte Nilsson, Francois Pattou, Deborah Penet, Violeta Raverdy, Martin Ridderstråle, Luciana Romano, Femke Rutters, Sapna Sharma, Harriet Teare, Leen ‘t Hart, Konstantinos D. Tsirigos, Jagadish Vangipurapu, Henrik Vestergaard, Søren Brunak, Paul W. Franks, Gary Frost, Harald Grallert, Bernd Jablonka, Mark I. McCarthy, Imre Pavo, Oluf Pedersen, Hartmut Ruetten, Mark Walker, The DIRECT Consortium, Jerzy Adamski, Jochen M. Schwenk, Ewan R. Pearson, Emmanouil T. Dermitzakis, and Ana Viñuela

Subjects
Science
Abstract

Abstract We evaluate the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3029 human donors. We find abundant allelic heterogeneity, where multiple variants regulate a particular molecular phenotype, and pleiotropy, where a single variant associates with multiple molecular phenotypes over multiple genomic regions. The highest proportion of share genetic regulation is detected between gene expression and proteins (66.6%), with a further median shared genetic associations across 49 different tissues of 78.3% and 62.4% between plasma proteins and gene expression. We represent the genetic and molecular associations in networks including 2828 known GWAS variants, showing that GWAS variants are more often connected to gene expression in trans than other molecular phenotypes in the network. Our work provides a roadmap to understanding molecular networks and deriving the underlying mechanism of action of GWAS variants using different molecular phenotypes in an accessible tissue.

Published
2023
Full Text
View/download PDF

28. Visuomotor adaptation across the lifespan.

Author

Holly A Clayton, Sahir Abbas, Bernard Marius T Hart, and Denise Y P Henriques

Subjects
Medicine, Science
Abstract

Being able to adapt our movements to changing circumstances allows people to maintain performance across a wide range of tasks throughout life, but it is unclear whether visuomotor learning abilities are fully developed in young children and, if so, whether they remain stable in the elderly. There is limited evidence of changes in motor adaptation ability throughout life, and the findings are inconsistent. Therefore, our goal was to compare visuomotor learning abilities throughout the lifespan. We used a shorter, gamified experimental task and collected data from participants in 5 age groups. Young children (M = 7 years), older children (M = 11 years), young adults (M = 20 years), adults (M = 40 years) and older adults (M = 67 years) adapted to a 45° visuomotor rotation in a centre-out reaching task. Across measures of rate of adaptation, extent of learning, rate of unlearning, generalization, and savings, we found that all groups performed similarly. That is, at least for short bouts of gamified learning, children and older adults perform just as well as young adults.

Published
2024
Full Text
View/download PDF

29. HDAC1/2 inhibitor therapy improves multiple organ systems in aged mice

Author

Alessandra Tammaro, Eileen G. Daniels, Iman M. Hu, Kelly C. ‘t Hart, Kim Reid, Rio P. Juni, Loes M. Butter, Goutham Vasam, Rashmi Kamble, Aldo Jongejan, Richard I. Aviv, Joris J.T.H. Roelofs, Eleonora Aronica, Reinier A. Boon, Keir J. Menzies, Riekelt H. Houtkooper, and Georges E. Janssens

Subjects
Drugs, Molecular biology, Epigenetics, Omics, Transcriptomics, Science
Abstract

Summary: Aging increases the risk of age-related diseases, imposing substantial healthcare and personal costs. Targeting fundamental aging mechanisms pharmacologically can promote healthy aging and reduce this disease susceptibility. In this work, we employed transcriptome-based drug screening to identify compounds emulating transcriptional signatures of long-lived genetic interventions. We discovered compound 60 (Cmpd60), a selective histone deacetylase 1 and 2 (HDAC1/2) inhibitor, mimicking diverse longevity interventions. In extensive molecular, phenotypic, and bioinformatic assessments using various cell and aged mouse models, we found Cmpd60 treatment to improve age-related phenotypes in multiple organs. Cmpd60 reduces renal epithelial-mesenchymal transition and fibrosis in kidney, diminishes dementia-related gene expression in brain, and enhances cardiac contractility and relaxation for the heart. In sum, our two-week HDAC1/2 inhibitor treatment in aged mice establishes a multi-tissue, healthy aging intervention in mammals, holding promise for therapeutic translation to promote healthy aging in humans.

Published
2024
Full Text
View/download PDF

30. Chimera: An atlas of regular vines on up to 8 nodes

Author

Oswaldo Morales-Nápoles, Mojtaba Rajabi-Bahaabadi, Gina Alexandra Torres-Alves, and Cornelis Marcel Pieter ’t Hart

Subjects
Science
Abstract

Abstract Vine copulas have become the standard tool for modelling complex probabilistic dependence. It has been shown that the number of regular vines grows extremely quickly with the number of nodes. Chimera is the first attempt to map the vast space of regular vines. Software for operating with regular vines is available for R, matlab and Python. However, no dataset containing all regular vines is available. Our atlas of regular vines, Chimera, comprises all 24 4 × 4 matrices representing regular vines on 4 nodes, 480 5 × 5 matrices representing regular vines on 5 nodes, 23,040 6 × 6 matrices representing regular vines on 6 nodes, 2,580,480 7 × 7 matrices representing regular vines on 7 nodes and 660,602,880 8 × 8 matrices representing regular vines on 8 nodes. Regular vines in Chimera are classified according to their tree-equivalence class. We fit all regular vines to synthetic data to demonstrate the potential of Chimera. Chimera provides thus a tool for researchers to navigate this vast space in an orderly fashion.

Published
2023
Full Text
View/download PDF

31. Identification of biomarkers for glycaemic deterioration in type 2 diabetes

Author

Roderick C. Slieker, Louise A. Donnelly, Elina Akalestou, Livia Lopez-Noriega, Rana Melhem, Ayşim Güneş, Frederic Abou Azar, Alexander Efanov, Eleni Georgiadou, Hermine Muniangi-Muhitu, Mahsa Sheikh, Giuseppe N. Giordano, Mikael Åkerlund, Emma Ahlqvist, Ashfaq Ali, Karina Banasik, Søren Brunak, Marko Barovic, Gerard A. Bouland, Frédéric Burdet, Mickaël Canouil, Iulian Dragan, Petra J. M. Elders, Celine Fernandez, Andreas Festa, Hugo Fitipaldi, Phillippe Froguel, Valborg Gudmundsdottir, Vilmundur Gudnason, Mathias J. Gerl, Amber A. van der Heijden, Lori L. Jennings, Michael K. Hansen, Min Kim, Isabelle Leclerc, Christian Klose, Dmitry Kuznetsov, Dina Mansour Aly, Florence Mehl, Diana Marek, Olle Melander, Anne Niknejad, Filip Ottosson, Imre Pavo, Kevin Duffin, Samreen K. Syed, Janice L. Shaw, Over Cabrera, Timothy J. Pullen, Kai Simons, Michele Solimena, Tommi Suvitaival, Asger Wretlind, Peter Rossing, Valeriya Lyssenko, Cristina Legido Quigley, Leif Groop, Bernard Thorens, Paul W. Franks, Gareth E. Lim, Jennifer Estall, Mark Ibberson, Joline W. J. Beulens, Leen M ’t Hart, Ewan R. Pearson, and Guy A. Rutter

Subjects
Science
Abstract

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.

Published
2023
Full Text
View/download PDF

32. Adapting to visuomotor rotations in stepped increments increases implicit motor learning

Author

Shanaathanan Modchalingam, Marco Ciccone, Sebastian D’Amario, Bernard Marius ’t Hart, and Denise Y. P. Henriques

Subjects
Medicine, Science
Abstract

Abstract Human motor adaptation relies on both explicit conscious strategies and implicit unconscious updating of internal models to correct motor errors. Implicit adaptation is powerful, requiring less preparation time before executing adapted movements, but recent work suggests it is limited to some absolute magnitude regardless of the size of a visuomotor perturbation when the perturbation is introduced abruptly. It is commonly assumed that gradually introducing a perturbation should lead to improved implicit learning beyond this limit, but outcomes are conflicting. We tested whether introducing a perturbation in two distinct gradual methods can overcome the apparent limit and explain past conflicting findings. We found that gradually introducing a perturbation in a stepped manner, where participants were given time to adapt to each partial step before being introduced to a larger partial step, led to ~ 80% higher implicit aftereffects of learning, but introducing it in a ramped manner, where participants adapted larger rotations on each subsequent reach, did not. Our results clearly show that gradual introduction of a perturbation can lead to substantially larger implicit adaptation, as well as identify the type of introduction that is necessary to do so.

