114 results on '"Njolstad, Pal R."'
Search Results
2. Placental efflux transporters and antiseizure or antidepressant medication use impact birth weight in MoBa cohort
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Hernandez, Marta H., Cohen, Jacqueline M., Skåra, Karoline H., Grindstad, Thea K., Lee, Yunsung, Magnus, Per, Njølstad, Pål R., Andreassen, Ole A., Corfield, Elizabeth C., Havdahl, Alexandra, Molden, Espen, Furu, Kari, Magnus, Maria C., and Hernaez, Alvaro
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- 2024
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3. Genome-wide Association Meta-analysis of Childhood and Adolescent Internalizing Symptoms
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Jami, Eshim S., Hammerschlag, Anke R., Ip, Hill F., Allegrini, Andrea G., Benyamin, Beben, Border, Richard, Diemer, Elizabeth W., Jiang, Chang, Karhunen, Ville, Lu, Yi, Lu, Qing, Mallard, Travis T., Mishra, Pashupati P., Nolte, Ilja M., Palviainen, Teemu, Peterson, Roseann E., Sallis, Hannah M., Shabalin, Andrey A., Tate, Ashley E., Thiering, Elisabeth, Vilor-Tejedor, Natàlia, Wang, Carol, Zhou, Ang, Adkins, Daniel E., Alemany, Silvia, Ask, Helga, Chen, Qi, Corley, Robin P., Ehli, Erik A., Evans, Luke M., Havdahl, Alexandra, Hagenbeek, Fiona A., Hakulinen, Christian, Henders, Anjali K., Hottenga, Jouke Jan, Korhonen, Tellervo, Mamun, Abdullah, Marrington, Shelby, Neumann, Alexander, Rimfeld, Kaili, Rivadeneira, Fernando, Silberg, Judy L., van Beijsterveldt, Catharina E., Vuoksimaa, Eero, Whipp, Alyce M., Tong, Xiaoran, Andreassen, Ole A., Boomsma, Dorret I., Brown, Sandra A., Burt, S. Alexandra, Copeland, William, Dick, Danielle M., Harden, K. Paige, Harris, Kathleen Mullan, Hartman, Catharina A., Heinrich, Joachim, Hewitt, John K., Hopfer, Christian, Hypponen, Elina, Jarvelin, Marjo-Riitta, Kaprio, Jaakko, Keltikangas-Järvinen, Liisa, Klump, Kelly L., Krauter, Kenneth, Kuja-Halkola, Ralf, Larsson, Henrik, Lehtimäki, Terho, Lichtenstein, Paul, Lundström, Sebastian, Maes, Hermine H., Magnus, Per, Munafò, Marcus R., Najman, Jake M., Njølstad, Pål R., Oldehinkel, Albertine J., Pennell, Craig E., Plomin, Robert, Reichborn-Kjennerud, Ted, Reynolds, Chandra, Rose, Richard J., Smolen, Andrew, Snieder, Harold, Stallings, Michael, Standl, Marie, Sunyer, Jordi, Tiemeier, Henning, Wadsworth, Sally J., Wall, Tamara L., Whitehouse, Andrew J.O., Williams, Gail M., Ystrøm, Eivind, Nivard, Michel G., Bartels, Meike, and Middeldorp, Christel M.
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- 2022
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4. Smoking and infertility: multivariable regression and Mendelian randomization analyses in the Norwegian Mother, Father and Child Cohort Study
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Hernáez, Álvaro, Wootton, Robyn E., Page, Christian M., Skåra, Karoline H., Fraser, Abigail, Rogne, Tormod, Magnus, Per, Njølstad, Pål R., Andreassen, Ole A., Burgess, Stephen, Lawlor, Deborah A., and Magnus, Maria Christine
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- 2022
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5. Characterization of CEL-DUP2: Complete duplication of the carboxyl ester lipase gene is unlikely to influence risk of chronic pancreatitis
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Fjeld, Karianne, Masson, Emmanuelle, Lin, Jin-Huan, Michl, Patrick, Stokowy, Tomasz, Gravdal, Anny, El Jellas, Khadija, Steine, Solrun J., Hoem, Dag, Johansson, Bente B., Dalva, Monica, Ruffert, Claudia, Zou, Wen-Bin, Li, Zhao-Shen, Njølstad, Pål R., Chen, Jian-Min, Liao, Zhuan, Johansson, Stefan, Rosendahl, Jonas, Férec, Claude, and Molven, Anders
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- 2020
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6. The homeobox factor Irx3 maintains adipogenic identity
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Bjune, Jan-Inge, Lawrence-Archer, Laurence, Røsland, Gro V., Tronstad, Karl Johan, Njølstad, Pål R., Sagen, Jørn V., Dankel, Simon N., and Mellgren, Gunnar
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- 2020
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7. Long chain omega-3 fatty acid intake in pregnancy and risk of type 1 diabetes in the offspring: Two large Scandinavian pregnancy cohorts -- MoBa and DNBC
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Lund-Blix, Nicolai A, primary, Bjerregaard, Anne A, additional, Tapia, German, additional, Stordal, Ketil, additional, Brantsaeter, Anne L, additional, Strom, Marin, additional, Halldorsson, Thorhallur I, additional, Granstrom, Charlotta, additional, Svensson, Jannet, additional, Joner, Geir, additional, Skrivarhaug, Torild, additional, Njolstad, Pal R, additional, Olsen, Sjurdur F, additional, and Stene, Lars C, additional
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- 2023
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8. Parental Smoking and Risk of Childhood-onset Type 1 Diabetes
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Magnus, Maria C., Tapia, German, Olsen, Sjurdur F., Granstrom, Charlotta, Mårild, Karl, Ueland, Per M., Midttun, Øivind, Svensson, Jannet, Johannesen, Jesper, Skrivarhaug, Torild, Joner, Geir, Njølstad, Pål R., Størdal, Ketil, and Stene, Lars C.
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- 2018
9. Effectiveness and safety of long-term treatment with sulfonylureas in patients with neonatal diabetes due to KCNJ11 mutations: an international cohort study
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Aisenberg, Javier, Akkurt, Ilker, Abdul-Latif, Hussein, Al-Abdullah, Anees, Barak, Lubomir, Van Den Bergh, Joop, Bertrand, Anne-Marie, Bizzarri, Carla, Bonfanti, Riccardo, Bruel, Henri, Burrows, Anthony, Cadario, Francesco, Cameron, Fergus J., Carson, Dennis, Cartigny, Maryse, Cauvin, Vittoria, Cave, Helene, Chakera, Ali, Chetan, Ravi, Chiari, Giovanni, Couch, Bob, Coutant, Régis, Cummings, Elizabeth, Dankovcikova, Adriana, Davis, Liz, Deiss, Dorothee, Delvecchio, Maurizio, Faleschini, Elena, Fauret, Anne-Laure, Finn, Roisin, Ford, Tamsin, Franco, Elisa De, Gallen, Bastian De, Gasperíková, Daniela, Guntamukkala, Padma, Hakeem, Vaseem, Hasegawa, Shinji, Hathout, Eba H., Heffernan, Emmeline, Hill, David, Ho, Josephine, Hoarau, Marie, Holl, Reinhard, Hoddinott, Rebecca, Houghton, Jane, Howard, Neville, Hughes, Natalie, Hunter, Ian, Høgåsen, Anne Kirsti, Kuulasmaa, Helena, Ioacara, Sorin, Iotova, Violeta, Irgens, Henrik, Jaap, Alan, Jones, Kenneth, Kapellen, Thomas, Kaufman, Ellen, Klinge, Andreas, Klupa, Tomasz, Krishnaswamy, Ramaiyer, Lafferty, Tony, LeGault, Laurent, Lambert, Paul, Malecki, Maciej T, Malievsky, Olag, Mathew, Revi, Mathews, Frances, McVie, Robert, Menzel, Ulrike, Metz, Chantale, Meulen, John Van Der, Modgil, Gita, Mul, Dick, Muther, Silvia, Nuboer, Roos, O'Connell, Susan M., O'Riordan, Stephen, Palko, Miroslav, Patel, Kashyap Amratlal, Pesavento, Roberta, Piccinno, Elvira, Pillai, Janani Kumaraguru, Pruhova, Stephanka, Punthakee, Zubin, Rabbone, Ivana, Raile, Klemens, Rincon, Marielisa, Rose, Danette, Sanchez, Janine, Sandereson, Susan, Saxena, Vinay, Schebek, Martin, Schmidt, Dorothee, Shehadeh, Naim, Shiels, Julian P.H., Silva, Jose M. C. L, Stanik, Juraj, Tinklin, Tracy, Tjora, Erling, Tumini, Stefano, Tuomi, Tiinamaija, Uehara, Akiko, Velde, Robert Van der, Vermeulen, Guido, Visser, Uma, Voorhoeve, Paul, Walker, Jan, Weill, Jaques, Weisner, Tobias, Werner, Andrea, Williams, Toni, Woodhead, Helen, øddegård, Rønnaug, Bowman, Pamela, Sulen, Åsta, Barbetti, Fabrizio, Beltrand, Jacques, Svalastoga, Pernille, Codner, Ethel, Tessmann, Ellen H, Juliusson, Petur B, Skrivarhaug, Torild, Pearson, Ewan R, Flanagan, Sarah E, Babiker, Tarig, Thomas, Nicholas J, Shepherd, Maggie H, Ellard, Sian, Klimes, Iwar, Szopa, Magdalena, Polak, Michel, Iafusco, Dario, Hattersley, Andrew T, and Njølstad, Pål R
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- 2018
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10. The role of the carboxyl ester lipase (CEL) gene in pancreatic disease
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Johansson, Bente B., Fjeld, Karianne, El Jellas, Khadija, Gravdal, Anny, Dalva, Monica, Tjora, Erling, Ræder, Helge, Kulkarni, Rohit N., Johansson, Stefan, Njølstad, Pål R., and Molven, Anders
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- 2018
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11. Copy number variants and VNTR length polymorphisms of the carboxyl-ester lipase (CEL) gene as risk factors in pancreatic cancer
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Dalva, Monica, El Jellas, Khadija, Steine, Solrun J., Johansson, Bente B., Ringdal, Monika, Torsvik, Janniche, Immervoll, Heike, Hoem, Dag, Laemmerhirt, Felix, Simon, Peter, Lerch, Markus M., Johansson, Stefan, Njølstad, Pål R., Weiss, Frank U., Fjeld, Karianne, and Molven, Anders
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- 2017
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12. Intergenerational effects of parental educational attainment on parenting and childhood educational outcomes: Evidence from MoBa using within-family Mendelian randomization
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Havdahl, Alexandra, primary, Hughes, Amanda, additional, Sanderson, Eleanor, additional, Ask, Helga, additional, Cheesman, Rosa, additional, Reichborn-Kjennerud, Ted, additional, Andreassen, Ole, additional, Corfield, Elizabeth, additional, Hannigan, Laurie, additional, Magnus, Per, additional, Njolstad, Pal R, additional, Stoltenberg,, Camilla, additional, Ask Torvik, Fartein, additional, Brandlistuen, Ragnhild, additional, Davey Smith, George, additional, Ystrom, Eivind, additional, and Davies, Neil M, additional
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- 2023
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13. Bounding the average causal effect in Mendelian randomisation studies with multiple proposed instruments: An application to prenatal alcohol exposure and attention deficit hyperactivity disorder
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Diemer, Elizabeth W., primary, Havdahl, Alexandra, additional, Andreassen, Ole A., additional, Munafò, Marcus R., additional, Njolstad, Pal R., additional, Tiemeier, Henning, additional, Zuccolo, Luisa, additional, and Swanson, Sonja A., additional
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- 2023
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14. Bounding the average causal effect in Mendelian randomisation studies with multiple proposed instruments:An application to prenatal alcohol exposure and attention deficit hyperactivity disorder
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Diemer, Elizabeth W., Havdahl, Alexandra, Andreassen, Ole A., Munafò, Marcus R, Njolstad, Pal R., Tiemeier, Henning, Zuccolo, Luisa, Swanson, Sonja A., Diemer, Elizabeth W., Havdahl, Alexandra, Andreassen, Ole A., Munafò, Marcus R, Njolstad, Pal R., Tiemeier, Henning, Zuccolo, Luisa, and Swanson, Sonja A.