Published
2023
Full Text
View/download PDF

33. NK cell subsets and dysfunction during viral infection: a new avenue for therapeutics?

Author

Jacob C. Bjorgen, Jenna K. Dick, Ross Cromarty, Geoffrey T. Hart, and Joshua Rhein

Subjects
NK cells, NK cell dysfunction, HIV, hepatitis C, CMV, influenza, Immunologic diseases. Allergy, RC581-607
Abstract

In the setting of viral challenge, natural killer (NK) cells play an important role as an early immune responder against infection. During this response, significant changes in the NK cell population occur, particularly in terms of their frequency, location, and subtype prevalence. In this review, changes in the NK cell repertoire associated with several pathogenic viral infections are summarized, with a particular focus placed on changes that contribute to NK cell dysregulation in these settings. This dysregulation, in turn, can contribute to host pathology either by causing NK cells to be hyperresponsive or hyporesponsive. Hyperresponsive NK cells mediate significant host cell death and contribute to generating a hyperinflammatory environment. Hyporesponsive NK cell populations shift toward exhaustion and often fail to limit viral pathogenesis, possibly enabling viral persistence. Several emerging therapeutic approaches aimed at addressing NK cell dysregulation have arisen in the last three decades in the setting of cancer and may prove to hold promise in treating viral diseases. However, the application of such therapeutics to treat viral infections remains critically underexplored. This review briefly explores several therapeutic approaches, including the administration of TGF-β inhibitors, immune checkpoint inhibitors, adoptive NK cell therapies, CAR NK cells, and NK cell engagers among other therapeutics.

Published
2023
Full Text
View/download PDF

34. Dynamic Elliptical Shaping Control for Swarm Robots

Author

Shae T. Hart, Jake Kamenetsky, and Christopher A. Kitts

Subjects
Coverage problem, elliptical aggregation, shape control, swarm robotics, Electrical engineering. Electronics. Nuclear engineering, TK1-9971
Abstract

Solving the robotic swarm coverage problem for an elliptical area has various applications for exploring novel environments. Solutions for this problem should cover a specified ellipse and seamlessly adapt to changing numbers of robots. Previous solutions used techniques such as formation control, vector fields, and neural networks. While these techniques were successful, they all lacked one or more of the three key tenants of swarm elliptical attraction: complete coverage of an ellipse with commandable parameters, simplicity for scaling in the number of robots, and adaptive sizing. Additionally, no previous work presented guidelines for ensuring that the swarms could successfully and safely converge to the commanded ellipse without collisions. In contrast, this work presents a novel swarm elliptical attraction behavior with all three key tenants with guidelines for ellipse and swarm parameter selection. First, a new Lyapunov stable elliptical attraction behavior for Reactive Particle Swarms is presented. The behavior commands robots to cover the entire ellipse area for a specific semimajor axis, eccentricity, and orientation. Additionally, dynamic interagent spacing naturally ensures coverage for different numbers of robots. Second, the work presents a novel adaptive sizing algorithm that varies the ellipse’s semimajor axis based on the swarm state. The adaptive sizing algorithm specifies the eccentricity and orientation using time-varying functions. Third, guidelines for selecting the number of robots, commanded ellipse area, obstacle avoidance distance, and robot communication range that allow for successful aggregation to the commanded ellipse are presented. All three of the results are verified using simulation and hardware-in-the-loop trials.

Published
2023
Full Text
View/download PDF

35. Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Author

Stavroula Kanoni, Sarah E. Graham, Yuxuan Wang, Ida Surakka, Shweta Ramdas, Xiang Zhu, Shoa L. Clarke, Konain Fatima Bhatti, Sailaja Vedantam, Thomas W. Winkler, Adam E. Locke, Eirini Marouli, Greg J. M. Zajac, Kuan-Han H. Wu, Ioanna Ntalla, Qin Hui, Derek Klarin, Austin T. Hilliard, Zeyuan Wang, Chao Xue, Gudmar Thorleifsson, Anna Helgadottir, Daniel F. Gudbjartsson, Hilma Holm, Isleifur Olafsson, Mi Yeong Hwang, Sohee Han, Masato Akiyama, Saori Sakaue, Chikashi Terao, Masahiro Kanai, Wei Zhou, Ben M. Brumpton, Humaira Rasheed, Aki S. Havulinna, Yogasudha Veturi, Jennifer Allen Pacheco, Elisabeth A. Rosenthal, Todd Lingren, QiPing Feng, Iftikhar J. Kullo, Akira Narita, Jun Takayama, Hilary C. Martin, Karen A. Hunt, Bhavi Trivedi, Jeffrey Haessler, Franco Giulianini, Yuki Bradford, Jason E. Miller, Archie Campbell, Kuang Lin, Iona Y. Millwood, Asif Rasheed, George Hindy, Jessica D. Faul, Wei Zhao, David R. Weir, Constance Turman, Hongyan Huang, Mariaelisa Graff, Ananyo Choudhury, Dhriti Sengupta, Anubha Mahajan, Michael R. Brown, Weihua Zhang, Ketian Yu, Ellen M. Schmidt, Anita Pandit, Stefan Gustafsson, Xianyong Yin, Jian’an Luan, Jing-Hua Zhao, Fumihiko Matsuda, Hye-Mi Jang, Kyungheon Yoon, Carolina Medina-Gomez, Achilleas Pitsillides, Jouke Jan Hottenga, Andrew R. Wood, Yingji Ji, Zishan Gao, Simon Haworth, Noha A. Yousri, Ruth E. Mitchell, Jin Fang Chai, Mette Aadahl, Anne A. Bjerregaard, Jie Yao, Ani Manichaikul, Chii-Min Hwu, Yi-Jen Hung, Helen R. Warren, Julia Ramirez, Jette Bork-Jensen, Line L. Kårhus, Anuj Goel, Maria Sabater-Lleal, Raymond Noordam, Pala Mauro, Floris Matteo, Aaron F. McDaid, Pedro Marques-Vidal, Matthias Wielscher, Stella Trompet, Naveed Sattar, Line T. Møllehave, Matthias Munz, Lingyao Zeng, Jianfeng Huang, Bin Yang, Alaitz Poveda, Azra Kurbasic, Claudia Lamina, Lukas Forer, Markus Scholz, Tessel E. Galesloot, Jonathan P. Bradfield, Sanni E. Ruotsalainen, EWarwick Daw, Joseph M. Zmuda, Jonathan S. Mitchell, Christian Fuchsberger, Henry Christensen, Jennifer A. Brody, Miguel Vazquez-Moreno, Mary F. Feitosa, Mary K. Wojczynski, Zhe Wang, Michael H. Preuss, Massimo Mangino, Paraskevi Christofidou, Niek Verweij, Jan W. Benjamins, Jorgen Engmann, Noah L. Tsao, Anurag Verma, Roderick C. Slieker, Ken Sin Lo, Nuno R. Zilhao, Phuong Le, Marcus E. Kleber, Graciela E. Delgado, Shaofeng Huo, Daisuke D. Ikeda, Hiroyuki Iha, Jian Yang, Jun Liu, Ayşe Demirkan, Hampton L. Leonard, Jonathan Marten, Mirjam Frank, Börge Schmidt, Laura J. Smyth, Marisa Cañadas-Garre, Chaolong Wang, Masahiro Nakatochi, Andrew Wong, Nina Hutri-Kähönen, Xueling Sim, Rui Xia, Alicia Huerta-Chagoya, Juan Carlos Fernandez-Lopez, Valeriya Lyssenko, Suraj S. Nongmaithem, Swati Bayyana, Heather M. Stringham, Marguerite R. Irvin, Christopher Oldmeadow, Han-Na Kim, Seungho Ryu, Paul R. H. J. Timmers, Liubov Arbeeva, Rajkumar Dorajoo, Leslie A. Lange, Gauri Prasad, Laura Lorés-Motta, Marc Pauper, Jirong Long, Xiaohui Li, Elizabeth Theusch, Fumihiko Takeuchi, Cassandra N. Spracklen, Anu Loukola, Sailalitha Bollepalli, Sophie C. Warner, Ya Xing Wang, Wen B. Wei, Teresa Nutile, Daniela Ruggiero, Yun Ju Sung, Shufeng Chen, Fangchao Liu, Jingyun Yang, Katherine A. Kentistou, Bernhard Banas, Giuseppe Giovanni Nardone, Karina Meidtner, Lawrence F. Bielak, Jennifer A. Smith, Prashantha Hebbar, Aliki-Eleni Farmaki, Edith Hofer, Maoxuan Lin, Maria Pina Concas, Simona Vaccargiu, Peter J. van der Most, Niina Pitkänen, Brian E. Cade, Sander W. van der Laan, Kumaraswamy Naidu Chitrala, Stefan Weiss, Amy R. Bentley, Ayo P. Doumatey, Adebowale A. Adeyemo, Jong Young Lee, Eva R. B. Petersen, Aneta A. Nielsen, Hyeok Sun Choi, Maria Nethander, Sandra Freitag-Wolf, Lorraine Southam, Nigel W. Rayner, Carol A. Wang, Shih-Yi Lin, Jun-Sing Wang, Christian Couture, Leo-Pekka Lyytikäinen, Kjell Nikus, Gabriel Cuellar-Partida, Henrik Vestergaard, Bertha Hidalgo, Olga Giannakopoulou, Qiuyin Cai, Morgan O. Obura, Jessica van Setten, Xiaoyin Li, Jingjing Liang, Hua Tang, Natalie Terzikhan, Jae Hun Shin, Rebecca D. Jackson, Alexander P. Reiner, Lisa Warsinger Martin, Zhengming Chen, Liming Li, Takahisa Kawaguchi, Joachim Thiery, Joshua C. Bis, Lenore J. Launer, Huaixing Li, Mike A. Nalls, Olli T. Raitakari, Sahoko Ichihara, Sarah H. Wild, Christopher P. Nelson, Harry Campbell, Susanne Jäger, Toru Nabika, Fahd Al-Mulla, Harri Niinikoski, Peter S. Braund, Ivana Kolcic, Peter Kovacs, Tota Giardoglou, Tomohiro Katsuya, Dominique de Kleijn, Gert J. de Borst, Eung Kweon Kim, Hieab H. H. Adams, M. Arfan Ikram, Xiaofeng Zhu, Folkert W. Asselbergs, Adriaan O. Kraaijeveld, Joline W. J. Beulens, Xiao-Ou Shu, Loukianos S. Rallidis, Oluf Pedersen, Torben Hansen, Paul Mitchell, Alex W. Hewitt, Mika Kähönen, Louis Pérusse, Claude Bouchard, Anke Tönjes, Yii-Der Ida Chen, Craig E. Pennell, Trevor A. Mori, Wolfgang Lieb, Andre Franke, Claes Ohlsson, Dan Mellström, Yoon Shin Cho, Hyejin Lee, Jian-Min Yuan, Woon-Puay Koh, Sang Youl Rhee, Jeong-Taek Woo, Iris M. Heid, Klaus J. Stark, Martina E. Zimmermann, Henry Völzke, Georg Homuth, Michele K. Evans, Alan B. Zonderman, Ozren Polasek, Gerard Pasterkamp, Imo E. Hoefer, Susan Redline, Katja Pahkala, Albertine J. Oldehinkel, Harold Snieder, Ginevra Biino, Reinhold Schmidt, Helena Schmidt, Stefania Bandinelli, George Dedoussis, Thangavel Alphonse Thanaraj, Sharon L. R. Kardia, Patricia A. Peyser, Norihiro Kato, Matthias B. Schulze, Giorgia Girotto, Carsten A. Böger, Bettina Jung, Peter K. Joshi, David A. Bennett, Philip L. De Jager, Xiangfeng Lu, Vasiliki Mamakou, Morris Brown, Mark J. Caulfield, Patricia B. Munroe, Xiuqing Guo, Marina Ciullo, Jost B. Jonas, Nilesh J. Samani, Jaakko Kaprio, Päivi Pajukanta, Teresa Tusié-Luna, Carlos A. Aguilar-Salinas, Linda S. Adair, Sonny Augustin Bechayda, H. Janaka de Silva, Ananda R. Wickremasinghe, Ronald M. Krauss, Jer-Yuarn Wu, Wei Zheng, Anneke Iden Hollander, Dwaipayan Bharadwaj, Adolfo Correa, James G. Wilson, Lars Lind, Chew-Kiat Heng, Amanda E. Nelson, Yvonne M. Golightly, James F. Wilson, Brenda Penninx, Hyung-Lae Kim, John Attia, Rodney J. Scott, D. C. Rao, Donna K. Arnett, Steven C. Hunt, Mark Walker, Heikki A. Koistinen, Giriraj R. Chandak, Josep M. Mercader, Maria C. Costanzo, Dongkeun Jang, Noël P. Burtt, Clicerio Gonzalez Villalpando, Lorena Orozco, Myriam Fornage, EShyong Tai, Rob M. van Dam, Terho Lehtimäki, Nish Chaturvedi, Mitsuhiro Yokota, Jianjun Liu, Dermot F. Reilly, Amy Jayne McKnight, Frank Kee, Karl-Heinz Jöckel, Mark I. McCarthy, Colin N. A. Palmer, Veronique Vitart, Caroline Hayward, Eleanor Simonsick, Cornelia M. van Duijn, Zi-Bing Jin, Jia Qu, Haretsugu Hishigaki, Xu Lin, Winfried März, Vilmundur Gudnason, Jean-Claude Tardif, Guillaume Lettre, Leen M.‘t Hart, Petra J. M. Elders, Scott M. Damrauer, Meena Kumari, Mika Kivimaki, Pim van der Harst, Tim D. Spector, Ruth J. F. Loos, Michael A. Province, Esteban J. Parra, Miguel Cruz, Bruce M. Psaty, Ivan Brandslund, Peter P. Pramstaller, Charles N. Rotimi, Kaare Christensen, Samuli Ripatti, Elisabeth Widén, Hakon Hakonarson, Struan F. A. Grant, Lambertus A. L. M. Kiemeney, Jacqueline de Graaf, Markus Loeffler, Florian Kronenberg, Dongfeng Gu, Jeanette Erdmann, Heribert Schunkert, Paul W. Franks, Allan Linneberg, J. Wouter Jukema, Amit V. Khera, Minna Männikkö, Marjo-Riitta Jarvelin, Zoltan Kutalik, Cucca Francesco, Dennis O. Mook-Kanamori, Ko Willems van Dijk, Hugh Watkins, David P. Strachan, Niels Grarup, Peter Sever, Neil Poulter, Lee-Ming Chuang, Jerome I. Rotter, Thomas M. Dantoft, Fredrik Karpe, Matt J. Neville, Nicholas J. Timpson, Ching-Yu Cheng, Tien-Yin Wong, Chiea Chuen Khor, Hengtong Li, Charumathi Sabanayagam, Annette Peters, Christian Gieger, Andrew T. Hattersley, Nancy L. Pedersen, Patrik K. E. Magnusson, Dorret I. Boomsma, Allegonda H. M. Willemsen, LAdrienne Cupples, Joyce B. J. van Meurs, Mohsen Ghanbari, Penny Gordon-Larsen, Wei Huang, Young Jin Kim, Yasuharu Tabara, Nicholas J. Wareham, Claudia Langenberg, Eleftheria Zeggini, Johanna Kuusisto, Markku Laakso, Erik Ingelsson, Goncalo Abecasis, John C. Chambers, Jaspal S. Kooner, Paul S. de Vries, Alanna C. Morrison, Scott Hazelhurst, Michèle Ramsay, Kari E. North, Martha Daviglus, Peter Kraft, Nicholas G. Martin, John B. Whitfield, Shahid Abbas, Danish Saleheen, Robin G. Walters, Michael V. Holmes, Corri Black, Blair H. Smith, Aris Baras, Anne E. Justice, Julie E. Buring, Paul M. Ridker, Daniel I. Chasman, Charles Kooperberg, Gen Tamiya, Masayuki Yamamoto, David A. van Heel, Richard C. Trembath, Wei-Qi Wei, Gail P. Jarvik, Bahram Namjou, M. Geoffrey Hayes, Marylyn D. Ritchie, Pekka Jousilahti, Veikko Salomaa, Kristian Hveem, Bjørn Olav Åsvold, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Yoshinori Murakami, Bong-Jo Kim, Unnur Thorsteinsdottir, Kari Stefansson, Jifeng Zhang, YEugene Chen, Yuk-Lam Ho, Julie A. Lynch, Daniel J. Rader, Philip S. Tsao, Kyong-Mi Chang, Kelly Cho, Christopher J. O’Donnell, John M. Gaziano, Peter W. F. Wilson, Timothy M. Frayling, Joel N. Hirschhorn, Sekar Kathiresan, Karen L. Mohlke, Yan V. Sun, Andrew P. Morris, Michael Boehnke, Christopher D. Brown, Pradeep Natarajan, Panos Deloukas, Cristen J. Willer, Themistocles L. Assimes, and Gina M. Peloso

Subjects
Cholesterol, Lipids, Genetics, Genome-wide association study, GWAS, Biology (General), QH301-705.5, QH426-470
Abstract

Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

Published
2022
Full Text
View/download PDF

36. A saturated map of common genetic variants associated with human height

Author

Yengo, Loïc, Vedantam, Sailaja, Marouli, Eirini, Sidorenko, Julia, Bartell, Eric, Sakaue, Saori, Graff, Marielisa, Eliasen, Anders U., Jiang, Yunxuan, Raghavan, Sridharan, Miao, Jenkai, Arias, Joshua D., Graham, Sarah E., Mukamel, Ronen E., Spracklen, Cassandra N., Yin, Xianyong, Chen, Shyh-Huei, Ferreira, Teresa, Highland, Heather H., Ji, Yingjie, Karaderi, Tugce, Lin, Kuang, Lüll, Kreete, Malden, Deborah E., Medina-Gomez, Carolina, Machado, Moara, Moore, Amy, Rüeger, Sina, Sim, Xueling, Vrieze, Scott, Ahluwalia, Tarunveer S., Akiyama, Masato, Allison, Matthew A., Alvarez, Marcus, Andersen, Mette K., Ani, Alireza, Appadurai, Vivek, Arbeeva, Liubov, Bhaskar, Seema, Bielak, Lawrence F., Bollepalli, Sailalitha, Bonnycastle, Lori L., Bork-Jensen, Jette, Bradfield, Jonathan P., Bradford, Yuki, Braund, Peter S., Brody, Jennifer A., Burgdorf, Kristoffer S., Cade, Brian E., Cai, Hui, Cai, Qiuyin, Campbell, Archie, Cañadas-Garre, Marisa, Catamo, Eulalia, Chai, Jin-Fang, Chai, Xiaoran, Chang, Li-Ching, Chang, Yi-Cheng, Chen, Chien-Hsiun, Chesi, Alessandra, Choi, Seung Hoan, Chung, Ren-Hua, Cocca, Massimiliano, Concas, Maria Pina, Couture, Christian, Cuellar-Partida, Gabriel, Danning, Rebecca, Daw, E. Warwick, Degenhard, Frauke, Delgado, Graciela E., Delitala, Alessandro, Demirkan, Ayse, Deng, Xuan, Devineni, Poornima, Dietl, Alexander, Dimitriou, Maria, Dimitrov, Latchezar, Dorajoo, Rajkumar, Ekici, Arif B., Engmann, Jorgen E., Fairhurst-Hunter, Zammy, Farmaki, Aliki-Eleni, Faul, Jessica D., Fernandez-Lopez, Juan-Carlos, Forer, Lukas, Francescatto, Margherita, Freitag-Wolf, Sandra, Fuchsberger, Christian, Galesloot, Tessel E., Gao, Yan, Gao, Zishan, Geller, Frank, Giannakopoulou, Olga, Giulianini, Franco, Gjesing, Anette P., Goel, Anuj, Gordon, Scott D., Gorski, Mathias, Grove, Jakob, Guo, Xiuqing, Gustafsson, Stefan, Haessler, Jeffrey, Hansen, Thomas F., Havulinna, Aki S., Haworth, Simon J., He, Jing, Heard-Costa, Nancy, Hebbar, Prashantha, Hindy, George, Ho, Yuk-Lam A., Hofer, Edith, Holliday, Elizabeth, Horn, Katrin, Hornsby, Whitney E., Hottenga, Jouke-Jan, Huang, Hongyan, Huang, Jie, Huerta-Chagoya, Alicia, Huffman, Jennifer E., Hung, Yi-Jen, Huo, Shaofeng, Hwang, Mi Yeong, Iha, Hiroyuki, Ikeda, Daisuke D., Isono, Masato, Jackson, Anne U., Jäger, Susanne, Jansen, Iris E., Johansson, Ingegerd, Jonas, Jost B., Jonsson, Anna, Jørgensen, Torben, Kalafati, Ioanna-Panagiota, Kanai, Masahiro, Kanoni, Stavroula, Kårhus, Line L., Kasturiratne, Anuradhani, Katsuya, Tomohiro, Kawaguchi, Takahisa, Kember, Rachel L., Kentistou, Katherine A., Kim, Han-Na, Kim, Young Jin, Kleber, Marcus E., Knol, Maria J., Kurbasic, Azra, Lauzon, Marie, Le, Phuong, Lea, Rodney, Lee, Jong-Young, Leonard, Hampton L., Li, Shengchao A., Li, Xiaohui, Li, Xiaoyin, Liang, Jingjing, Lin, Honghuang, Lin, Shih-Yi, Liu, Jun, Liu, Xueping, Lo, Ken Sin, Long, Jirong, Lores-Motta, Laura, Luan, Jian’an, Lyssenko, Valeriya, Lyytikäinen, Leo-Pekka, Mahajan, Anubha, Mamakou, Vasiliki, Mangino, Massimo, Manichaikul, Ani, Marten, Jonathan, Mattheisen, Manuel, Mavarani, Laven, McDaid, Aaron F., Meidtner, Karina, Melendez, Tori L., Mercader, Josep M., Milaneschi, Yuri, Miller, Jason E., Millwood, Iona Y., Mishra, Pashupati P., Mitchell, Ruth E., Møllehave, Line T., Morgan, Anna, Mucha, Soeren, Munz, Matthias, Nakatochi, Masahiro, Nelson, Christopher P., Nethander, Maria, Nho, Chu Won, Nielsen, Aneta A., Nolte, Ilja M., Nongmaithem, Suraj S., Noordam, Raymond, Ntalla, Ioanna, Nutile, Teresa, Pandit, Anita, Christofidou, Paraskevi, Pärna, Katri, Pauper, Marc, Petersen, Eva R. B., Petersen, Liselotte V., Pitkänen, Niina, Polašek, Ozren, Poveda, Alaitz, Preuss, Michael H., Pyarajan, Saiju, Raffield, Laura M., Rakugi, Hiromi, Ramirez, Julia, Rasheed, Asif, Raven, Dennis, Rayner, Nigel W., Riveros, Carlos, Rohde, Rebecca, Ruggiero, Daniela, Ruotsalainen, Sanni E., Ryan, Kathleen A., Sabater-Lleal, Maria, Saxena, Richa, Scholz, Markus, Sendamarai, Anoop, Shen, Botong, Shi, Jingchunzi, Shin, Jae Hun, Sidore, Carlo, Sitlani, Colleen M., Slieker, Roderick C., Smit, Roelof A. J., Smith, Albert V., Smith, Jennifer A., Smyth, Laura J., Southam, Lorraine, Steinthorsdottir, Valgerdur, Sun, Liang, Takeuchi, Fumihiko, Tallapragada, Divya Sri Priyanka, Taylor, Kent D., Tayo, Bamidele O., Tcheandjieu, Catherine, Terzikhan, Natalie, Tesolin, Paola, Teumer, Alexander, Theusch, Elizabeth, Thompson, Deborah J., Thorleifsson, Gudmar, Timmers, Paul R. H. J., Trompet, Stella, Turman, Constance, Vaccargiu, Simona, van der Laan, Sander W., van der Most, Peter J., van Klinken, Jan B., van Setten, Jessica, Verma, Shefali S., Verweij, Niek, Veturi, Yogasudha, Wang, Carol A., Wang, Chaolong, Wang, Lihua, Wang, Zhe, Warren, Helen R., Bin Wei, Wen, Wickremasinghe, Ananda R., Wielscher, Matthias, Wiggins, Kerri L., Winsvold, Bendik S., Wong, Andrew, Wu, Yang, Wuttke, Matthias, Xia, Rui, Xie, Tian, Yamamoto, Ken, Yang, Jingyun, Yao, Jie, Young, Hannah, Yousri, Noha A., Yu, Lei, Zeng, Lingyao, Zhang, Weihua, Zhang, Xinyuan, Zhao, Jing-Hua, Zhao, Wei, Zhou, Wei, Zimmermann, Martina E., Zoledziewska, Magdalena, Adair, Linda S., Adams, Hieab H. H., Aguilar-Salinas, Carlos A., Al-Mulla, Fahd, Arnett, Donna K., Asselbergs, Folkert W., Åsvold, Bjørn Olav, Attia, John, Banas, Bernhard, Bandinelli, Stefania, Bennett, David A., Bergler, Tobias, Bharadwaj, Dwaipayan, Biino, Ginevra, Bisgaard, Hans, Boerwinkle, Eric, Böger, Carsten A., Bønnelykke, Klaus, Boomsma, Dorret I., Børglum, Anders D., Borja, Judith B., Bouchard, Claude, Bowden, Donald W., Brandslund, Ivan, Brumpton, Ben, Buring, Julie E., Caulfield, Mark J., Chambers, John C., Chandak, Giriraj R., Chanock, Stephen J., Chaturvedi, Nish, Chen, Yii-Der Ida, Chen, Zhengming, Cheng, Ching-Yu, Christophersen, Ingrid E., Ciullo, Marina, Cole, John W., Collins, Francis S., Cooper, Richard S., Cruz, Miguel, Cucca, Francesco, Cupples, L. Adrienne, Cutler, Michael J., Damrauer, Scott M., Dantoft, Thomas M., de Borst, Gert J., de Groot, Lisette C. P. G. M., De Jager, Philip L., de Kleijn, Dominique P. V., Janaka de Silva, H., Dedoussis, George V., den Hollander, Anneke I., Du, Shufa, Easton, Douglas F., Elders, Petra J. M., Eliassen, A. Heather, Ellinor, Patrick T., Elmståhl, Sölve, Erdmann, Jeanette, Evans, Michele K., Fatkin, Diane, Feenstra, Bjarke, Feitosa, Mary F., Ferrucci, Luigi, Ford, Ian, Fornage, Myriam, Franke, Andre, Franks, Paul W., Freedman, Barry I., Gasparini, Paolo, Gieger, Christian, Girotto, Giorgia, Goddard, Michael E., Golightly, Yvonne M., Gonzalez-Villalpando, Clicerio, Gordon-Larsen, Penny, Grallert, Harald, Grant, Struan F. A., Grarup, Niels, Griffiths, Lyn, Gudnason, Vilmundur, Haiman, Christopher, Hakonarson, Hakon, Hansen, Torben, Hartman, Catharina A., Hattersley, Andrew T., Hayward, Caroline, Heckbert, Susan R., Heng, Chew-Kiat, Hengstenberg, Christian, Hewitt, Alex W., Hishigaki, Haretsugu, Hoyng, Carel B., Huang, Paul L., Huang, Wei, Hunt, Steven C., Hveem, Kristian, Hyppönen, Elina, Iacono, William G., Ichihara, Sahoko, Ikram, M. Arfan, Isasi, Carmen R., Jackson, Rebecca D., Jarvelin, Marjo-Riitta, Jin, Zi-Bing, Jöckel, Karl-Heinz, Joshi, Peter K., Jousilahti, Pekka, Jukema, J. Wouter, Kähönen, Mika, Kamatani, Yoichiro, Kang, Kui Dong, Kaprio, Jaakko, Kardia, Sharon L. R., Karpe, Fredrik, Kato, Norihiro, Kee, Frank, Kessler, Thorsten, Khera, Amit V., Khor, Chiea Chuen, Kiemeney, Lambertus A. L. M., Kim, Bong-Jo, Kim, Eung Kweon, Kim, Hyung-Lae, Kirchhof, Paulus, Kivimaki, Mika, Koh, Woon-Puay, Koistinen, Heikki A., Kolovou, Genovefa D., Kooner, Jaspal S., Kooperberg, Charles, Köttgen, Anna, Kovacs, Peter, Kraaijeveld, Adriaan, Kraft, Peter, Krauss, Ronald M., Kumari, Meena, Kutalik, Zoltan, Laakso, Markku, Lange, Leslie A., Langenberg, Claudia, Launer, Lenore J., Le Marchand, Loic, Lee, Hyejin, Lee, Nanette R., Lehtimäki, Terho, Li, Huaixing, Li, Liming, Lieb, Wolfgang, Lin, Xu, Lind, Lars, Linneberg, Allan, Liu, Ching-Ti, Liu, Jianjun, Loeffler, Markus, London, Barry, Lubitz, Steven A., Lye, Stephen J., Mackey, David A., Mägi, Reedik, Magnusson, Patrik K. E., Marcus, Gregory M., Vidal, Pedro Marques, Martin, Nicholas G., März, Winfried, Matsuda, Fumihiko, McGarrah, Robert W., McGue, Matt, McKnight, Amy Jayne, Medland, Sarah E., Mellström, Dan, Metspalu, Andres, Mitchell, Braxton D., Mitchell, Paul, Mook-Kanamori, Dennis O., Morris, Andrew D., Mucci, Lorelei A., Munroe, Patricia B., Nalls, Mike A., Nazarian, Saman, Nelson, Amanda E., Neville, Matt J., Newton-Cheh, Christopher, Nielsen, Christopher S., Nöthen, Markus M., Ohlsson, Claes, Oldehinkel, Albertine J., Orozco, Lorena, Pahkala, Katja, Pajukanta, Päivi, Palmer, Colin N. A., Parra, Esteban J., Pattaro, Cristian, Pedersen, Oluf, Pennell, Craig E., Penninx, Brenda W. J. H., Perusse, Louis, Peters, Annette, Peyser, Patricia A., Porteous, David J., Posthuma, Danielle, Power, Chris, Pramstaller, Peter P., Province, Michael A., Qi, Qibin, Qu, Jia, Rader, Daniel J., Raitakari, Olli T., Ralhan, Sarju, Rallidis, Loukianos S., Rao, Dabeeru C., Redline, Susan, Reilly, Dermot F., Reiner, Alexander P., Rhee, Sang Youl, Ridker, Paul M., Rienstra, Michiel, Ripatti, Samuli, Ritchie, Marylyn D., Roden, Dan M., Rosendaal, Frits R., Rotter, Jerome I., Rudan, Igor, Rutters, Femke, Sabanayagam, Charumathi, Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Sanghera, Dharambir K., Sattar, Naveed, Schmidt, Börge, Schmidt, Helena, Schmidt, Reinhold, Schulze, Matthias B., Schunkert, Heribert, Scott, Laura J., Scott, Rodney J., Sever, Peter, Shiroma, Eric J., Shoemaker, M. Benjamin, Shu, Xiao-Ou, Simonsick, Eleanor M., Sims, Mario, Singh, Jai Rup, Singleton, Andrew B., Sinner, Moritz F., Smith, J. Gustav, Snieder, Harold, Spector, Tim D., Stampfer, Meir J., Stark, Klaus J., Strachan, David P., ‘t Hart, Leen M., Tabara, Yasuharu, Tang, Hua, Tardif, Jean-Claude, Thanaraj, Thangavel A., Timpson, Nicholas J., Tönjes, Anke, Tremblay, Angelo, Tuomi, Tiinamaija, Tuomilehto, Jaakko, Tusié-Luna, Maria-Teresa, Uitterlinden, Andre G., van Dam, Rob M., van der Harst, Pim, Van der Velde, Nathalie, van Duijn, Cornelia M., van Schoor, Natasja M., Vitart, Veronique, Völker, Uwe, Vollenweider, Peter, Völzke, Henry, Wacher-Rodarte, Niels H., Walker, Mark, Wang, Ya Xing, Wareham, Nicholas J., Watanabe, Richard M., Watkins, Hugh, Weir, David R., Werge, Thomas M., Widen, Elisabeth, Wilkens, Lynne R., Willemsen, Gonneke, Willett, Walter C., Wilson, James F., Wong, Tien-Yin, Woo, Jeong-Taek, Wright, Alan F., Wu, Jer-Yuarn, Xu, Huichun, Yajnik, Chittaranjan S., Yokota, Mitsuhiro, Yuan, Jian-Min, Zeggini, Eleftheria, Zemel, Babette S., Zheng, Wei, Zhu, Xiaofeng, Zmuda, Joseph M., Zonderman, Alan B., Zwart, John-Anker, Chasman, Daniel I., Cho, Yoon Shin, Heid, Iris M., McCarthy, Mark I., Ng, Maggie C. Y., O’Donnell, Christopher J., Rivadeneira, Fernando, Thorsteinsdottir, Unnur, Sun, Yan V., Tai, E. Shyong, Boehnke, Michael, Deloukas, Panos, Justice, Anne E., Lindgren, Cecilia M., Loos, Ruth J. F., Mohlke, Karen L., North, Kari E., Stefansson, Kari, Walters, Robin G., Winkler, Thomas W., Young, Kristin L., Loh, Po-Ru, Yang, Jian, Esko, Tõnu, Assimes, Themistocles L., Auton, Adam, Abecasis, Goncalo R., Willer, Cristen J., Locke, Adam E., Berndt, Sonja I., Lettre, Guillaume, Frayling, Timothy M., Okada, Yukinori, Wood, Andrew R., Visscher, Peter M., and Hirschhorn, Joel N.