- Abstract
Background: As large-scale observational data become more available, caution regarding causal assumptions remains critically important. This may be especially true for Mendelian randomisation (MR), an increasingly popular approach. Point estimation in MR usually requires strong, often implausible homogeneity assumptions beyond the core instrumental conditions. Bounding, which does not require homogeneity assumptions, is infrequently applied in MR. Objectives: We aimed to demonstrate computing nonparametric bounds for the causal risk difference derived from multiple proposed instruments in an MR study where effect heterogeneity is expected. Methods: Using data from the Norwegian Mother, Father and Child Cohort Study (n = 2056) and Avon Longitudinal Study of Parents and Children (n = 6216) to study the average causal effect of maternal pregnancy alcohol use on offspring attention deficit hyperactivity disorder symptoms, we proposed 11 maternal SNPs as instruments. We computed bounds assuming subsets of SNPs were jointly valid instruments, for all combinations of SNPs where the MR model was not falsified. Results: The MR assumptions were violated for all sets with more than 4 SNPs in one cohort and for all sets with more than 2 SNPs in the other. Bounds assuming one SNP was an individually valid instrument barely improved on assumption-free bounds. Bounds tightened as more SNPs were assumed to be jointly valid instruments, and occasionally identified directions of effect, though bounds from different sets varied. Conclusions: Our results suggest that, when proposing multiple instruments, bounds can contextualise plausible magnitudes and directions of effects. Computing bounds over multiple assumption sets, particularly in large, high-dimensional data, offers a means of triangulating results across different potential sources of bias within a study and may help researchers to better evaluate and emphasise which estimates are compatible with the most plausible assumpt
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- 2023
15. P13-kinase mutation linked to insulin and growth factor resistance in vivo
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Winnay, Jonathon N., Solheim, Marie H., Dirice, Ercument, Sakaguchi, Masaji, Noh, Hye-Lim, Kang, Hee Joon, Takahashi, Hirokazu, Chudasama, Kishan K., Kim, Jason K., Molven, Anders, Kahn, C. Ronald, and Njolstad, Pal R.
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Insulin resistance -- Genetic aspects -- Physiological aspects -- Development and progression ,Phosphotransferases -- Properties ,Cellular signal transduction -- Genetic aspects -- Health aspects ,Growth factors -- Properties ,Health care industry - Abstract
The phosphatidylinositol 3-kinase (PI3K) signaling pathway is central to the action of insulin and many growth factors. Heterozygous mutations in the gene encoding the p85α regulatory subunit of PI3K (PIK3R1) have been identified in patients with SHORT syndrome--a disorder characterized by short stature, partial lipodystrophy, and insulin resistance. Here, we evaluated whether SHORT syndrome-associated PIK3R1 mutations account for the pathophysiology that underlies the abnormalities by generating knockin mice that are heterozygous for the [Pik3r1.sup.Arg649Trp] mutation, which is homologous to the mutation found in the majority of affected individuals. Similar to the patients, mutant mice exhibited a reduction in body weight and length, partial lipodystrophy, and systemic insulin resistance. These derangements were associated with a reduced capacity of insulin and other growth factors to activate PI3K in liver, muscle, and fat; marked insulin resistance in liver and fat of mutation-harboring animals; and insulin resistance in vitro in cells derived from these mice. In addition, mutant mice displayed defective insulin secretion and GLP-1 action on islets in vivo and in vitro. These data demonstrate the ability of this heterozygous mutation to alter PI3K activity in vivo and the central role of PI3K in insulin/growth factor action, adipocyte function, and glucose metabolism., Introduction Insulin and most growth factors regulate diverse biological processes, including cell growth, cell survival, and metabolism, by virtue of their ability to activate phosphatidylinositol 3-kinase (PI3K). This leads to [...]
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- 2016
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16. Bounding the average causal effect in Mendelian randomization studies with multiple proposed instruments: An application to prenatal alcohol exposure and attention deficit hyperactivity disorder
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Diemer, Elizabeth W, primary, Havdahl, Alexandra, additional, Andreassen, Ole A, additional, Munafò, Marcus R, additional, Njolstad, Pal R, additional, Tiemeier, Henning, additional, Zuccolo, Luisa, additional, and Swanson, Sonja A, additional
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- 2022
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17. The number of tandem repeats in the carboxyl-ester lipase (CEL) gene as a risk factor in alcoholic and idiopathic chronic pancreatitis
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Ragvin, Anja, Fjeld, Karianne, Weiss, F. Ulrich, Torsvik, Janniche, Aghdassi, Ali, Mayerle, Julia, Simon, Peter, Njølstad, Pål R., Lerch, Markus M., Johansson, Stefan, and Molven, Anders
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- 2013
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18. Health behaviours prior to pregnancy and fertility outcomes: Triangulation of evidence in the Norwegian Mother, Father and Child Cohort Study (MoBa)
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Wootton, Robyn E, primary, Lawn, Rebecca B, additional, Magnus, Maria, additional, Treur, Jorien, additional, Corfield, Elizabeth, additional, Njolstad, Pal R, additional, Andreassen, Ole A, additional, Lawlor, Deborah A, additional, Munafo, Marcus R, additional, Haberg, Siri E, additional, Davey Smith, George, additional, Reichborn-Kjennerud, Ted, additional, Magnus, Per, additional, and Havdahl, Alexandra, additional
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- 2022
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19. Long-Range Gene Regulation Links Genomic Type 2 Diabetes and Obesity Risk Regions to HHEX, SOX4, and IRX3
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Ragvin, Anja, Moro, Enrico, Fredman, David, Navratilova, Pavla, Drivenes, Øyvind, Engström, Pär G., Alonso, M. Eva, de la Calle Mustienes, Elisa, Skarmeta, José Luis Gómez, Tavares, Maria J., Casares, Fernando, Manzanares, Miguel, van Heyningen, Veronica, Molven, Anders, Njølstad, Pål R., Argenton, Francesco, Lenhard, Boris, Becker, Thomas S., and Levine, Michael S.
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- 2010
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20. Carboxyl-ester lipase maturity-onset diabetes of the young is associated with development of pancreatic cysts and upregulated MAPK signaling in secretin-stimulated duodenal fluid
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Raeder, Helge, McAllister, Fiona E., Tjora, Erling, Bhatt, Shweta, Haldorsen, Ingfrid, Hu, Jiang, Willems, Stefan M., Vesterhus, Mette, Ouaamari, Abdelfattah El, Liu, Manway, Raeder, Maria B., Immervoll, Heike, Hoem, Dag, Dimcevski, Georg, Njolstad, Pal R., Molven, Anders, Gygi, Steven P., and Kulkarni, Rohit N.
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Diabetes -- Genetic aspects -- Development and progression ,Lipase -- Identification and classification -- Health aspects ,Cellular signal transduction -- Research ,Mitogen-activated protein kinases -- Properties ,Health - Abstract
Carboxyl-ester lipase (CEL) maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes and pancreatic exocrine dysfunction due to mutations in the CEL gene encoding CEL. The pathogenic mechanism for diabetes development is unknown. Since CEL is expressed mainly in pancreatic acinar cells, we asked whether we could find structural pancreatic changes in CEL-MODY subjects during the course of diabetes development. Furthermore, we hypothesized that the diseased pancreas releases proteins that are detectable in pancreatic fluid and potentially reflect activation or inactivation of disease-specific pathways. We therefore investigated nondiabetic and diabetic CEL-mutation carriers by pancreatic imaging studies and secretin-stimulated duodenal juice sampling. The secretin-stimulated duodenal juice was studied using cytokine assays, mass spectrometry (MS) proteomics, and multiplexed MS-based measurement of kinase activities. We identified multiple pancreatic cysts in all eight diabetic mutation carriers but not in any of the four nondiabetic mutation carriers or the six healthy controls. Furthermore, we identified upregulated mitogen-activated protein kinase (MAPK) target proteins and MAPK-driven cytokines and increased MAPK activity in the secretin-stimulated duodenal juice. These findings show that subjects with CEL-MODY develop multiple pancreatic cysts by the time they develop diabetes and that upregulated MAPK signaling in the pancreatic secretome may reflect the pathophysiological development of pancreatic cysts and diabetes. Diabetes 2014;63:259-269 | DOI: 10.2337/db13-1012, Studies of patients with maturity-onset diabetes of the young (MODY) have provided important insight into disease mechanisms of pancreatic β-cell failure and diabetes development and also contributed to novel treatment [...]
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- 2014
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21. Novel Loci for Childhood Body Mass Index and Shared Heritability with Adult Cardiometabolic Traits
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Genética, antropología física y fisiología animal, Genetika,antropologia fisikoa eta animalien fisiologia, Vogelezang, Suzanne, Bradfield, Jonathan P., Ahluwalia, Tarunveer S., Curtin, John A., Lakka, Timo A., Grarup, Niels, Scholz, Markus, Van der Most, Peter J., Monnereau, Claire, Stergiakouli, Evie, Heiskala, Anni, Horikoshi, Momoko, Fedko, Iryna O., Vilor Tejedor, Natalia, Cousminer, Diana L., Standl, Marie, Wang, Carol A., Viikari, Jorma, Geller, Frank, Íñiguez, Carmen, Pitkanen, Niina, Chesi, Alessandra, Bacelis, Jonas, Yengo, Loic, Torrent, Maties, Ntalla, Ioanna, Helgeland, Oyvind, Selzam, Saskia, Vonk, Judith M., Zafarmand, Mohammed H., Heude, Barbara, Farooqi, Ismaa Sadaf, Alyass, Akram, Beaumont, Robin N., Have, Christian T., Rzehak, Peter, Bilbao Catalá, José Ramón, Schnurr, Theresia M., Barroso, Ines, Bonnelykke, Klaus, Beilin, Lawrence J., Carstensen, Lisbeth, Charles, Marie Aline, Chawes, Bo, Clement, Karine, Closa Monasterolo, Ricardo, Custovic, Adnan, Eriksson, Johan G., Escribano, Joaquín, Groen-Blokhuis, Maria, Grote, Veit, Gruszfeld, Dariusz, Hakonarson, Hakon, Hansen, Torben, Hattersley, Andrew T., Hollensted, Mette, Hottenga, Jouke Jan, Hypponen, Elina, Johansson, Stefan, Joro, Raimo, Kahonen, Mika, Karhunen, Ville, Kiess, Wieland, Knight, Bridget A., Koletzko, Berthold, Kuehnapfel, Andreas, Landgraf, Kathrin, Langhendries, Jean-Paul, Lehtimaki, Terho, Leinonen, Jaakko T., Li, Aihuali, Lindi, Virpi, Lowry, Estelle, Bustamante, Mariona, Medina Gómez, Carolina, Melbye, Mads, Michaelsen, Kim F., Morgen, Camilla S., Mori, Trevor A., Nielsen, Tenna R. H., Niinikoski, Harri, Oldehinkel, Albertine J., Pahkala, Katja, Panoutsopoulou, Kalliope, Pedersen, Oluf, Pennell, Craig E., Power, Christine, Reijneveld, Sijmen A., Rivadeneira, Fernando, Simpson, Angela, Sly, Peter D., Stokholm, Jakob, Teo, Kook K., Thiering, Elisabeth, Timpson, Nicholas J., Uitterlinden, Andre G., Van Beijsterveldt, Catharina E. M., Van Schaik, Barbera D. C., Vaudel, Marc, Verduci, Elvira, Vinding, Rebecca K., Vogel, Mandy, Zeggini, Eleftheria, Sebert, Sylvain, Lind, Mads V., Brown, Christopher D., Santa Marina, Loreto, Reischl, Eva, Frithioff-Bojsoe, Christine, Meyre, David, Wheeler, Eleanor, Ong, Ken, Nohr, Ellen A., Vrijkotte, Tanja G. M., Koppelman, Gerard H., Plomin, Robert, Njolstad, Pal R., Dedoussis, George D., Froguel, Philippe, Sorensen, Thorkild I. A., Jacobsson, Bo, Freathy, Rachel M., Zemel, Babette S., Raitakari, Olli, Vrijheid, Martine, Feenstra, Bjarke, Lyytikainen, Leo-Pekka, Snieder, Harold, Kirsten, Holger, Holt, Patrick G., Heinrich, Joachim, Widen, Elisabeth, Sunyer, Jordi, Boomsma, Dorret I., Jarvelin, Marjo-Riitta, Koerner, Antje, Smith, George Davey, Holm, Jens-Christian, Atalay, Mustafa, Murray, Clare, Bisgaard, Hans, McCarthy, Mark I., Jaddoe, Vincent W. V., Grant, Struan F. A., Felix, Janine F., Genética, antropología física y fisiología animal, Genetika,antropologia fisikoa eta animalien fisiologia, Vogelezang, Suzanne, Bradfield, Jonathan P., Ahluwalia, Tarunveer S., Curtin, John A., Lakka, Timo A., Grarup, Niels, Scholz, Markus, Van der Most, Peter J., Monnereau, Claire, Stergiakouli, Evie, Heiskala, Anni, Horikoshi, Momoko, Fedko, Iryna O., Vilor Tejedor, Natalia, Cousminer, Diana L., Standl, Marie, Wang, Carol A., Viikari, Jorma, Geller, Frank, Íñiguez, Carmen, Pitkanen, Niina, Chesi, Alessandra, Bacelis, Jonas, Yengo, Loic, Torrent, Maties, Ntalla, Ioanna, Helgeland, Oyvind, Selzam, Saskia, Vonk, Judith M., Zafarmand, Mohammed H., Heude, Barbara, Farooqi, Ismaa Sadaf, Alyass, Akram, Beaumont, Robin N., Have, Christian T., Rzehak, Peter, Bilbao Catalá, José Ramón, Schnurr, Theresia M., Barroso, Ines, Bonnelykke, Klaus, Beilin, Lawrence J., Carstensen, Lisbeth, Charles, Marie Aline, Chawes, Bo, Clement, Karine, Closa Monasterolo, Ricardo, Custovic, Adnan, Eriksson, Johan G., Escribano, Joaquín, Groen-Blokhuis, Maria, Grote, Veit, Gruszfeld, Dariusz, Hakonarson, Hakon, Hansen, Torben, Hattersley, Andrew T., Hollensted, Mette, Hottenga, Jouke Jan, Hypponen, Elina, Johansson, Stefan, Joro, Raimo, Kahonen, Mika, Karhunen, Ville, Kiess, Wieland, Knight, Bridget A., Koletzko, Berthold, Kuehnapfel, Andreas, Landgraf, Kathrin, Langhendries, Jean-Paul, Lehtimaki, Terho, Leinonen, Jaakko T., Li, Aihuali, Lindi, Virpi, Lowry, Estelle, Bustamante, Mariona, Medina Gómez, Carolina, Melbye, Mads, Michaelsen, Kim F., Morgen, Camilla S., Mori, Trevor A., Nielsen, Tenna R. H., Niinikoski, Harri, Oldehinkel, Albertine J., Pahkala, Katja, Panoutsopoulou, Kalliope, Pedersen, Oluf, Pennell, Craig E., Power, Christine, Reijneveld, Sijmen A., Rivadeneira, Fernando, Simpson, Angela, Sly, Peter D., Stokholm, Jakob, Teo, Kook K., Thiering, Elisabeth, Timpson, Nicholas J., Uitterlinden, Andre G., Van Beijsterveldt, Catharina E. M., Van Schaik, Barbera D. C., Vaudel, Marc, Verduci, Elvira, Vinding, Rebecca K., Vogel, Mandy, Zeggini, Eleftheria, Sebert, Sylvain, Lind, Mads V., Brown, Christopher D., Santa Marina, Loreto, Reischl, Eva, Frithioff-Bojsoe, Christine, Meyre, David, Wheeler, Eleanor, Ong, Ken, Nohr, Ellen A., Vrijkotte, Tanja G. M., Koppelman, Gerard H., Plomin, Robert, Njolstad, Pal R., Dedoussis, George D., Froguel, Philippe, Sorensen, Thorkild I. A., Jacobsson, Bo, Freathy, Rachel M., Zemel, Babette S., Raitakari, Olli, Vrijheid, Martine, Feenstra, Bjarke, Lyytikainen, Leo-Pekka, Snieder, Harold, Kirsten, Holger, Holt, Patrick G., Heinrich, Joachim, Widen, Elisabeth, Sunyer, Jordi, Boomsma, Dorret I., Jarvelin, Marjo-Riitta, Koerner, Antje, Smith, George Davey, Holm, Jens-Christian, Atalay, Mustafa, Murray, Clare, Bisgaard, Hans, McCarthy, Mark I., Jaddoe, Vincent W. V., Grant, Struan F. A., and Felix, Janine F.
- Abstract
The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located nearNEDD4LandSLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (R(g)ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood. Author summary Although twin studies have shown that body mass index (BMI) is highly heritable, many common genetic variants involved in the development of BMI have not yet been identified, especially in children. We studied associations of more than 40 million genetic variants with childhood BMI in 61,111 children aged between 2 and 10 years. We identified 25 genetic variants that were associated with childhood BMI. Two of these have not been implicated for BMI previously, located close to the genesNEDD4LandSLC45A3. We also show that the genetic background of childhood BMI overlaps with that of birth weight, adult BMI, waist-to-hip-ratio, diastolic blood pressure, type 2 diabetes, and age at menarche. O
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- 2020
22. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations
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Pearson, Eawn R., Flechter, Isabelle, Njolstad, Pal R., Malecki, Maciej T., Flanagan, Sarah E., Larkin, Brian, Ashcroft, Frances M., Klimes, Iwar, Shield, Julian, Codner, Ethel, Iotova, Violeta; Slingerland, Annabelle S., Robert, Jean-Jacques; Holst, Jens J., Clark, Penny M.; Ellard, Sian, and Sovik, Oddmund; Polak, Michel; Hattersley, Andrew T.
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Hypoglycemic sulfonylureas -- Care and treatment ,Sulfonylurea compounds -- Care and treatment ,Insulin -- Health aspects ,Blood sugar -- Control - Abstract
The glycemic control in patients with Kir6.2 mutations who received appropriate doses of sulfonylureas are assessed and the mechanism of insulin dependence in patients who are able to switch from insulin to oral sulfonylurea therapy are examined. The results have shown that sulfonylurea therapy is safe in the short term for patients with diabetes caused by KCNJ11 mutations and is probably more effective than insulin therapy.
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- 2006
23. Metabolic outcomes in young children with type 1 diabetes differ between treatment centers: the Hvidoere Study in Young Children 2009*
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de Beaufort, Carine E, Lange, Karin, Swift, Peter GF, Aman, Jan, Cameron, Fergus, Castano, Luis, Dorchy, Harry, Fisher, Lynda K, Hoey, Hilary, Kaprio, Eero, Kocova, Mirjana, Neu, Andreas, Njolstad, Pal R, Phillip, Moshe, Schoenle, Eugen, Robert, Jean J, Urukami, Tatsuhiko, Vanelli, Maurizio, Danne, Thomas, Barrett, Tim, Chiarelli, Franco, Aanstoot, Henk J, and Mortensen, Henrik B
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- 2013
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- View/download PDF
24. Mutations in HNF1A result in marked alterations of plasma glycan profile
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Thanabalasingham, Gaya, Huffman, Jennifer E., Kattla, Jayesh J., Novokmet, Mislav, Rudan, Igor, Gloyn, Anna L., Hayward, Caroline, Adamczyk, Barbara, Reynolds, Rebecca M., Muzinic, Ana, Hassanali, Neelam, Pucic, Maja, Bennett, Amanda J., Essafi, Abdelkader, Polasek, Ozren, Mughal, Saima A., Redzic, Irma, Primorac, Dragan, Zgaga, Lina, Kolcic, Ivana, Hansen, Torben, Gasperikova, Daniela, Tjora, Erling, Strachan, Mark W.J., Nielsen, Trine, Stanik, Juraj, Klimes, Iwar, Pedersen, Oluf B., Njolstad, Pal R., Wild, Sarah H., Gyllensten, Ulf, Gornik, Olga, Wilson, James F., Hastie, Nicholas D., Campbell, Harry, McCarthy, Mark I., Rudd, Pauline M., Owen, Katharine R., Lauc, Gordan, and Wright, Alan F.
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Gene mutations -- Physiological aspects -- Research ,Diabetes -- Risk factors -- Genetic aspects -- Diagnosis -- Research ,Biological markers -- Physiological aspects -- Genetic aspects -- Research ,Health - Abstract
A recent genome-wide association study identified hepatocyte nuclear factor 1-α (HNF1A) as a key regulator of fucosylation. We hypothesized that loss-of-function HNF1A mutations causal for maturity-onset diabetes of the young (MODY) would display altered fucosylation of N-linked glycans on plasma proteins and that glycan biomarkers could improve the efficiency of a diagnosis of HNF1A-MODY. In a pilot comparison of 33 subjects with HNF1A-MODY and 41 subjects with type 2 diabetes, 15 of 29 glycan measurements differed between the two groups. The DG9-glycan index, which is the ratio of fucosylated to nonfucosylated triantennary glycans, provided optimum discrimination in the pilot study and was examined further among additional subjects with HNF1A-MODY (n = 188), glucokinase (GCK)-MODY (n = 118), hepatocyte nuclear factor 4-α (HNF4A)-MODY (n = 40), type 1 diabetes (n = 98), type 2 diabetes (n = 167), and nondiabetic controls (n = 98). The DG9-glycan index was markedly lower in HNF1A-MODY than in controls or other diabetes subtypes, offered good discrimination between HNF1A-MODY and both type 1 and type 2 diabetes (C statistic [greater than or equal to]0.90), and enabled us to detect three previously undetected HNF1A mutations in patients with diabetes. In conclusion, glycan profiles are altered substantially in HNF1A-MODY, and the DG9-glycan index has potential clinical value as a diagnostic biomarker of HNF1A dysfunction., Genome-wide association studies are providing novel insights into the genetic architecture and biological basis of many diseases, but immediate translation into clinical practice has been limited. We recently performed a [...]
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- 2013
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25. FTO, type 2 diabetes, and weight gain throughout adult life: a meta-analysis of 41,504 subjects from the Scandinavian HUNT, MDC, and MPP studies
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Hertel, Jens K., Johansson, Stefan, Sonestedt, Emily, Jonsson, Anna, Lie, Rolv T., Platou, Carl G.P., Nilsson, Peter M., Rukh, Gull, Midthjell, Kristian, Hveem, Kristian, Melander, Olle, Groop, Leif, Lyssenko, Valeriya, Molven, Anders, Orho-Melander, Marju, and Njolstad, Pal R.
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Obesity -- Complications and side effects -- Research ,Fat -- Influence ,Type 2 diabetes -- Risk factors -- Research ,Health - Abstract
OBJECTIVE--FTO is the most important polygene identified for obesity. We aimed to investigate whether a variant in FTO affects type 2 diabetes risk entirely through its effect on BMI and how FTO influences BMI across adult life span. RESEARCH DESIGN AND METHODS--Through regression models, we assessed the relationship between the FTO single nucleotide polymorphisms rs9939609, type 2 diabetes, and BMI across life span in subjects from the Norwegian population-based HUNT study using cross-sectional and longitudinal perspectives. For replication and meta-analysis, we used data from the Malm5 Diet and Cancer (MDC) and Malm5 Preventive Project (MPP) cohorts, comprising a total sample of 41,504 Scandinavians. RESULTS--The meta-analysis revealed a highly significant association for rs9939609 with both type 2 diabetes (OR 1.13; P = 4.5 x [10.sup.-8) and the risk to develop incident type 2 diabetes (OR 1.16; P = 3.2 x [10.sup.-8]). The associations remained also after correction for BMI and other anthropometric measures. Furthermore, we confirmed the strong effect on BMI (0.28 kg/[m.sup.2] per risk allele; P = 2.0 x [10.sup.-26]), with no heterogeneity between different age-groups. We found no differences in change of BMI over time according to rs9939609 risk alleles, neither overall (ΔBMI = 0.0 [-0.05, 0.05]) nor in any individual age stratum, indicating no further weight gain attributable to FTO genotype in adults. CONCLUSIONS--We have identified that a variant in FTO alters type 2 diabetes risk partly independent of its observed effect on BMI. The additional weight gain as a result of the FTO risk variant seems to occur before adulthood, and the BMI difference remains stable thereafter. Diabetes 60:1637-1644, 2011, Genomewide association studies (GWAS) have identified a strong correlation between BMI and FTO single nucleotide polymorphisms (SNPs) (1-4), and the association has been confirmed in multiple populations (reviewed in 5). [...]
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- 2011
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26. A CLEC16A variant confers risk of juvenile idiopathic arthritis and anti-cyclic citrullinated peptide antibody negative rheumatoid arthritis
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Skinningsrud, Beate, Lie, Benedicte A., Husebye, Eystein S., Kvien, Tore K., Forre, Oystein, Flato, Berit, Stormyr, Alice, Joner, Geir, Njolstad, Pal R., Egeland, Thore, and Undlien, Dag E.
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Genetic variation -- Research ,Lectins -- Genetic aspects ,Lectins -- Research ,Rheumatoid arthritis in children -- Genetic aspects ,Rheumatoid arthritis in children -- Risk factors ,Rheumatoid arthritis in children -- Research ,Health - Published
- 2010
27. Polygenic risk variants for type 2 diabetes susceptibility modify age at diagnosis in monogenic HNF1A diabetes
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Allen, Hana Lango, Johansson, Stefan, Ellard, Sian, Shields, Beverley, Hertel, Jens K., Raeder, Helge, Colclough, Kevin, Molven, Anders, Frayling, Timothy M., Njolstad, Pal R., Hattersley, Andrew T., and Weedon, Michael N.