Published
2022
Full Text
View/download PDF

38. Chemotherapy resistant Burkitt lymphoma: Possible novel therapies including CAR‐T cell infusion

Author

Paulus A. F. Geerts, Nils ’t Hart, Otto Visser, Valentín Ortiz‐Maldonado, and Martine E. D. Chamuleau

Subjects
Burkitt lymphoma, cellular therapy, chemotherapy, immunotherapy, targeted therapy, Medicine, Medicine (General), R5-920
Abstract

Key Clinical Message The prognosis of patients with relapsed or refractory (R/R) BL is poor with limited response to salvage therapy, especially for patients with early relapse (

Published
2023
Full Text
View/download PDF

39. Spectral Properties and the Influence of Coronal Mass Ejections in 3He-rich Solar Energetic Particle Events

Author

Samuel T. Hart, M. A. Dayeh, R. Bučík, G. M. Mason, M. I. Desai, R. W. Ebert, G. C. Ho, and A. A. Shmies

Subjects
Solar energetic particles, Solar flares, Heliosphere, Active Sun, Solar magnetic reconnection, Astrophysics, QB460-466
Abstract

We analyze the spectral properties of ^3 He and ^4 He as well as the heavy ions (oxygen, neon, magnesium, silicon, and iron) in 80 ^3 He-rich solar energetic particle (SEP) events observed by the Ultra-Low-Energy Ion Spectrometer on board the Advanced Composition Explorer spacecraft since its launch in 1997 until 2024. We split the spectral analysis into two criteria: events with fast and wide coronal mass ejections (CMEs; called “FW events”) and events with slow, narrow, or no observed CMEs (called “non-FW events”). Overall, we find that events with fast and wide CMEs exhibit more uniform spectra across all species, and their low-energy spectral indices are strongly correlated, suggesting a CME provides an additional reacceleration mechanism for the ^3 He-rich SEPs. When comparing each species’ low-energy spectral index for events with no associated fast-and-wide CME, we find a primary peak in the spectral hardness of ^3 He, and a secondary peak in Mg and Si. If we consider a plasma temperature of 1.0–1.3 MK, Mg and Si have a charge-to-mass ratio ( Q / M ) nearest to one-third (1/3), directly half that of ^3 He. Thus, our results support the results of Roth & Temerin, which suggest heavy ions resonate with the second harmonic of the same ion cyclotron waves energizing ^3 He. However, it is unclear why the Fe enhancement is not reflected in its spectral index, and we propose that additional acceleration and/or transport mechanisms are playing a role in the abundance enhancement of Fe and heavier ions.