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Liver cells -- Physiological aspects -- Research ,Type 2 diabetes -- Diagnosis -- Genetic aspects ,Hyperglycemia -- Diagnosis -- Genetic aspects ,Health - Abstract
OBJECTIVE--Mutations in the HNF1A gene are the most common cause of maturity-onset diabetes of the young (MODY). There is a substantial variation in the age at diabetes diagnosis, even within families where diabetes is caused by the same mutation. We investigated the hypothesis that common polygenic variants that predispose to type 2 diabetes might account for the difference in age at diagnosis. RESEARCH DESIGN AND METHODS--Fifteen robustly associated type 2 diabetes variants were successfully genotyped in 410 individuals from 203 HNF1A-MODY families, from two study centers in the U.K. and Norway. We assessed their effect on the age at diagnosis both individually and in a combined genetic score by summing the number of type 2 diabetes risk alleles carried by each patient. RESULTS--We confirmed the effects of environmental and genetic factors known to modify the age at HNF1A-MODY diagnosis, namely intrauterine hyperglycemia (-5.1 years ff present, P = 1.6 x [10.sup.-10]) and HNF1A mutation position (-5.2 years if at least two isoforms affected, P = 1.8 x [10.sup.-2]). Additionally, our data showed strong effects of sex (females diagnosed 3.0 years earlier, P = 6.0 x [10.sup.-4]) and age at study (0.3 years later diagnosis per year increase in age, P = 4.7 x [10.sup.-38]). There were no strong individual single nucleotide polymorphism effects; however, in the combined genetic score model, each additional risk allele was associated with 0.35 years earlier diabetes diagnosis (P = 5.1 x [10.sup.-3]). CONCLUSIONS--We show that type 2 diabetes risk variants of modest effect sizes reduce the age at diagnosis in HNF1A-MODY. This is one of the first studies to demonstrate that clinical characteristics of a monogenic disease can be modified by common polygenic variants., Maturity-onset diabetes of the young (MODY) is a young-onset, dominantly inherited noninsulin-dependent diabetes resulting from β-cell dysfunction (1). There are at least eight genetic subgroups of MODY (1,2), with most [...]
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- 2010
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28. A comprehensive screen for TWIST (ital) mutations in patients with craniosynostosis identifies a new microdeletion syndrome of chromosome band 7-21.1
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Johnson, David, Horsley, Sharon W., Moloney, Dominique M., Oldridge, Michael, Twigg, Stephen R.F., Walsh, Sinead, Barrow, Margaret, Njolstad, Pal R., Kunz, Jurgen, Ashworth, Geraldine J., Wall, Steven A., Kearney, Lyndal, and Wilkie, Andrew O.M.
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Genetic disorders -- Research ,Craniofacial dysostosis -- Genetic aspects ,Mental retardation -- Diagnosis ,Chromosome deletion -- Physiological aspects ,Chromosome mapping -- Usage ,Biological sciences - Abstract
Identification of a new microdeletion syndrome of chromosome band 7-21.1 by use of a comprehensive screen for TWIST (ital) mutations in patients with craniosynostosis is discussed. A significant fraction of the cases of Saethre-Chotzen syndrome are the result of the microdeletion, and it seems that haploinsufficiency of genes close to TWIST (ital) contributes to developmental problems.
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- 1998
29. The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia
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Middeldorp, Christel M., Mahajan, Anubha, Horikoshi, Momoko, Robertson, Neil R., Beaumont, Robin N., Bradfield, Jonathan P., Bustamante, Mariona, Cousminer, Diana L., Day, Felix R., De Silva, N. Maneka, Guxens, Monica, Mook-Kanamori, Dennis O., St Pourcain, Beate, Warrington, Nicole M., Adair, Linda S., Ahlqvist, Emma, Ahluwalia, Tarunveer Singh, Almgren, Peter, Ang, Wei, Atalay, Mustafa, Auvinen, Juha, Bartels, Meike, Beckmann, Jacques S., Bilbao, Jose Ramon, Bond, Tom, Borja, Judith B., Cavadino, Alana, Charoen, Pimphen, Chen, Zhanghua, Coin, Lachlan, Cooper, Cyrus, Curtin, John A., Custovic, Adnan, Das, Shikta, Davies, Gareth E., Dedoussis, George V., Duijts, Liesbeth, Eastwood, Peter R., Eliasen, Anders U., Elliott, Paul, Eriksson, Johan G., Estivill, Xavier, Fadista, Joao, Fedko, Iryna O., Frayling, Timothy M., Gaillard, Romy, Gauderman, W. James, Geller, Frank, Gilliland, Frank, Gilsanz, Vincente, Granell, Raquel, Grarup, Niels, Groop, Leif, Hadley, Dexter, Hakonarson, Hakon, Hansen, Torben, Hartman, Catharina A., Hattersley, Andrew T., Hayes, M. Geoffrey, Hebebrand, Johannes, Heinrich, Joachim, Helgeland, Oyvind, Henders, Anjali K., Henderson, John, Henriksen, Tine B., Hirschhorn, Joel N., Hivert, Marie-France, Hocher, Berthold, Holloway, John W., Holt, Patrick, Hottenga, Jouke-Jan, Hypponen, Elina, Iniguez, Carmen, Johansson, Stefan, Jugessur, Astanand, Kahonen, Mika, Kalkwarf, Heidi J., Kaprio, Jaakko, Karhunen, Ville, Kemp, John P., Kerkhof, Marjan, Koppelman, Gerard H., Korner, Antje, Kotecha, Sailesh, Kreiner-Moller, Eskil, Kulohoma, Benard, Kumar, Ashish, Kutalik, Zoltan, Lahti, Jari, Lappe, Joan M., Larsson, Henrik, Lehtimaki, Terho, Lewin, Alexandra M., Li, Jin, Lichtenstein, Paul, Lindgren, Cecilia M., Lindi, Virpi, Linneberg, Allan, Liu, Xueping, Liu, Jun, Lowe, William L., Lundstrom, Sebastian, Lyytikainen, Leo-Pekka, Ma, Ronald C. W., Mace, Aurelien, Magi, Reedik, Magnus, Per, Mamun, Abdullah A., Mannikko, Minna, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Nina S., Medland, Sarah E., Melbye, Mads, Melen, Erik, Mohlke, Karen L., Monnereau, Claire, Morgen, Camilla S., Morris, Andrew P., Murray, Jeffrey C., Myhre, Ronny, Najman, Jackob M., Nivard, Michel G., Nohr, Ellen A., Nolte, Ilja M., Ntalla, Ioanna, Oberfield, Sharon E., Oken, Emily, Oldehinkel, Albertine J., Pahkala, Katja, Palviainen, Teemu, Panoutsopoulou, Kalliope, Pedersen, Oluf, Pennell, Craig E., Pershagen, Goran, Pitkanen, Niina, Plomin, Robert, Power, Christine, Prasad, Rashmi B., Prokopenko, Inga, Pulkkinen, Lea, Raikkonen, Katri, Raitakari, Olli T., Reynolds, Rebecca M., Richmond, Rebecca C., Rivadeneira, Fernando, Rodriguez, Alina, Rose, Richard J., Salem, Rany, Santa-Marina, Loreto, Saw, Seang-Mei, Schnurr, Theresia M., Scott, James G., Selzam, Saskia, Shepherd, John A., Simpson, Angela, Skotte, Line, Sleiman, Patrick M. A., Snieder, Harold, Sorensen, Thorkild I. A., Standl, Marie, Steegers, Eric A. P., Strachan, David P., Straker, Leon, Strandberg, Timo, Taylor, Michelle, Teo, Yik-Ying, Thiering, Elisabeth, Torrent, Maties, Tyrrell, Jessica, Uitterlinden, Andre G., van Beijsterveldt, Toos, van der Most, Peter J., van Duijn, Cornelia M., Viikari, Jorma, Vilor-Tejedor, Natalia, Vogelezang, Suzanne, Vonk, Judith M., Vrijkotte, Tanja G. M., Vuoksimaa, Eero, Wang, Carol A., Watkins, William J., Wichmann, H-Erich, Willemsen, Gonneke, Williams, Gail M., Wilson, James F., Wray, Naomi R., Xu, Shujing, Xu, Cheng-Jian, Yaghootkar, Hanieh, Yi, Lu, Zafarmand, Mohammad Hadi, Zeggini, Eleftheria, Zemel, Babette S., Hinney, Anke, Lakka, Timo A., Whitehouse, Andrew J. O., Sunyer, Jordi, Widen, Elisabeth E., Feenstra, Bjarke, Sebert, Sylvain, Jacobsson, Bo, Njolstad, Pal R., Stoltenberg, Camilla, Smith, George Davey, Lawlor, Debbie A., Paternoster, Lavinia, Timpson, Nicholas J., Ong, Ken K., Bisgaard, Hans, Bonnelykke, Klaus, Jaddoe, Vincent W. V., Tiemeier, Henning, Jarvelin, Marjo-Riitta, Evans, David M., Perry, John R. B., Grant, Struan F. A., Boomsma, Dorret I., Freathy, Rachel M., McCarthy, Mark I., and Felix, Janine F.
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ddc:570 ,Institut für Biochemie und Biologie - Abstract
The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.
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- 2019
30. The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia : design, results and future prospects
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Middeldorp, Christel M., Mahajan, Anubha, Horikoshi, Momoko, Robertson, Neil R., Beaumont, Robin N., Bradfield, Jonathan P., Bustamante, Mariona, Cousminer, Diana L., Day, Felix R., De Silva, N. Maneka, Guxens, Monica, Mook-Kanamori, Dennis O., St Pourcain, Beate, Warrington, Nicole M., Adair, Linda S., Ahlqvist, Emma, Ahluwalia, Tarunveer S., Almgren, Peter, Ang, Wei, Atalay, Mustafa, Auvinen, Juha, Bartels, Meike, Beckmann, Jacques S., Bilbao, Jose Ramon, Bond, Tom, Borja, Judith B., Cavadino, Alana, Charoen, Pimphen, Chen, Zhanghua, Coin, Lachlan, Cooper, Cyrus, Curtin, John A., Custovic, Adnan, Das, Shikta, Davies, Gareth E., Dedoussis, George V., Duijts, Liesbeth, Eastwood, Peter R., Eliasen, Anders U., Elliott, Paul, Eriksson, Johan G., Estivill, Xavier, Fadista, Joao, Fedko, Iryna O., Frayling, Timothy M., Gaillard, Romy, Gauderman, W. James, Geller, Frank, Gilliland, Frank, Gilsanz, Vincente, Granell, Raquel, Grarup, Niels, Groop, Leif, Hadley, Dexter, Hakonarson, Hakon, Hansen, Torben, Hartman, Catharina A., Hattersley, Andrew T., Hayes, M. Geoffrey, Hebebrand, Johannes, Heinrich, Joachim, Helgeland, Oyvind, Henders, Anjali K., Henderson, John, Henriksen, Tine B., Hirschhorn, Joel N., Hivert, Marie-France, Hocher, Berthold, Holloway, John W., Holt, Patrick, Hottenga, Jouke-Jan, Hypponen, Elina, Iniguez, Carmen, Johansson, Stefan, Jugessur, Astanand, Kahonen, Mika, Kalkwarf, Heidi J., Kaprio, Jaakko, Karhunen, Ville, Kemp, John P., Kerkhof, Marjan, Koppelman, Gerard H., Korner, Antje, Kotecha, Sailesh, Kreiner-Moller, Eskil, Kulohoma, Benard, Kumar, Ashish, Kutalik, Zoltan, Lahti, Jari, Lappe, Joan M., Larsson, Henrik, Lehtimaki, Terho, Lewin, Alexandra M., Li, Jin, Lichtenstein, Paul, Lindgren, Cecilia M., Lindi, Virpi, Linneberg, Allan, Liu, Xueping, Liu, Jun, Lowe, William L., Jr., Lundstrom, Sebastian, Lyytikainen, Leo-Pekka, Ma, Ronald C. W., Mace, Aurelien, Magi, Reedik, Magnus, Per, Mamun, Abdullah A., Mannikko, Minna, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Nina S., Medland, Sarah E., Melbye, Mads, Melen, Erik, Mohlke, Karen L., Monnereau, Claire, Morgen, Camilla S., Morris, Andrew P., Murray, Jeffrey C., Myhre, Ronny, Najman, Jackob M., Nivard, Michel G., Nohr, Ellen A., Nolte, Ilja M., Ntalla, Ioanna, O'Reilly, Paul, Oberfield, Sharon E., Oken, Emily, Oldehinkel, Albertine J., Pahkala, Katja, Palviainen, Teemu, Panoutsopoulou, Kalliope, Pedersen, Oluf, Pennell, Craig E., Pershagen, Goran, Pitkanen, Niina, Plomin, Robert, Power, Christine, Prasad, Rashmi B., Prokopenko, Inga, Pulkkinen, Lea, Raikkonen, Katri, Raitakari, Olli T., Reynolds, Rebecca M., Richmond, Rebecca C., Rivadeneira, Fernando, Rodriguez, Alina, Rose, Richard J., Salem, Rany, Santa-Marina, Loreto, Saw, Seang-Mei, Schnurr, Theresia M., Scott, James G., Selzam, Saskia, Shepherd, John A., Simpson, Angela, Skotte, Line, Sleiman, Patrick M. A., Snieder, Harold, Sørensen, Thorkild I. A., Standl, Marie, Steegers, Eric A. P., Strachan, David P., Straker, Leon, Strandberg, Timo, Taylor, Michelle, Teo, Yik-Ying, Thiering, Elisabeth, Torrent, Maties, Tyrrell, Jessica, Uitterlinden, Andre G., van Beijsterveldt, Toos, van der Most, Peter J., van Duijn, Cornelia M., Viikari, Jorma, Vilor-Tejedor, Natalia, Vogelezang, Suzanne, Vonk, Judith M., Vrijkotte, Tanja G. M., Vuoksimaa, Eero, Wang, Carol A., Watkins, William J., Wichmann, H-Erich, Willemsen, Gonneke, Williams, Gail M., Wilson, James F., Wray, Naomi R., Xu, Shujing, Xu, Cheng-Jian, Yaghootkar, Hanieh, Yi, Lu, Zafarmand, Mohammad Hadi, Zeggini, Eleftheria, Zemel, Babette S., Hinney, Anke, Lakka, Timo A., Whitehouse, Andrew J. O., Sunyer, Jordi, Widen, Elisabeth E., Feenstra, Bjarke, Sebert, Sylvain, Jacobsson, Bo, Njolstad, Pal R., Stoltenberg, Camilla, Smith, George Davey, Lawlor, Debbie A., Paternoster, Lavinia, Timpson, Nicholas J., Ong, Ken K., Bisgaard, Hans, Bonnelykke, Klaus, Jaddoe, Vincent W. V., Tiemeier, Henning, Jarvelin, Marjo-Riitta, Evans, David M., Perry, John R. B., Grant, Struan F. A., Boomsma, Dorret I., Freathy, Rachel M., McCarthy, Mark I., Felix, Janine F., Sorensen, Thorkild I. A., Tiemeier, Hen-Ning, Biological Psychology, APH - Mental Health, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Methodology, APH - Health Behaviors & Chronic Diseases, Pediatrics, Epidemiology, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Groningen Research Institute for Asthma and COPD (GRIAC), Life Course Epidemiology (LCE), Public and occupational health, APH - Aging & Later Life, ARD - Amsterdam Reproduction and Development, ACS - Atherosclerosis & ischemic syndromes, APH - Global Health, Epidemiology and Data Science, Medical Research Council (MRC), Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Centre of Excellence in Complex Disease Genetics, Institute for Molecular Medicine Finland, University of Helsinki, Department of Public Health, Clinicum, Doctoral Programme in Cognition, Learning, Instruction and Communication, Department of Psychology and Logopedics, Helsinki Collegium for Advanced Studies, Faculty of Medicine, Timo Strandberg / Principal Investigator, Department of Medicine, Elisabeth Ingrid Maria Widen / Principal Investigator, HUS Internal Medicine and Rehabilitation, HUS Abdominal Center, Developmental Psychology Research Group, Genetic Epidemiology, Genomic Discoveries and Clinical Translation, Cognitive and Brain Aging, Middeldorp, Christel M [0000-0002-6218-0428], and Apollo - University of Cambridge Repository