Published
2024
Full Text
View/download PDF

40. Multispacecraft Energetic Particle Enhancements Associated with a Single Corotating Interaction Region

Author

M. J. Starkey, M. A. Dayeh, M. I. Desai, R. Bučík, S. T. Hart, and H. A. Elliott

Subjects
Corotating streams, Interplanetary particle acceleration, Astrophysics, QB460-466
Abstract

The radial evolution of particles accelerated at corotating interaction regions (CIRs) is not fully understood, particularly the distance range over which this particle acceleration occurs and how the energy spectra are modulated by transport through the inner heliosphere. Here, we present observations of energetic proton enhancements associated with a CIR observed by Parker Solar Probe on 2021 April 25 during the inbound leg of its orbit near ∼46 R _s (∼0.21 au). The CIR is identified at additional spacecraft (Solar Terrestrial Relations Observatory, STEREO-A; Solar Orbiter, SolO; and Advanced Composition Explorer, ACE) using a corotation time delay estimation, and energetic proton spectra from each spacecraft are compared. We find that (1) energetic protons are observed near 46 R _s streaming sunward ahead of the CIR; (2) the CIR persists for at least one solar rotation and the corresponding energetic proton enhancements are observed at STEREO-A, SolO, and ACE; and (3) the proton energy spectrum is steeper near the Sun and hardens near 1 au. This observation presents the closest in situ energetic particle observation of a CIR to the Sun ever recorded. Results presented here suggest that particles can be accelerated by CIR structures within 1 au and these particles can penetrate very deep into the inner heliosphere.

Published
2024
Full Text
View/download PDF

42. Imaginaries and the Commons: Insights From Irrigation Modernization in Valencia, Spain

Author

Jaime Hoogesteger, Vivian Konijnenberg, Lieke Brackel, Sjoerd Kemink, Michiel Kusters, Bas Meester, Anusha Sanjeev Mehta, Tjalling ‘t Hart, Mark van der Poel, Pippi van Ommen, Rutgerd Boelens, and Carles Sanchis-Ibor

Subjects
alternative imaginaries, water assemblages, commons, irrigators’ communities, drip irrigation, spain, Political institutions and public administration (General), JF20-2112
Abstract

In this article we introduce the notion of imaginaries as a conceptual entry to study and better understand how and why commons re-create and transform. We do so by first exploring imaginaries as assemblages, and second by analytically dividing imaginaries in dominant and alternative imaginaries. While the former refer to how people imagine and live their social existence around built expectations and their underlying notions, the latter refers to imaginaries that critique instituted society and through it create ‘germs’ that can lead to transformation. Through this lens we analyze contestations that have emerged around the introduction of drip irrigation in two irrigation communities in the Valencia Region of Spain. These two case studies (Carcaixent and Potries) show how, among the commons, alternative imaginaries are challenging the dominant imaginaries of drip irrigation. We show how these alternative imaginaries result from a different way of assembling irrigation and the social, cultural, material, and economic relations around it. These insights, we argue, open up avenues that allow us to better understand the imaginary creations that reproduce a specific existing order, as well as the germ(s) that can lead to transformations and change.

Published
2023
Full Text
View/download PDF

45. Diabetes risk loci-associated pathways are shared across metabolic tissues

Author

Gerard A. Bouland, Joline W. J. Beulens, Joey Nap, Arno R. van der Slik, Arnaud Zaldumbide, Leen M. ’t Hart, and Roderick C. Slieker

Subjects
Type 2 diabetes, SNPs, Pathways, Metabolism, Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Aims/hypothesis Numerous genome-wide association studies have been performed to understand the influence of genetic variation on type 2 diabetes etiology. Many identified risk variants are located in non-coding and intergenic regions, which complicates understanding of how genes and their downstream pathways are influenced. An integrative data approach will help to understand the mechanism and consequences of identified risk variants. Methods In the current study we use our previously developed method CONQUER to overlap 403 type 2 diabetes risk variants with regulatory, expression and protein data to identify tissue-shared disease-relevant mechanisms. Results One SNP rs474513 was found to be an expression-, protein- and metabolite QTL. Rs474513 influenced LPA mRNA and protein levels in the pancreas and plasma, respectively. On the pathway level, in investigated tissues most SNPs linked to metabolism. However, in eleven of the twelve tissues investigated nine SNPs were linked to differential expression of the ribosome pathway. Furthermore, seven SNPs were linked to altered expression of genes linked to the immune system. Among them, rs601945 was found to influence multiple HLA genes, including HLA-DQA2, in all twelve tissues investigated. Conclusion Our results show that in addition to the classical metabolism pathways, other pathways may be important to type 2 diabetes that show a potential overlap with type 1 diabetes.

Published
2022
Full Text
View/download PDF

46. Author Correction: Discovery of drug–omics associations in type 2 diabetes with generative deep-learning models

Author

Allesøe, Rosa Lundbye, Lundgaard, Agnete Troen, Hernández Medina, Ricardo, Aguayo-Orozco, Alejandro, Johansen, Joachim, Nissen, Jakob Nybo, Brorsson, Caroline, Mazzoni, Gianluca, Niu, Lili, Biel, Jorge Hernansanz, Leal Rodríguez, Cristina, Brasas, Valentas, Webel, Henry, Benros, Michael Eriksen, Pedersen, Anders Gorm, Chmura, Piotr Jaroslaw, Jacobsen, Ulrik Plesner, Mari, Andrea, Koivula, Robert, Mahajan, Anubha, Vinuela, Ana, Tajes, Juan Fernandez, Sharma, Sapna, Haid, Mark, Hong, Mun-Gwan, Musholt, Petra B., De Masi, Federico, Vogt, Josef, Pedersen, Helle Krogh, Gudmundsdottir, Valborg, Jones, Angus, Kennedy, Gwen, Bell, Jimmy, Thomas, E. Louise, Frost, Gary, Thomsen, Henrik, Hansen, Elizaveta, Hansen, Tue Haldor, Vestergaard, Henrik, Muilwijk, Mirthe, Blom, Marieke T., ‘t Hart, Leen M., Pattou, Francois, Raverdy, Violeta, Brage, Soren, Kokkola, Tarja, Heggie, Alison, McEvoy, Donna, Mourby, Miranda, Kaye, Jane, Hattersley, Andrew, McDonald, Timothy, Ridderstråle, Martin, Walker, Mark, Forgie, Ian, Giordano, Giuseppe N., Pavo, Imre, Ruetten, Hartmut, Pedersen, Oluf, Hansen, Torben, Dermitzakis, Emmanouil, Franks, Paul W., Schwenk, Jochen M., Adamski, Jerzy, McCarthy, Mark I., Pearson, Ewan, Banasik, Karina, Rasmussen, Simon, and Brunak, Søren