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Male ,Netherlands Twin Register (NTR) ,embarazo ,Epidemiology ,C840 Clinical Psychology ,LD SCORE REGRESSION ,humanos ,LOCI ,Medizin ,adolescente ,Genome-wide association study ,BLOOD-PRESSURE ,Disease ,030204 cardiovascular system & hematology ,Cohort Studies ,0302 clinical medicine ,Pregnancy ,Medicine ,030212 general & internal medicine ,Early childhood ,C820 Developmental Psychology ,estudios de cohortes ,Child ,C440 Molecular Genetics ,Public, Environmental & Occupational Health ,Genetics ,education.field_of_study ,United Kingdom/epidemiology ,COMMON VARIANTS ,Hälsovetenskaper ,adulto ,A900 Others in Medicine and Dentistry ,3142 Public health care science, environmental and occupational health ,3. Good health ,predicción ,ddc ,Childhood traits and disorders ,Phenotype ,Disease/genetics ,Research Design ,Child, Preschool ,fenotipo ,Female ,ICEP ,medicine.symptom ,CHILDHOOD OBESITY ,Life Sciences & Biomedicine ,EArly Genetics Lifecourse Epidemiology (EAGLE) consortium ,Adult ,medicine.medical_specialty ,Adolescent ,Birth weight ,Population ,Consortium ,Childhood Traits And Disorders ,Longitudinal ,enfermedad ,Childhood obesity ,1117 Public Health and Health Services ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,Health Sciences ,Humans ,Genetic Predisposition to Disease ,GENOME-WIDE ASSOCIATION ,education ,LONGITUDINAL TWIN ,METAANALYSIS ,lactante ,Science & Technology ,Early Growth Genetics (EGG) consortium ,business.industry ,Infant, Newborn ,Infant ,predisposición genética a la enfermedad ,medicine.disease ,BODY-MASS ,C800 Psychology ,BIRTH-WEIGHT ,C420 Human Genetics ,United Kingdom ,Low birth weight ,business ,diseño de la investigación ,Forecasting - Abstract
The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites., We are grateful to all families and participants who took part in these studies. We also acknowledge and appreciate the unique efforts of the research teams and practitioners contributing to the collection of this wealth of data. C. M. M. is supported by funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement no. 721567. J. F. F. has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 633595 (DynaHEALTH) and 733206 (LifeCycle). R. M. F. and R. N. B. are supported by Sir Henry Dale Fellowship (Wellcome Trust and Royal Society grant: WT104150). D. L. C. is funded by the American Diabetes Association Grant 1-17-PDF-077. D. O. M-K. was supported by Dutch Science Organization (ZonMW-VENI Grant 916.14.023). N. M. W. is supported by an Australian National Health and Medical Research Council Early Career Fellowship (APP1104818). T. S. A. was partially funded by the Gene-Diet Interactions in Obesity (GENDINOB) project on behalf of GOYA male cohort data management and analyses and acknowledges the same. S. D. was supported by National Institute of Health Research. T. M. F. is supported by the European Research Council grant: 323195 SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku.dk).H.H.is funded by The Children's Hospital of Philadelphia Endowed Chair in Genomic Research. A. T. H. is supported by the Wellcome Trust Senior Investigator Awards (WT098395), National Institute for Health Research (NIHR) Senior Investigator Award (NF-SI-0611-10219). J. Hebebrand received grants from German Research Society, German Ministry of Education and Research. M-F. H. is currently supported by an American Diabetes Association (ADA) Pathway Program Accelerator Early Investigator Award (1-15-ACE-26). S. J. is supported by Helse Vest no. 23929, Bergen Forskningsstiftelse and KG Jebsen Foundation and University of Bergen. J. K. has been supported by the Academy of Finland Research Professor program (grants 265240 & 263278). J. P. K. is funded by a University of Queensland Development Fellowship (UQFEL1718945). H. L. has served as a speaker for Eli-Lilly and Shire and has received research grants from Shire; all outside the submitted work. C. M. L is supported by the Li Ka Shing Foundation, WT-SSI/John Fell funds and by the NIHR Biomedical Research Centre, Oxford, by Widenlife and NIH (5P50HD028138-27). S. E. M. was funded by an NHMRC Senior Reseach Fellowship (APP1103623). K. Panoutsopoulou is funded by a career development fellowship (grant 20308) and by the Wellcome Trust (WT098051). C. P. at UCL Institute of Child Health, with support from the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. I. P. was funded in part by the Wellcome Trust (WT205915), and the European Union's Horizon 2020 research, the European Union FP7-IDEAS-ERC Advanced Grant (GEPIDIAB, ERC-AG -ERC-294785), and innovation programme (DYNAhealth, H2020-PHC-2014-633595). R. C. R. is supported by CRUK (grant number C18281/A19169). J. G. S. is supported by an NHMRC Practitioner Fellowship Grant (APP1105807). J. T.; r is funded by the European Regional Development Fund (ERDF), the European Social Fund (ESF), Convergence Programme for Cornwall and the Isles of Scilly and the Diabetes Research and Wellness Foundation Non-Clinical Fellowship. N. V-T. is funded by a pre-doctoral grant from the Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR) (2015 FI_B 00636), Generalitat de Catalunya. T. G. M. V was supported by ZonMW (TOP 40-00812-98-11010. J. F. W. is supported by the MRC Human Genetics Unit quinquennial programme QTL in Health and Disease. H. Y. is funded by Diabetes UK RD Lawrence fellowship (grant: 17/0005594). M. H. Z was supported by BBMRI-NL (CP2013-50). E. Z. is supported by the Wellcome Trust (098051). B. F. is supported by Novo Nordisk Foundation (12955) and an Oak Foundation Fellowship. S. S. and M-R. J. have received funding from the European Union's Horizon 2020 research and innovation programme [under grant agreement No 633595] for the DynaHEALTH action. P. R. N. was supported by the European Research Council (ERC), University of Bergen, KG Jebsen and Helse Vest. G. D. S. works within the MRC Integrative Epidemiology Unit at the University of Bristol (MC_UU_12013/1). D. A. L was supported by the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement (Grant number 669545; DevelopObese), US National Institute of Health (grant: R01 DK10324), the UK Medical Research Council (grant: MC_UU_00011/6), Wellcome Trust GWAS grant (WT088806), an NIHR Senior Investigator Award (NF-SI-0611-10196) and the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. L. Paternoster was supported by the UK Medical Research Council Unit grants MC_UU_12013_5. N. J. T. is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 102215/2/13/2), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC) and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A19169). V.W.V.J. received an additional grant from the Netherlands Organization for Health Research and Development (NWO, ZonMw-VIDI 016.136.361), a European Research Council Consolidator Grant (ERC-2014-CoG-648916) and funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 633595 (DynaHEALTH) and 733206 (LifeCycle). D. M. E. is funded by the UK Medical Research Council Unit grant MC_UU_12013_4, Australian Research Council Future Fellowship (FT130101709) and a NHMRC Senior Research Fellowship (GNT1137714). S. F. A. G. is funded by the Daniel B. Burke Endowed Chair for Diabetes Research and R01 HD056465. D. I. B. is supported by Spinozapremie (NWO-56-464-14192) and the Royal Netherlands Academy of Science Professor Award (PAH/6635) to DIB. M. I. M. is a Wellcome Senior Investgator and NIHR Senior Investigator supported by the Wellcome (090532, 098381, 203141), NIHR (NF-SI-0617-10090) and the US National Institute of Health (grant: R01 DK10324), the UK Medical Research Council (grant: MCiabetes UK RD Lawrence fellowship (grant: 17/0005594). M. H. Z was supported by BBMRI-NLNIHR Biomedical Research Centre, Oxford. The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.
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- 2019
31. The diabetic phenotype in HNF4A mutation carriers is moderated by the expression of HNF4A isoforms from the P1 promoter during fetal development
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Harries, Lorna W., Locke, Jonathan M., Shields, Beverley, Hanley, Neil A., Hanley, Karen Piper, Steele, Anna, Njolstad, Pal R., Ellard, Sian, and Hattersley, Andrew T.
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Fetus -- Growth ,Promoters (Genetics) -- Physiological aspects -- Research -- Genetic aspects ,Diabetes -- Genetic aspects -- Risk factors -- Research ,Transcription factors -- Genetic aspects -- Research -- Physiological aspects ,Health - Abstract
OBJECTIVE--Mutations in the alternatively spliced HNF4A gene cause maturity-onset diabetes of the young (MODY). We characterized the spatial and developmental expression patterns of HNF4A transcripts in human tissues and investigated their role as potential moderators of the MODY phenotype. RESEARCH DESIGN AND METHODS--We measured the expression of HNF4A isoforms in human adult tissues and gestationally staged fetal pancreas by isoform-specific real-time PCR. The correlation between mutation position and age of diagnosis or age-related penetrance was assessed in a cohort of 190 patients with HNF4A mutations. RESULTS--HNF4A was expressed exclusively from the P2 promoter in adult pancreas, but from 9 weeks until at least 26 weeks after conception, up to 23% of expression in fetal pancreas was of P1 origin. HNF4A4- 6 transcripts were not detected in any tissue. In whole pancreas, HNF4A9 expression was greater than in islets isolated from the endocrine pancreas (relative level 22 vs. 7%). Patients with mutations in exons 9 and 10 (absent from HNF4A3, HNF4A6, and HNF4A9 isoforms) developed diabetes later than those with mutations in exons 2-8, where all isoforms were affected (40 vs. 24 years; P = 0.029). Exon 9/10 mutations were also associated with a reduced age-related penetrance (53 vs. 10% without diabetes at age 55 years; P < 0.00001). CONCLUSIONS--We conclude that isoforms derived from the HNF4A P1 promoter are expressed in human fetal, but not adult, pancreas, and that their presence during pancreatic development may moderate the diabetic phenotype in individuals with mutations in the HNF4A gene., The HNF4A gene codes for hepatocyte nuclear factor (HNF)-4α, which has an important role in pancreatic development and maintenance of β-cell function (1). P2 promoter region variants are associated with [...]
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- 2008
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32. Pancreatic exocrine dysfunction in maturity-onset diabetes of the young type 3
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Vesterhus, Mette, Raeder, Helge, Johansson, Stefan, Molven, Anders, and Njolstad, Pal R.
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Diabetes -- Complications and side effects -- Risk factors ,Pancreatic diseases -- Risk factors -- Complications and side effects ,Health ,Complications and side effects ,Risk factors - Abstract
OBJECTIVE--Exocrine pancreas dysfunction is seen in 10-30% of patients with type 1 and 2 diabetes. We have recently identified a syndrome of diabetes and exocrine pancreas dysfunction attributable to mutations [...]
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- 2008
33. Continuing stability of center differences in pediatric diabetes care: do advances in diabetes treatment improve outcome? The Hvidoere Study Group on Childhood Diabetes
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De Beaufort, Carine E., Swift, Peter G.F., Skinner, Chas T., Aanstoot, Henk J., Aman, Jan, Cameron, Fergus, Martul, Pedro, Chiarelli, Francesco, Daneman, Dennis, Danne, Thomas, Dorchy, Harry, Hoey, Hilary, Kaprio, Eero A., Kaufman, Francine, Kocova, Mirjana, Mortensen, Henrik B., Njolstad, Pal R., Phillip, Moshe, Robertson, Kenneth J., Schoenle, Eugen J., Urakami, Tatsuhiko, and Vanelli, Maurizio
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Diabetes -- Risk factors -- Patient outcomes ,Children -- Health aspects ,Health ,Risk factors ,Patient outcomes - Abstract
OBJECTIVE--To reevaluate the persistence and stability of previously observed differences between pediatric diabetes centers and to investigate the influence of demography, language communication problems, and changes in insulin regimens on [...]
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- 2007
34. Pancreas Lipomatosis Is an Early Structural Marker of Exocrine Pancreatic Deficiency in Non-Diabetic Children with Mutations in the Carboxyl-Ester Lipase Gene: 1118-P
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RAEDER, HELGE, HALDORSEN, INGFRTD S., ERSLAND, LARS, GRUNER, RENATE, MOLVEN, ANDERS, TAXT, TORFINN, and NJOLSTAD, PAL R.
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- 2006
35. Therapeutic Study in a Family with a Novel Diabetes Syndrome with Exocrine Insufficiency: 1128-P
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VESTERHUS, METTE, RADER, HELGE, BINDOFF, LAURENCE, MOLVEN, ANDERS, BERSTAD, ARNOLD, and NJOLSTAD, PAL R.
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- 2006
36. Diabetes, Pancreatic Exocrine Dysfunction and Sequence Variations in the Carboxyl-Ester Lipase Gene: 1114-P
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NJOLSTAD, PAL R., JOHANSSON, STEFAN, RAEDER, HELGE, VESTERHUS, METTE, HALDORSEN, INGFRID S., JONER, GEIR, UNDLIEN, DAG E., EK, JAKOB, JOHANSEN, ANDERS, PEDEREN, OLUF B., HANSEN, TORBEN, VTK, ODDMUND SO, AKSNES, LAGE, and MOLVEN, ANDERS
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- 2006
37. Spatiotemporal trends and age-period-cohort modeling of the incidence of type 1 diabetes among children aged <15 years in Norway 1973-1982 and 1989-2003
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Aamodt, Geir, Stene, Lars C., Njolstad, Pal R., Sovik, Oddmund, and Joner, Geir
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Type 1 diabetes -- Risk factors -- Diagnosis -- Care and treatment ,Children -- Health aspects ,Health ,Diagnosis ,Care and treatment ,Risk factors - Abstract
OBJECTIVE--We have investigated age-period-cohort effects and spatial and temporal trends for the incidence of type 1 diabetes among 0- to 14-year-old children in Norway. RESEARCH DESIGN AND METHODS--We included children [...]
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- 2007
38. Pancreatic lipomatosis is a structural marker in nondiabetic children with mutations in carboxyl-ester lipase
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Raeder, Helge, Haldorsen, Ingfrid S., Ersland, Lars, Gruner, Renate, Taxt, Torfinn, Sovik, Oddmund, Molven, Anders, and Njolstad, Pal R.
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Gene mutations -- Research -- Genetic aspects ,Diabetes -- Genetic aspects -- Care and treatment -- Research ,Pancreatic beta cells -- Research ,Health ,Care and treatment ,Genetic aspects ,Research - Abstract
Both pancreatic volume reduction and lipomatosis have been observed in subjects with diabetes. The underlying molecular and pathological mechanisms are, however, poorly known, and it has been speculated that both features are secondary to diabetes. We have recently described pancreatic atrophy and lipomatosis in diabetic subjects of two Norwegian families with a novel syndrome of diabetes and exocrine pancreatic dysfunction caused by heterozygous carboxyl-ester lipase (CEL) mutations. To explore the early pathological events in this syndrome, we performed radiological examinations of the pancreas in nondiabetic mutation carriers with signs of exocrine dysfunction. In a case series study at a tertiary hospital, we evaluated 11 nondiabetic and mutation-positive children with fecal elastase deficiency and 11 age- and sex-matched control subjects using ultrasound and magnetic resonance imaging (MRI) to estimate pancreatic fat content. The pancreata of nondiabetic mutation carriers exhibited increased reflectivity on ultrasound and had MRI findings indicative of lipomatosis. Apparently, carriers of heterozygous CEL mutations accumulate fat in their pancreas before the anticipated development of diabetes. Our findings suggest that lipomatosis of the pancreas reflects early events involved in the pathogenesis of diabetes and exocrine pancreatic dysfunction syndrome. Diabetes 56: 444-449, 2007, The pancreas consists of acinar and ductal cells with the islets of Langerhans scattered within the exocrine tissue. β-Cells, which are central in the development of diabetes, constitute the major [...]
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- 2007
39. A hepatocyte nuclear factor-4α gene (HNF4A) P2 promoter haplotype linked with late-onset diabetes: studies of HNF4A variants in the Norwegian MODY registry
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Raeder, Helge, Bjorkhaug, Lise, Johansson, Stefan, Mangseth, Kjersti, Sagen, Jorn V., Hunting, Anne, Folling, Ivar, Johansen, Odd, Bjorgaas, Marit, Paus, Povel N., Sovik, Oddmund, Molven, Anders, and Njolstad, Pal R.
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Liver cells -- Research ,Nucleotide sequence -- Research ,Health ,Research - Abstract
Variants in hepatocyte nuclear factor (HNF)-4α cause maturity-onset diabetes of the young, type 1 (MODY1) and may also be risk factors for type 2 diabetes. We sequenced the HNF4A gene of 95 MODY3-negative probands from the Norwegian MODY Registry. We found three novel coding variants in exon 8 of HNF4A: G326R, T339I, and W340X. In intron 7, we noted a single nucleotide polymorphism in the binding site of a previously published primer pair, which in some cases caused allelic drop out when amplifying exon 8. We also detected two novel sequence variants of the P2 promoter region, of which P2 -192C>G showed linkage with diabetes in two families (maximal logarithm of odds score of 3.1 and 0.8, respectively). This variant and a surrounding haplotype restricted by 3.7 Mb was also found in two Danish MODY pedigrees. The age of onset was higher in the P2 -192C>G carriers (median 45 years) compared with that reported for other MODY1 individuals. We could not support a biological role of the P2 promoter variant by in vitro transfection assays. In conclusion, we have identified three novel HNF4A mutations and a 3.7-Mb haplotype, including the HNF4A P2 promoter, which was linked with diabetes. Diabetes 55:1899-1903, 2006, Maturity-onset diabetes of the young (MODY) can result from disease-causing sequence variants in any of at least six different genes that encode the glycolytic enzyme glucokinase (GCK) and five transcription [...]
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- 2006
40. Functional effects of mutations at F35 in the N[H.sub.2]-terminus of Kir6.2 (KCNJ11), causing neonatal diabetes, and response to sulfonylurea therapy
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Proks, Peter, Girard, Christophe, Baevre, Halvor, Njolstad, Pal R., and Ashcroft, Frances M.
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Gene mutations -- Risk factors ,Diabetes in pregnancy -- Causes of -- Risk factors ,Diabetes -- Research ,Health ,Risk factors ,Causes of - Abstract
Heterozygous mutations in the human Kir6.2 gene (KCNJ11), the pore-forming subunit of the ATP-sensitive [K.sup.+] channel ([K.sub.ATP] channel), cause neonatal diabetes. To date, all mutations increase whole-cell [K.sub.ATP] channel currents by reducing channel inhibition by MgATP. Here, we provide functional characterization of two mutations (F35L and F35V) at residue F35 of Kir6.2, which lies within the N[H.sub.2]-terminus. We further show that the F35V patient can be successfully transferred from insulin to sulfonylurea therapy. The patient has been off insulin for 24 months and shows improved metabolic control (mean Hb[A.sub.1c] 7.58 before and 6.18% after sulfonylurea treatment; P < 0.007). Wild-type and mutant Kir6.2 were heterologously coexpressed with SUR1 in Xenopus oocytes. Whole-cell [K.sub.ATP] channel currents through homomeric and heterozygous F35V and F35L channels were increased due to a reduced sensitivity to inhibition by MgATP. The mutation also increased the open probability ([P.sub.o]) of homomeric F35 mutant channels in the absence of ATP. These effects on [P.sub.o] and ATP sensitivity were abolished in the absence of SUR1. Our results suggest that mutations at F35 cause permanent neonatal diabetes by affecting [K.sub.ATP] channel gating and thereby, indirectly, ATP inhibition. Heterozygous F35V channels were markedly inhibited by the sulfonylurea tolbutamide, accounting for the efficacy of sulfonylurea therapy in the patient., Heterozygous mutations in KCNJ11 have been shown to be a common cause of neonatal diabetes (1,2). These mutations cause pronounced hyperglycemia, which may be either transient or permanent, and is [...]
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- 2006
41. From clinicogenetic studies of maturity-onset diabetes of the young to unraveling complex mechanisms of glucokinase regulation
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Sagen, Jorn V., Odili, Stella, Bjorkhaug, Lise, Zelent, Dorothy, Buettger, Carol, Kwagh, Jae, Stanley, Charles, Dahl-Jorgensen, Knut, de Beaufort, Carine, Bell, Graeme I., Han, Yi, Grimsby, Joseph, Taub, Rebecca, Molven, Anders, Sovik, Oddmund, Njolstad, Pal R., and Matschinsky, Franz M.
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Diabetes -- Genetic aspects -- Research ,Pancreatic beta cells -- Research ,Health ,Research ,Genetic aspects - Abstract
Glucokinase functions as a glucose sensor in pancreatic β-cells and regulates hepatic glucose metabolism. A total of 83 probands were referred for a diagnostic screening of mutations in the glucokinase (GCK) gene. We found 11 different mutations (V62A, G72R, L146R, A208T, M210K, Y215X, S263P, E339G, R377C, S453L, and IVS5 + 1G>C) in 14 probands. Functional characterization of recombinant glutathionyl S-transferase-G72R glucokinase showed slightly increased activity, whereas S263P and G264S had near-normal activity. The other point mutations were inactivating. S263P showed marked thermal instability, whereas the stability of G72R and G264S differed only slightly from that of wild type. G72R and M210K did not respond to an allosteric glucokinase activator (GKA) or the hepatic glucokinase regulatory protein (GKRP). Mutation analysis of the role of glycine at position 72 by substituting E, F, K, M, S, or Q showed that G is unique since all these mutants had very low or no activity and were refractory to GKRP and GKA. Structural analysis provided plausible explanations for the drug resistance of G72R and M210K. Our study provides further evidence that protein instability in combination with loss of control by a putative endogenous activator and GKRP could be involved in the development of hyperglycemia in maturity-onset diabetes of the young, type 2. Furthermore, based on data obtained on G264S, we propose that other and still unknown mechanisms participate in the regulation of glucokinase., Glucokinase phosphorylates glucose to glucose-6-phosphate in the first step of glycolysis. Owing to its kinetic characteristics, glucokinase is capable of phosphorylating glucose over the physiological range of 3-8 mmol/l. Unique [...]