Published
2023
Full Text
View/download PDF

47. The power of genetic diversity in genome-wide association studies of lipids

Author

Graham, Sarah E., Clarke, Shoa L., Wu, Kuan-Han H., Kanoni, Stavroula, Zajac, Greg J. M., Ramdas, Shweta, Surakka, Ida, Ntalla, Ioanna, Vedantam, Sailaja, Winkler, Thomas W., Locke, Adam E., Marouli, Eirini, Hwang, Mi Yeong, Han, Sohee, Narita, Akira, Choudhury, Ananyo, Bentley, Amy R., Ekoru, Kenneth, Verma, Anurag, Trivedi, Bhavi, Martin, Hilary C., Hunt, Karen A., Hui, Qin, Klarin, Derek, Zhu, Xiang, Thorleifsson, Gudmar, Helgadottir, Anna, Gudbjartsson, Daniel F., Holm, Hilma, Olafsson, Isleifur, Akiyama, Masato, Sakaue, Saori, Terao, Chikashi, Kanai, Masahiro, Zhou, Wei, Brumpton, Ben M., Rasheed, Humaira, Ruotsalainen, Sanni E., Havulinna, Aki S., Veturi, Yogasudha, Feng, QiPing, Rosenthal, Elisabeth A., Lingren, Todd, Pacheco, Jennifer Allen, Pendergrass, Sarah A., Haessler, Jeffrey, Giulianini, Franco, Bradford, Yuki, Miller, Jason E., Campbell, Archie, Lin, Kuang, Millwood, Iona Y., Hindy, George, Rasheed, Asif, Faul, Jessica D., Zhao, Wei, Weir, David R., Turman, Constance, Huang, Hongyan, Graff, Mariaelisa, Mahajan, Anubha, Brown, Michael R., Zhang, Weihua, Yu, Ketian, Schmidt, Ellen M., Pandit, Anita, Gustafsson, Stefan, Yin, Xianyong, Luan, Jian’an, Zhao, Jing-Hua, Matsuda, Fumihiko, Jang, Hye-Mi, Yoon, Kyungheon, Medina-Gomez, Carolina, Pitsillides, Achilleas, Hottenga, Jouke Jan, Willemsen, Gonneke, Wood, Andrew R., Ji, Yingji, Gao, Zishan, Haworth, Simon, Mitchell, Ruth E., Chai, Jin Fang, Aadahl, Mette, Yao, Jie, Manichaikul, Ani, Warren, Helen R., Ramirez, Julia, Bork-Jensen, Jette, Kårhus, Line L., Goel, Anuj, Sabater-Lleal, Maria, Noordam, Raymond, Sidore, Carlo, Fiorillo, Edoardo, McDaid, Aaron F., Marques-Vidal, Pedro, Wielscher, Matthias, Trompet, Stella, Sattar, Naveed, Møllehave, Line T., Thuesen, Betina H., Munz, Matthias, Zeng, Lingyao, Huang, Jianfeng, Yang, Bin, Poveda, Alaitz, Kurbasic, Azra, Lamina, Claudia, Forer, Lukas, Scholz, Markus, Galesloot, Tessel E., Bradfield, Jonathan P., Daw, E. Warwick, Zmuda, Joseph M., Mitchell, Jonathan S., Fuchsberger, Christian, Christensen, Henry, Brody, Jennifer A., Feitosa, Mary F., Wojczynski, Mary K., Preuss, Michael, Mangino, Massimo, Christofidou, Paraskevi, Verweij, Niek, Benjamins, Jan W., Engmann, Jorgen, Kember, Rachel L., Slieker, Roderick C., Lo, Ken Sin, Zilhao, Nuno R., Le, Phuong, Kleber, Marcus E., Delgado, Graciela E., Huo, Shaofeng, Ikeda, Daisuke D., Iha, Hiroyuki, Yang, Jian, Liu, Jun, Leonard, Hampton L., Marten, Jonathan, Schmidt, Börge, Arendt, Marina, Smyth, Laura J., Cañadas-Garre, Marisa, Wang, Chaolong, Nakatochi, Masahiro, Wong, Andrew, Hutri-Kähönen, Nina, Sim, Xueling, Xia, Rui, Huerta-Chagoya, Alicia, Fernandez-Lopez, Juan Carlos, Lyssenko, Valeriya, Ahmed, Meraj, Jackson, Anne U., Yousri, Noha A., Irvin, Marguerite R., Oldmeadow, Christopher, Kim, Han-Na, Ryu, Seungho, Timmers, Paul R. H. J., Arbeeva, Liubov, Dorajoo, Rajkumar, Lange, Leslie A., Chai, Xiaoran, Prasad, Gauri, Lorés-Motta, Laura, Pauper, Marc, Long, Jirong, Li, Xiaohui, Theusch, Elizabeth, Takeuchi, Fumihiko, Spracklen, Cassandra N., Loukola, Anu, Bollepalli, Sailalitha, Warner, Sophie C., Wang, Ya Xing, Wei, Wen B., Nutile, Teresa, Ruggiero, Daniela, Sung, Yun Ju, Hung, Yi-Jen, Chen, Shufeng, Liu, Fangchao, Yang, Jingyun, Kentistou, Katherine A., Gorski, Mathias, Brumat, Marco, Meidtner, Karina, Bielak, Lawrence F., Smith, Jennifer A., Hebbar, Prashantha, Farmaki, Aliki-Eleni, Hofer, Edith, Lin, Maoxuan, Xue, Chao, Zhang, Jifeng, Concas, Maria Pina, Vaccargiu, Simona, van der Most, Peter J., Pitkänen, Niina, Cade, Brian E., Lee, Jiwon, van der Laan, Sander W., Chitrala, Kumaraswamy Naidu, Weiss, Stefan, Zimmermann, Martina E., Lee, Jong Young, Choi, Hyeok Sun, Nethander, Maria, Freitag-Wolf, Sandra, Southam, Lorraine, Rayner, Nigel W., Wang, Carol A., Lin, Shih-Yi, Wang, Jun-Sing, Couture, Christian, Lyytikäinen, Leo-Pekka, Nikus, Kjell, Cuellar-Partida, Gabriel, Vestergaard, Henrik, Hildalgo, Bertha, Giannakopoulou, Olga, Cai, Qiuyin, Obura, Morgan O., van Setten, Jessica, Li, Xiaoyin, Schwander, Karen, Terzikhan, Natalie, Shin, Jae Hun, Jackson, Rebecca D., Reiner, Alexander P., Martin, Lisa Warsinger, Chen, Zhengming, Li, Liming, Highland, Heather M., Young, Kristin L., Kawaguchi, Takahisa, Thiery, Joachim, Bis, Joshua C., Nadkarni, Girish N., Launer, Lenore J., Li, Huaixing, Nalls, Mike A., Raitakari, Olli T., Ichihara, Sahoko, Wild, Sarah H., Nelson, Christopher P., Campbell, Harry, Jäger, Susanne, Nabika, Toru, Al-Mulla, Fahd, Niinikoski, Harri, Braund, Peter S., Kolcic, Ivana, Kovacs, Peter, Giardoglou, Tota, Katsuya, Tomohiro, Bhatti, Konain Fatima, de Kleijn, Dominique, de Borst, Gert J., Kim, Eung Kweon, Adams, Hieab H. H., Ikram, M. Arfan, Zhu, Xiaofeng, Asselbergs, Folkert W., Kraaijeveld, Adriaan O., Beulens, Joline W. J., Shu, Xiao-Ou, Rallidis, Loukianos S., Pedersen, Oluf, Hansen, Torben, Mitchell, Paul, Hewitt, Alex W., Kähönen, Mika, Pérusse, Louis, Bouchard, Claude, Tönjes, Anke, Chen, Yii-Der Ida, Pennell, Craig E., Mori, Trevor A., Lieb, Wolfgang, Franke, Andre, Ohlsson, Claes, Mellström, Dan, Cho, Yoon Shin, Lee, Hyejin, Yuan, Jian-Min, Koh, Woon-Puay, Rhee, Sang Youl, Woo, Jeong-Taek, Heid, Iris M., Stark, Klaus J., Völzke, Henry, Homuth, Georg, Evans, Michele K., Zonderman, Alan B., Polasek, Ozren, Pasterkamp, Gerard, Hoefer, Imo E., Redline, Susan, Pahkala, Katja, Oldehinkel, Albertine J., Snieder, Harold, Biino, Ginevra, Schmidt, Reinhold, Schmidt, Helena, Chen, Y. Eugene, Bandinelli, Stefania, Dedoussis, George, Thanaraj, Thangavel Alphonse, Kardia, Sharon L. R., Kato, Norihiro, Schulze, Matthias B., Girotto, Giorgia, Jung, Bettina, Böger, Carsten A., Joshi, Peter K., Bennett, David A., De Jager, Philip L., Lu, Xiangfeng, Mamakou, Vasiliki, Brown, Morris, Caulfield, Mark J., Munroe, Patricia B., Guo, Xiuqing, Ciullo, Marina, Jonas, Jost B., Samani, Nilesh J., Kaprio, Jaakko, Pajukanta, Päivi, Adair, Linda S., Bechayda, Sonny Augustin, de Silva, H. Janaka, Wickremasinghe, Ananda R., Krauss, Ronald M., Wu, Jer-Yuarn, Zheng, Wei, den Hollander, Anneke I., Bharadwaj, Dwaipayan, Correa, Adolfo, Wilson, James G., Lind, Lars, Heng, Chew-Kiat, Nelson, Amanda E., Golightly, Yvonne M., Wilson, James F., Penninx, Brenda, Kim, Hyung-Lae, Attia, John, Scott, Rodney J., Rao, D. C., Arnett, Donna K., Hunt, Steven C., Walker, Mark, Koistinen, Heikki A., Chandak, Giriraj R., Yajnik, Chittaranjan S., Mercader, Josep M., Tusié-Luna, Teresa, Aguilar-Salinas, Carlos A., Villalpando, Clicerio Gonzalez, Orozco, Lorena, Fornage, Myriam, Tai, E. Shyong, van Dam, Rob M., Lehtimäki, Terho, Chaturvedi, Nish, Yokota, Mitsuhiro, Liu, Jianjun, Reilly, Dermot F., McKnight, Amy Jayne, Kee, Frank, Jöckel, Karl-Heinz, McCarthy, Mark I., Palmer, Colin N. A., Vitart, Veronique, Hayward, Caroline, Simonsick, Eleanor, van Duijn, Cornelia M., Lu, Fan, Qu, Jia, Hishigaki, Haretsugu, Lin, Xu, März, Winfried, Parra, Esteban J., Cruz, Miguel, Gudnason, Vilmundur, Tardif, Jean-Claude, Lettre, Guillaume, ’t Hart, Leen M., Elders, Petra J. M., Damrauer, Scott M., Kumari, Meena, Kivimaki, Mika, van der Harst, Pim, Spector, Tim D., Loos, Ruth J. F., Province, Michael A., Psaty, Bruce M., Brandslund, Ivan, Pramstaller, Peter P., Christensen, Kaare, Ripatti, Samuli, Widén, Elisabeth, Hakonarson, Hakon, Grant, Struan F. A., Kiemeney, Lambertus A. L. M., de Graaf, Jacqueline, Loeffler, Markus, Kronenberg, Florian, Gu, Dongfeng, Erdmann, Jeanette, Schunkert, Heribert, Franks, Paul W., Linneberg, Allan, Jukema, J. Wouter, Khera, Amit V., Männikkö, Minna, Jarvelin, Marjo-Riitta, Kutalik, Zoltan, Cucca, Francesco, Mook-Kanamori, Dennis O., van Dijk, Ko Willems, Watkins, Hugh, Strachan, David P., Grarup, Niels, Sever, Peter, Poulter, Neil, Rotter, Jerome I., Dantoft, Thomas M., Karpe, Fredrik, Neville, Matt J., Timpson, Nicholas J., Cheng, Ching-Yu, Wong, Tien-Yin, Khor, Chiea Chuen, Sabanayagam, Charumathi, Peters, Annette, Gieger, Christian, Hattersley, Andrew T., Pedersen, Nancy L., Magnusson, Patrik K. E., Boomsma, Dorret I., de Geus, Eco J. C., Cupples, L. Adrienne, van Meurs, Joyce B. J., Ghanbari, Mohsen, Gordon-Larsen, Penny, Huang, Wei, Kim, Young Jin, Tabara, Yasuharu, Wareham, Nicholas J., Langenberg, Claudia, Zeggini, Eleftheria, Kuusisto, Johanna, Laakso, Markku, Ingelsson, Erik, Abecasis, Goncalo, Chambers, John C., Kooner, Jaspal S., de Vries, Paul S., Morrison, Alanna C., North, Kari E., Daviglus, Martha, Kraft, Peter, Martin, Nicholas G., Whitfield, John B., Abbas, Shahid, Saleheen, Danish, Walters, Robin G., Holmes, Michael V., Black, Corri, Smith, Blair H., Justice, Anne E., Baras, Aris, Buring, Julie E., Ridker, Paul M., Chasman, Daniel I., Kooperberg, Charles, Wei, Wei-Qi, Jarvik, Gail P., Namjou, Bahram, Hayes, M. Geoffrey, Ritchie, Marylyn D., Jousilahti, Pekka, Salomaa, Veikko, Hveem, Kristian, Åsvold, Bjørn Olav, Kubo, Michiaki, Kamatani, Yoichiro, Okada, Yukinori, Murakami, Yoshinori, Thorsteinsdottir, Unnur, Stefansson, Kari, Ho, Yuk-Lam, Lynch, Julie A., Rader, Daniel J., Tsao, Philip S., Chang, Kyong-Mi, Cho, Kelly, O’Donnell, Christopher J., Gaziano, John M., Wilson, Peter, Rotimi, Charles N., Hazelhurst, Scott, Ramsay, Michèle, Trembath, Richard C., van Heel, David A., Tamiya, Gen, Yamamoto, Masayuki, Kim, Bong-Jo, Mohlke, Karen L., Frayling, Timothy M., Hirschhorn, Joel N., Kathiresan, Sekar, Boehnke, Michael, Natarajan, Pradeep, Peloso, Gina M., Brown, Christopher D., Morris, Andrew P., Assimes, Themistocles L., Deloukas, Panos, Sun, Yan V., and Willer, Cristen J.

Published
2021
Full Text
View/download PDF

48. Replication and cross-validation of type 2 diabetes subtypes based on clinical variables: an IMI-RHAPSODY study

Author

Slieker, Roderick C., Donnelly, Louise A., Fitipaldi, Hugo, Bouland, Gerard A., Giordano, Giuseppe N., Åkerlund, Mikael, Gerl, Mathias J., Ahlqvist, Emma, Ali, Ashfaq, Dragan, Iulian, Festa, Andreas, Hansen, Michael K., Mansour Aly, Dina, Kim, Min, Kuznetsov, Dmitry, Mehl, Florence, Klose, Christian, Simons, Kai, Pavo, Imre, Pullen, Timothy J., Suvitaival, Tommi, Wretlind, Asger, Rossing, Peter, Lyssenko, Valeriya, Legido-Quigley, Cristina, Groop, Leif, Thorens, Bernard, Franks, Paul W., Ibberson, Mark, Rutter, Guy A., Beulens, Joline W. J., ‘t Hart, Leen M., and Pearson, Ewan R.

Published
2021
Full Text
View/download PDF

49. Mechanistic underpinning of an inside–out concept for autoimmunity in multiple sclerosis

Author

Bert A. ’t Hart, Antonio Luchicchi, Geert J. Schenk, Peter K. Stys, and Jeroen J. G. Geurts

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract The neuroinflammatory disease multiple sclerosis is driven by autoimmune pathology in the central nervous system. However, the trigger of the autoimmune pathogenic process is unknown. MS models in immunologically naïve, specific‐pathogen‐free bred rodents support an exogenous trigger, such as an infection. The validity of this outside–in pathogenic concept for MS has been frequently challenged by the difficulty to translate pathogenic concepts developed in these models into effective therapies for the MS patient. Studies in well‐validated non‐human primate multiple sclerosis models where, just like in humans, the autoimmune pathogenic process develops from an experienced immune system trained by prior infections, rather support an endogenous trigger. Data reviewed here corroborate the validity of this inside–out pathogenic concept for multiple sclerosis. They also provide a plausible sequence of events reminiscent of Wilkin’s primary lesion theory: (i) that autoimmunity is a physiological response of the immune system against excess antigen turnover in diseased tissue (the primary lesion) and (ii) that individuals developing autoimmune disease are (genetically predisposed) high responders against critical antigens. Data obtained in multiple sclerosis brains reveal the presence in normally appearing white matter of myelinated axons where myelin sheaths have locally dissociated from their enwrapped axon (i.e., blistering). The ensuing disintegration of axon–myelin units potentially causes the excess systemic release of post‐translationally modified myelin. Data obtained in a unique primate multiple sclerosis model revealed a core pathogenic role of T cells present in the normal repertoire, which hyper‐react to post‐translationally modified (citrullinated) myelin–oligodendrocyte glycoprotein and evoke clinical and pathological aspects of multiple sclerosis.

Published
2021
Full Text
View/download PDF

50. Variants in Pharmacokinetic Transporters and Glycemic Response to Metformin: A Metgen Meta-Analysis.

Author

Dujic, T, Zhou, K, Yee, SW, van Leeuwen, N, de Keyser, CE, Javorský, M, Goswami, S, Zaharenko, L, Hougaard Christensen, MM, Out, M, Tavendale, R, Kubo, M, Hedderson, MM, van der Heijden, AA, Klimčáková, L, Pirags, V, Kooy, A, Brøsen, K, Klovins, J, Semiz, S, Tkáč, I, Stricker, BH, Palmer, Cna, 't Hart, LM, Giacomini, KM, and Pearson, ER

Subjects
Humans, Diabetes Mellitus, Type 2, Metformin, Blood Glucose, Membrane Transport Proteins, Organic Cation Transport Proteins, Symporters, Hypoglycemic Agents, Treatment Outcome, Genotype, Phenotype, Polymorphism, Single Nucleotide, Databases, Factual, Aged, Aged, 80 and over, Middle Aged, Female, Male, Octamer Transcription Factor-1, Biomarkers, Pharmacogenomic Variants, Organic Cation Transporter 2, Glycated Hemoglobin A, Diabetes Mellitus, Type 2, Polymorphism, Single Nucleotide, Databases, Factual, and over, Pharmacology and Pharmaceutical Sciences, Pharmacology & Pharmacy
Abstract

Therapeutic response to metformin, a first-line drug for type 2 diabetes (T2D), is highly variable, in part likely due to genetic factors. To date, metformin pharmacogenetic studies have mainly focused on the impact of variants in metformin transporter genes, with inconsistent results. To clarify the significance of these variants in glycemic response to metformin in T2D, we performed a large-scale meta-analysis across the cohorts of the Metformin Genetics Consortium (MetGen). Nine candidate polymorphisms in five transporter genes (organic cation transporter [OCT]1, OCT2, multidrug and toxin extrusion transporter [MATE]1, MATE2-K, and OCTN1) were analyzed in up to 7,968 individuals. None of the variants showed a significant effect on metformin response in the primary analysis, or in the exploratory secondary analyses, when patients were stratified according to possible confounding genotypes or prescribed a daily dose of metformin. Our results suggest that candidate transporter gene variants have little contribution to variability in glycemic response to metformin in T2D.

Published
2017

Catalog

Books, media, physical & digital resources
See catalog results