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- 2006
42. A trans-ancestral meta-analysis of genome-wide association studies reveals loci associated with childhood obesity
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Bradfield, Jonathan P., Vogelezang, Suzanne, Felix, Janine F., Chesi, Alessandra, Helgeland, Oyvind, Horikoshi, Momoko, Karhunen, Ville, Lowry, Estelle, Cousminer, Diana L., Ahluwalia, Tarunveer S., Thiering, Elisabeth, Boh, Eileen Tai-Hui, Zafarmand, Mohammad H., Vilor-Tejedor, Natalia, Wang, Carol A., Joro, Raimo, Chen, Zhanghua, Gauderman, William J., Pitkanen, Niina, Parra, Esteban J., Fernandez-Rhodes, Lindsay, Alyass, Akram, Monnereau, Claire, Curtin, John A., Have, Christian T., McCormack, Shana E., Hollensted, Mette, Frithioff-Bojsoe, Christine, Valladares-Salgado, Adan, Peralta-Romero, Jesus, Teo, Yik-Ying, Standl, Marie, Leinonen, Jaakko T., Holm, Jens-Christian, Peters, Triinu, Vioque, Jesus, Vrijheid, Martine, Simpson, Angela, Custovic, Adnan, Vaudel, Marc, Canouil, Mickael, Lindi, Virpi, Atalay, Mustafa, Kahonen, Mika, Raitakari, Olli T., van Schaik, Barbera D. C., Berkowitz, Robert, I, Cole, Shelley A., Voruganti, V. Saroja, Wang, Yujie, Highland, Heather M., Comuzzie, Anthony G., Butte, Nancy F., Justice, Anne E., Gahagan, Sheila, Blanco, Estela, Lehtimaki, Terho, Lakka, Timo A., Hebebrand, Johannes, Bonnefond, Amelie, Grarup, Niels, Froguel, Philippe, Lyytikainen, Leo-Pekka, Cruz, Miguel, Kobes, Sayuko, Hanson, Robert L., Zemel, Babette S., Hinney, Anke, Teo, Koon K., Meyre, David, North, Kari E., Gilliland, Frank D., Bisgaard, Hans, Bustamante, Mariona, Bønnelykke, Klaus, Pennell, Craig E., Rivadeneira, Fernando, Uitterlinden, Andre G., Baier, Leslie J., Vrijkotte, Tanja G. M., Heinrich, Joachim, Sorensen, Thorkild I. A., Saw, Seang-Mei, Pedersen, Oluf, Hansen, Torben, Eriksson, Johan, Widen, Elisabeth, McCarthy, Mark, I, Njolstad, Pal R., Power, Christine, Hypponen, Elina, Sebert, Sylvain, Brown, Christopher D., Jarvelin, Marjo-Riitta, Timpson, Nicholas J., Johansson, Stefan, Hakonarson, Hakon, Jaddoe, Vincent W. V., Grant, Struan F. A., Bradfield, Jonathan P., Vogelezang, Suzanne, Felix, Janine F., Chesi, Alessandra, Helgeland, Oyvind, Horikoshi, Momoko, Karhunen, Ville, Lowry, Estelle, Cousminer, Diana L., Ahluwalia, Tarunveer S., Thiering, Elisabeth, Boh, Eileen Tai-Hui, Zafarmand, Mohammad H., Vilor-Tejedor, Natalia, Wang, Carol A., Joro, Raimo, Chen, Zhanghua, Gauderman, William J., Pitkanen, Niina, Parra, Esteban J., Fernandez-Rhodes, Lindsay, Alyass, Akram, Monnereau, Claire, Curtin, John A., Have, Christian T., McCormack, Shana E., Hollensted, Mette, Frithioff-Bojsoe, Christine, Valladares-Salgado, Adan, Peralta-Romero, Jesus, Teo, Yik-Ying, Standl, Marie, Leinonen, Jaakko T., Holm, Jens-Christian, Peters, Triinu, Vioque, Jesus, Vrijheid, Martine, Simpson, Angela, Custovic, Adnan, Vaudel, Marc, Canouil, Mickael, Lindi, Virpi, Atalay, Mustafa, Kahonen, Mika, Raitakari, Olli T., van Schaik, Barbera D. C., Berkowitz, Robert, I, Cole, Shelley A., Voruganti, V. Saroja, Wang, Yujie, Highland, Heather M., Comuzzie, Anthony G., Butte, Nancy F., Justice, Anne E., Gahagan, Sheila, Blanco, Estela, Lehtimaki, Terho, Lakka, Timo A., Hebebrand, Johannes, Bonnefond, Amelie, Grarup, Niels, Froguel, Philippe, Lyytikainen, Leo-Pekka, Cruz, Miguel, Kobes, Sayuko, Hanson, Robert L., Zemel, Babette S., Hinney, Anke, Teo, Koon K., Meyre, David, North, Kari E., Gilliland, Frank D., Bisgaard, Hans, Bustamante, Mariona, Bønnelykke, Klaus, Pennell, Craig E., Rivadeneira, Fernando, Uitterlinden, Andre G., Baier, Leslie J., Vrijkotte, Tanja G. M., Heinrich, Joachim, Sorensen, Thorkild I. A., Saw, Seang-Mei, Pedersen, Oluf, Hansen, Torben, Eriksson, Johan, Widen, Elisabeth, McCarthy, Mark, I, Njolstad, Pal R., Power, Christine, Hypponen, Elina, Sebert, Sylvain, Brown, Christopher D., Jarvelin, Marjo-Riitta, Timpson, Nicholas J., Johansson, Stefan, Hakonarson, Hakon, Jaddoe, Vincent W. V., and Grant, Struan F. A.
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- 2019
43. The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia:design, results and future prospects
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Middeldorp, Christel M., Mahajan, Anubha, Horikoshi, Momoko, Robertson, Neil R., Beaumont, Robin N., Bradfield, Jonathan P., Bustamante, Mariona, Cousminer, Diana L., Day, Felix R., De Silva, N. Maneka, Guxens, Monica, Mook-Kanamori, Dennis O., St Pourcain, Beate, Warrington, Nicole M., Adair, Linda S., Ahlqvist, Emma, Ahluwalia, Tarunveer S., Almgren, Peter, Ang, Wei, Atalay, Mustafa, Auvinen, Juha, Bartels, Meike, Beckmann, Jacques S., Bilbao, Jose Ramon, Bond, Tom, Borja, Judith B., Cavadino, Alana, Charoen, Pimphen, Chen, Zhanghua, Coin, Lachlan, Cooper, Cyrus, Curtin, John A., Custovic, Adnan, Das, Shikta, Davies, Gareth E., Dedoussis, George V., Duijts, Liesbeth, Eastwood, Peter R., Eliasen, Anders U., Elliott, Paul, Eriksson, Johan G., Estivill, Xavier, Fadista, Joao, Fedko, Iryna O., Frayling, Timothy M., Gaillard, Romy, Gauderman, W. James, Geller, Frank, Gilliland, Frank, Gilsanz, Vincente, Granell, Raquel, Grarup, Niels, Groop, Leif, Hadley, Dexter, Hakonarson, Hakon, Hansen, Torben, Hartman, Catharina A., Hattersley, Andrew T., Hayes, M. Geoffrey, Hebebrand, Johannes, Heinrich, Joachim, Helgeland, Oyvind, Henders, Anjali K., Henderson, John, Henriksen, Tine B., Hirschhorn, Joel N., Hivert, Marie-France, Hocher, Berthold, Holloway, John W., Holt, Patrick, Hottenga, Jouke-Jan, Hypponen, Elina, Iniguez, Carmen, Johansson, Stefan, Jugessur, Astanand, Kahonen, Mika, Kalkwarf, Heidi J., Kaprio, Jaakko, Karhunen, Ville, Kemp, John P., Kerkhof, Marjan, Koppelman, Gerard H., Korner, Antje, Kotecha, Sailesh, Kreiner-Moller, Eskil, Kulohoma, Benard, Kumar, Ashish, Kutalik, Zoltan, Lahti, Jari, Lappe, Joan M., Larsson, Henrik, Lehtimaki, Terho, Lewin, Alexandra M., Li, Jin, Lichtenstein, Paul, Lindgren, Cecilia M., Lindi, Virpi, Linneberg, Allan, Liu, Xueping, Liu, Jun, Lowe, William L., Jr., Lundstrom, Sebastian, Lyytikainen, Leo-Pekka, Ma, Ronald C. W., Mace, Aurelien, Magi, Reedik, Magnus, Per, Mamun, Abdullah A., Mannikko, Minna, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Nina S., Medland, Sarah E., Melbye, Mads, Melen, Erik, Mohlke, Karen L., Monnereau, Claire, Morgen, Camilla S., Morris, Andrew P., Murray, Jeffrey C., Myhre, Ronny, Najman, Jackob M., Nivard, Michel G., Nohr, Ellen A., Nolte, Ilja M., Ntalla, Ioanna, O'Reilly, Paul, Oberfield, Sharon E., Oken, Emily, Oldehinkel, Albertine J., Pahkala, Katja, Palviainen, Teemu, Panoutsopoulou, Kalliope, Pedersen, Oluf, Pennell, Craig E., Pershagen, Goran, Pitkanen, Niina, Plomin, Robert, Power, Christine, Prasad, Rashmi B., Prokopenko, Inga, Pulkkinen, Lea, Raikkonen, Katri, Raitakari, Olli T., Reynolds, Rebecca M., Richmond, Rebecca C., Rivadeneira, Fernando, Rodriguez, Alina, Rose, Richard J., Salem, Rany, Santa-Marina, Loreto, Saw, Seang-Mei, Schnurr, Theresia M., Scott, James G., Selzam, Saskia, Shepherd, John A., Simpson, Angela, Skotte, Line, Sleiman, Patrick M. A., Snieder, Harold, Sørensen, Thorkild I. A., Standl, Marie, Steegers, Eric A. P., Strachan, David P., Straker, Leon, Strandberg, Timo, Taylor, Michelle, Teo, Yik-Ying, Thiering, Elisabeth, Torrent, Maties, Tyrrell, Jessica, Uitterlinden, Andre G., van Beijsterveldt, Toos, van der Most, Peter J., van Duijn, Cornelia M., Viikari, Jorma, Vilor-Tejedor, Natalia, Vogelezang, Suzanne, Vonk, Judith M., Vrijkotte, Tanja G. M., Vuoksimaa, Eero, Wang, Carol A., Watkins, William J., Wichmann, H-Erich, Willemsen, Gonneke, Williams, Gail M., Wilson, James F., Wray, Naomi R., Xu, Shujing, Xu, Cheng-Jian, Yaghootkar, Hanieh, Yi, Lu, Zafarmand, Mohammad Hadi, Zeggini, Eleftheria, Zemel, Babette S., Hinney, Anke, Lakka, Timo A., Whitehouse, Andrew J. O., Sunyer, Jordi, Widen, Elisabeth E., Feenstra, Bjarke, Sebert, Sylvain, Jacobsson, Bo, Njolstad, Pal R., Stoltenberg, Camilla, Smith, George Davey, Lawlor, Debbie A., Paternoster, Lavinia, Timpson, Nicholas J., Ong, Ken K., Bisgaard, Hans, Bonnelykke, Klaus, Jaddoe, Vincent W. V., Tiemeier, Henning, Jarvelin, Marjo-Riitta, Evans, David M., Perry, John R. B., Grant, Struan F. A., Boomsma, Dorret I., Freathy, Rachel M., McCarthy, Mark I., Felix, Janine F., Sorensen, Thorkild I. A., Tiemeier, Hen-Ning, Middeldorp, Christel M., Mahajan, Anubha, Horikoshi, Momoko, Robertson, Neil R., Beaumont, Robin N., Bradfield, Jonathan P., Bustamante, Mariona, Cousminer, Diana L., Day, Felix R., De Silva, N. Maneka, Guxens, Monica, Mook-Kanamori, Dennis O., St Pourcain, Beate, Warrington, Nicole M., Adair, Linda S., Ahlqvist, Emma, Ahluwalia, Tarunveer S., Almgren, Peter, Ang, Wei, Atalay, Mustafa, Auvinen, Juha, Bartels, Meike, Beckmann, Jacques S., Bilbao, Jose Ramon, Bond, Tom, Borja, Judith B., Cavadino, Alana, Charoen, Pimphen, Chen, Zhanghua, Coin, Lachlan, Cooper, Cyrus, Curtin, John A., Custovic, Adnan, Das, Shikta, Davies, Gareth E., Dedoussis, George V., Duijts, Liesbeth, Eastwood, Peter R., Eliasen, Anders U., Elliott, Paul, Eriksson, Johan G., Estivill, Xavier, Fadista, Joao, Fedko, Iryna O., Frayling, Timothy M., Gaillard, Romy, Gauderman, W. James, Geller, Frank, Gilliland, Frank, Gilsanz, Vincente, Granell, Raquel, Grarup, Niels, Groop, Leif, Hadley, Dexter, Hakonarson, Hakon, Hansen, Torben, Hartman, Catharina A., Hattersley, Andrew T., Hayes, M. Geoffrey, Hebebrand, Johannes, Heinrich, Joachim, Helgeland, Oyvind, Henders, Anjali K., Henderson, John, Henriksen, Tine B., Hirschhorn, Joel N., Hivert, Marie-France, Hocher, Berthold, Holloway, John W., Holt, Patrick, Hottenga, Jouke-Jan, Hypponen, Elina, Iniguez, Carmen, Johansson, Stefan, Jugessur, Astanand, Kahonen, Mika, Kalkwarf, Heidi J., Kaprio, Jaakko, Karhunen, Ville, Kemp, John P., Kerkhof, Marjan, Koppelman, Gerard H., Korner, Antje, Kotecha, Sailesh, Kreiner-Moller, Eskil, Kulohoma, Benard, Kumar, Ashish, Kutalik, Zoltan, Lahti, Jari, Lappe, Joan M., Larsson, Henrik, Lehtimaki, Terho, Lewin, Alexandra M., Li, Jin, Lichtenstein, Paul, Lindgren, Cecilia M., Lindi, Virpi, Linneberg, Allan, Liu, Xueping, Liu, Jun, Lowe, William L., Jr., Lundstrom, Sebastian, Lyytikainen, Leo-Pekka, Ma, Ronald C. W., Mace, Aurelien, Magi, Reedik, Magnus, Per, Mamun, Abdullah A., Mannikko, Minna, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Nina S., Medland, Sarah E., Melbye, Mads, Melen, Erik, Mohlke, Karen L., Monnereau, Claire, Morgen, Camilla S., Morris, Andrew P., Murray, Jeffrey C., Myhre, Ronny, Najman, Jackob M., Nivard, Michel G., Nohr, Ellen A., Nolte, Ilja M., Ntalla, Ioanna, O'Reilly, Paul, Oberfield, Sharon E., Oken, Emily, Oldehinkel, Albertine J., Pahkala, Katja, Palviainen, Teemu, Panoutsopoulou, Kalliope, Pedersen, Oluf, Pennell, Craig E., Pershagen, Goran, Pitkanen, Niina, Plomin, Robert, Power, Christine, Prasad, Rashmi B., Prokopenko, Inga, Pulkkinen, Lea, Raikkonen, Katri, Raitakari, Olli T., Reynolds, Rebecca M., Richmond, Rebecca C., Rivadeneira, Fernando, Rodriguez, Alina, Rose, Richard J., Salem, Rany, Santa-Marina, Loreto, Saw, Seang-Mei, Schnurr, Theresia M., Scott, James G., Selzam, Saskia, Shepherd, John A., Simpson, Angela, Skotte, Line, Sleiman, Patrick M. A., Snieder, Harold, Sørensen, Thorkild I. A., Standl, Marie, Steegers, Eric A. P., Strachan, David P., Straker, Leon, Strandberg, Timo, Taylor, Michelle, Teo, Yik-Ying, Thiering, Elisabeth, Torrent, Maties, Tyrrell, Jessica, Uitterlinden, Andre G., van Beijsterveldt, Toos, van der Most, Peter J., van Duijn, Cornelia M., Viikari, Jorma, Vilor-Tejedor, Natalia, Vogelezang, Suzanne, Vonk, Judith M., Vrijkotte, Tanja G. M., Vuoksimaa, Eero, Wang, Carol A., Watkins, William J., Wichmann, H-Erich, Willemsen, Gonneke, Williams, Gail M., Wilson, James F., Wray, Naomi R., Xu, Shujing, Xu, Cheng-Jian, Yaghootkar, Hanieh, Yi, Lu, Zafarmand, Mohammad Hadi, Zeggini, Eleftheria, Zemel, Babette S., Hinney, Anke, Lakka, Timo A., Whitehouse, Andrew J. O., Sunyer, Jordi, Widen, Elisabeth E., Feenstra, Bjarke, Sebert, Sylvain, Jacobsson, Bo, Njolstad, Pal R., Stoltenberg, Camilla, Smith, George Davey, Lawlor, Debbie A., Paternoster, Lavinia, Timpson, Nicholas J., Ong, Ken K., Bisgaard, Hans, Bonnelykke, Klaus, Jaddoe, Vincent W. V., Tiemeier, Henning, Jarvelin, Marjo-Riitta, Evans, David M., Perry, John R. B., Grant, Struan F. A., Boomsma, Dorret I., Freathy, Rachel M., McCarthy, Mark I., Felix, Janine F., Sorensen, Thorkild I. A., and Tiemeier, Hen-Ning
- Published
- 2019
44. Activating Mutations in the Gene Encoding the ATP-Sensitive Potassium-Channel Subunit Kir6.2 and Permanent Neonatal Diabetes
- Author
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Gloyn, Anna L., Pearson, Ewan R., Antcliff, Jennifer F., Proks, Peter, Bruining, G. Jan, Slingerland, Annabelle S., Howard, Neville, Srinivasan, Shubha, Silva, Jose M.C.L., Molnes, Janne, Edghill, Emma L., Frayling, Timothy M., Temple, I. Karen, Mackay, Deborah, Shield, Julian P.H., Sumnik, Zdenek, van Rhijn, Adrian, Wales, Jerry K.H., Clark, Penelope, Gorman, Shaun, Aisenberg, Javier, Ellard, Sian, Njolstad, Pal R., Ashcroft, Frances M., and Hattersley, Andrew T.
- Published
- 2004
- Full Text
- View/download PDF
45. Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: patient characteristics and initial response to sulfonylurea therapy
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Sagen, Jorn V., Raeder, Helge, Hathout, Eba, Shehadeh, Naim, Gudmundsson, Kolbeinn, Baevre, Halvor, Abuelo, Dianne, Phornphutkul, Chanika, Molnes, Janne, Bell, Graeme I., Gloyn, Anna L., Hattersley, Andrew T., Molven, Anders, Sovik, Oddmund, and Njolstad, Pal R.
- Subjects
Gene mutations -- Research ,Diabetes -- Care and treatment -- Research ,Health ,Care and treatment ,Research - Abstract
Permanent neonatal diabetes (PND) can be caused by mutations in the transcription factors insulin promoter factor (IPF)-1, eukaryotic translation initiation factor-2α kinase 3 (EIF2AK3), and forkhead box-P3 and in key components of insulin secretion: glucokinase (GCK) and the ATP-sensitive [K.sup.+] channel subunit Kir6.2. We sequenced the gene encoding Kir6.2 (KCNJ11) in 11 probands with GCK-negative PND. Heterozygous mutations were identified in seven probands, causing three novel (F35V, Y330C, and F333I) and two known (V59M and R201H) Kir6.2 amino acid substitutions. Only two probands had a family history of diabetes. Subjects with the V59M mutation had neurological features including motor delay. Three mutation carriers tested had an insulin secretory response to tolbutamide, but not to glucose or glucagon. Glibenclamide was introduced in increasing doses to investigate whether sulfonylurea could replace insulin. At a glibenclamide dose of 0.3-0.4 mg x [kg.sup.-1] x [day.sup.-1], insulin was discontinued. Blood glucose did not deteriorate, and Hb[A.sub.1c] was stable or fell during 2-6 months of follow-up. An oral glucose tolerance test performed in one subject revealed that glucose-stimulated insulin release was restored. Mutations in Kir6.2 were the most frequent cause of PND in our cohort. Apparently insulin-dependent patients with mutations in Kir6.2 may be managed on an oral sulfonylurea with sustained metabolic control rather than insulin injections, illustrating the principle of pharmacogenetics applied in diabetes treatment., Neonatal diabetes may be defined as hyperglycemia diagnosed within the first 3 months of life (1). Transient neonatal diabetes is associated with abnormalities in chromosome 6 (2), whereas the permanent [...]
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- 2004
46. Familial hyperinsulinemic hypoglycemia caused by a defect in the SCHAD enzyme of mitochondrial fatty acid oxidation
- Author
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Molven, Anders, Matre, Guri E., Duran, Marinus, Wanders, Ronald J., Rishaug, Unni, Njolstad, Pal R., Jellum, Egil, and Sovik, Oddmund
- Subjects
Gene mutations -- Physiological aspects -- Research -- Methods -- Analysis -- Health aspects -- Genetic aspects ,Familial diseases -- Health aspects -- Genetic aspects -- Causes of -- Development and progression -- Research ,Medical research -- Analysis -- Methods -- Physiological aspects -- Health aspects ,Medicine, Experimental -- Analysis -- Methods -- Physiological aspects -- Health aspects ,Gene expression -- Physiological aspects -- Research -- Methods -- Genetic aspects -- Analysis -- Health aspects ,Diabetes -- Health aspects -- Research -- Genetic aspects -- Development and progression ,Fatty acids -- Physiological aspects -- Research -- Health aspects -- Analysis -- Genetic aspects -- Methods ,Pancreatic beta cells -- Genetic aspects -- Physiological aspects -- Health aspects -- Research -- Analysis -- Methods ,Insulin -- Health aspects -- Physiological aspects -- Research ,Chromosomes -- Genetic aspects -- Analysis -- Health aspects -- Research -- Physiological aspects -- Methods ,Secretion -- Genetic aspects -- Health aspects -- Physiological aspects -- Analysis -- Research -- Methods ,Physiology, Pathological -- Research -- Health aspects -- Physiological aspects -- Analysis -- Methods ,Health ,Physiological aspects ,Analysis ,Development and progression ,Genetic aspects ,Research ,Methods ,Health aspects ,Causes of - Abstract
Inappropriately elevated insulin secretion is the hallmark of persistent hyperinsulinemic hypoglycemia of infancy (PHHI), also denoted congenital hyperinsulinism. Causal mutations have been uncovered in genes coding for the β-cell's ATP-sensitive potassium channel and the metabolic enzymes glucokinase and glutamate dehydrogenase. In addition, one hyperinsulinemic infant was recently found to have a mutation in the gene encoding short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD), an enzyme participating in mitochondrial fatty acid oxidation. We have studied a consanguineous family with severe neonatal hypoglycemia due to increased insulin levels and where well-established genetic causes of hyperinsulinism had been eliminated. A genome-wide, microsatellite-based screen for homozygous chromosomal segments was performed. Those regions that were inherited in accordance with the presupposed model were searched for mutations in genes encoding metabolic enzymes. A novel, homozygous deletion mutation was found in the gene coding for the SCHAD enzyme. The mutation affected RNA splicing and was predicted to lead to a protein lacking 30 amino acids. The observations at the molecular level were confirmed by demonstrating greatly reduced SCHAD activity in the patients' fibroblasts and enhanced levels of 3-hydroxybutyryl-carnitine in their blood plasma. Urine metabolite analysis showed that SCHAD deficiency resulted in specific excretion of 3-hydroxyglutaric acid. By the genetic explanation of our family's cases of severe hypoglycemia, it is now clear that recessively inherited SCHAD deficiency can result in PHHI. This finding suggests that mitochondrial fatty acid oxidation influences insulin secretion by a hitherto unknown mechanism., In most populations, persistent hyperinsulinemic hypoglycemia of infancy (PHHI) (Mendelian Inheritance in Man [MIM] no. 601820), also referred to as neonatal or congenital hyperinsulinism, is a rare disorder. Its incidence [...]
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- 2004
47. Permanent neonatal diabetes caused by glucokinase deficiency: inborn error of the glucose-insulin signaling pathway
- Author
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Njolstad, Pal R., Sagen, Jorn V., Bjorkhaug, Lise, Odili, Stella, Shehadeh, Naim, Bakry, Doua, Sarici, S. Umit, Alpay, Faruk, Molnes, Janne, Molven, Anders, Sovik, Oddmund, and Matschinsky, Franz M.
- Subjects
Case studies ,Causes of ,Type 1 diabetes -- Causes of -- Case studies ,Inborn errors of metabolism -- Case studies ,Metabolism, Inborn errors of -- Case studies - Abstract
Neonatal diabetes, insulin-requiring hyperglycemia occurring within the first month of life is often associated with intrauterine growth retardation (IUGR) and can be either transient or permanent (1). Transient neonatal diabetes [...], Neonatal diabetes can be either permanent or transient. We have recently shown that permanent neonatal diabetes can result from complete deficiency of glucokinase activity. Here we report three new cases of glucokinase-related permanent neonatal diabetes. The probands had intrauterine growth retardation (birth weight < 1,900 g) and insulin-treated diabetes from birth (diagnosis within the first week of life). One of the subjects was homozygous for the missense mutation Ala378Val (A378V), which is an inactivating mutation with an activity index of only 0.2% of wild-type glucokinase activity. The second subject was homozygous for a mutation in the splice donor site of exert 8 (intervening sequence 8 [IVS8] + 2T → G), which is predicted to lead to the synthesis of an inactive protein. The third subject (second cousin of subject 2) was a compound heterozygote with one allele having the splice-site mutation IVS8 + 2T → G and the other the missense mutation Gly264Ser (G264S), a mutation with an activity index of 86% of normal activity. The five subjects with permanent neonatal diabetes due to glucokinase deficiency identified to date are characterized by intrauterine growth retardation, permanent insulin-requiring diabetes from the first day of life, and hyperglycemia in both parents. Autosomal recessive inheritance and enzyme deficiency are features typical for an inborn error of metabolism, which occurred in the glucose-insulin signaling pathway in these subjects. Diabetes 52: 2854-2860, 2003
- Published
- 2003
48. Brief Report: Neonatal Diabetes Mellitus Due to Complete Glucokinase Deficiency
- Author
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Njolstad, Pal R., Sovik, Oddmund, Cuesta-Munoz, Antonio, Bjorkhaug, Lise, Massa, Ornella, Barbetti, Fabrizio, Undlien, Dag E., Shiota, Chiyo, Magnuson, Mark A., Molven, Anders, Matschinsky, Franz M., and Bell, Graeme I.
- Published
- 2001
49. Enlarged nephrons and severe nondiabetic nephropathy in hepatocyte nuclear factor-1β (HNF-1β) mutation carriers
- Author
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Sagen, Jørn V., Bostad, Leif, Njølstad, Pål R., and Søvik, Oddmund
- Published
- 2003
- Full Text
- View/download PDF
50. Genetic variants of hepatocyte nuclear factor-1β in Chinese young-onset diabetic patients with nephropathy
- Author
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So, W.Y., Ng, Maggie C.Y., Horikawa, Yukio, Njølstad, Pal R., Li, June K.Y., Ma, Ronald C.W., Bell, Graeme I., and Chan, Juliana C.N.
- Published
- 2003
- Full Text
- View/download PDF
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