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1. Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth

Author

Beaumont, Robin N., Flatley, Christopher, Vaudel, Marc, Wu, Xiaoping, Chen, Jing, Moen, Gunn-Helen, Skotte, Line, Helgeland, Øyvind, Solé-Navais, Pol, Banasik, Karina, Albiñana, Clara, Ronkainen, Justiina, Fadista, João, Stinson, Sara Elizabeth, Trajanoska, Katerina, Wang, Carol A., Westergaard, David, Srinivasan, Sundararajan, Sánchez-Soriano, Carlos, Bilbao, Jose Ramon, Allard, Catherine, Groleau, Marika, Kuulasmaa, Teemu, Leirer, Daniel J., White, Frédérique, Jacques, Pierre-Étienne, Cheng, Haoxiang, Hao, Ke, Andreassen, Ole A., Åsvold, Bjørn Olav, Atalay, Mustafa, Bhatta, Laxmi, Bouchard, Luigi, Brumpton, Ben Michael, Brunak, Søren, Bybjerg-Grauholm, Jonas, Ebbing, Cathrine, Elliott, Paul, Engelbrechtsen, Line, Erikstrup, Christian, Estarlich, Marisa, Franks, Stephen, Gaillard, Romy, Geller, Frank, Grove, Jakob, Hougaard, David M., Kajantie, Eero, Morgen, Camilla S., Nohr, Ellen A., Nyegaard, Mette, Palmer, Colin N. A., Pedersen, Ole Birger, Rivadeneira, Fernando, Sebert, Sylvain, Shields, Beverley M., Stoltenberg, Camilla, Surakka, Ida, Thørner, Lise Wegner, Ullum, Henrik, Vaarasmaki, Marja, Vilhjalmsson, Bjarni J., Willer, Cristen J., Lakka, Timo A., Gybel-Brask, Dorte, Bustamante, Mariona, Hansen, Torben, Pearson, Ewan R., Reynolds, Rebecca M., Ostrowski, Sisse R., Pennell, Craig E., Jaddoe, Vincent W. V., Felix, Janine F., Hattersley, Andrew T., Melbye, Mads, Lawlor, Deborah A., Hveem, Kristian, Werge, Thomas, Nielsen, Henriette Svarre, Magnus, Per, Evans, David M., Jacobsson, Bo, Järvelin, Marjo-Riitta, Zhang, Ge, Hivert, Marie-France, Johansson, Stefan, Freathy, Rachel M., Feenstra, Bjarke, and Njølstad, Pål R.

Published
2023
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3. Microbially Produced Imidazole Propionate Is Associated With Heart Failure and Mortality

Author

Alves, Renato, Amouyal, Chloe, Andersson Galijatovic, Ehm Astrid, Andreelli, Fabrizio, Barthelemy, Olivier, Bastard, Jean-Philippe, Batisse, Jean-Paul, Berland, Magalie, Bittar, Randa, Blüher, Matthias, Bork, Peer, Bourron, Olivier, Camus, Mickael, Cassuto, Dominique, Ciangura, Cecile, Coelho, Luis Pedro, Collet, Jean-Philippe, Dumas, Marc-Emmanuel, Ehrlich, S. Dusko, Engelbrechtsen, Line, Fezeu, Leopold, Forslund, Sofia, Fromentin, Sebastien, Galan, Pilar, Giral, Philippe, Gøtze, Jens Peter, Hansen, Torben, Hansen, Tue H., Hartemann, Agnes, Hartmann, Bolette, Hercberg, Serge, Holmes, Bridget, Holst, Jens Juul, Hornbak, Malene, Hoyles, Lesley, Hulot, Jean-Sebastien, Jaqueminet, Sophie, Kerneis, Mathieu, Khemis, Jean, Kozlowski, Ruby, Pedersen, Helle Krogh, Kuhn, Michael, Mannerås-Holm, Louise, Marko, Lajos, Martinez-Gili Robin Massey, Laura, Maziers, Nicolas, Medina-Stamminger, Jonathan, Moitinho-Silva, Lucas, Montalescot, Gilles, Moutel, Sandrine, Neves, Ana Luisa, Olanipekun, Michael, Oppert, Jean-Michel, Poitou, Christine, Pousset, Francoise, Pouzoulet, Laurence, Rouault, Christine, Silvain, Johanne, Vestergaard, Henrik, Molinaro, Antonio, Nemet, Ina, Bel Lassen, Pierre, Chakaroun, Rima, Nielsen, Trine, Aron-Wisnewsky, Judith, Bergh, Per-Olof, Li, Lin, Henricsson, Marcus, Køber, Lars, Isnard, Richard, Helft, Gerard, Stumvoll, Michael, Pedersen, Oluf, Smith, J. Gustav, Tang, W.H. Wilson, Clément, Karine, Hazen, Stanley L., and Bäckhed, Fredrik

Published
2023
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4. 14-fold increased prevalence of rare glucokinase gene variant carriers in unselected Danish patients with newly diagnosed type 2 diabetes

Author

Gjesing, Anette P., Engelbrechtsen, Line, Cathrine B. Thuesen, Anne, Have, Christian T., Hollensted, Mette, Grarup, Niels, Linneberg, Allan, Steen Nielsen, Jens, Christensen, Lotte B., Thomsen, Reimar W., Johansson, Kristoffer E., Cagiada, Matteo, Gersing, Sarah, Hartmann-Petersen, Rasmus, Lindorff-Larsen, Kresten, Vaag, Allan, Sørensen, Henrik T., Brandslund, Ivan, Beck-Nielsen, Henning, Pedersen, Oluf, Rungby, Jørgen, and Hansen, Torben

Published
2022
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5. RNA profiles reveal signatures of future health and disease in pregnancy

Author

Rasmussen, Morten, Reddy, Mitsu, Nolan, Rory, Camunas-Soler, Joan, Khodursky, Arkady, Scheller, Nikolai M., Cantonwine, David E., Engelbrechtsen, Line, Mi, Jia Dai, Dutta, Arup, Brundage, Tiffany, Siddiqui, Farooq, Thao, Mainou, Gee, Elaine P. S., La, Johnny, Baruch-Gravett, Courtney, Santillan, Mark K., Deb, Saikat, Ame, Shaali M., Ali, Said M., Adkins, Melanie, DePristo, Mark A., Lee, Manfred, Namsaraev, Eugeni, Gybel-Brask, Dorte Jensen, Skibsted, Lillian, Litch, James A., Santillan, Donna A., Sazawal, Sunil, Tribe, Rachel M., Roberts, James M., Jain, Maneesh, Høgdall, Estrid, Holzman, Claudia, Quake, Stephen R., Elovitz, Michal A., and McElrath, Thomas F.

Published
2022
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6. Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration

Author

Jennison, Christopher, Ehrhardt, Beate, Baum, Patrick, Schoelsch, Corinna, Freijer, Jan, Grempler, Rolf, Graefe-Mody, Ulrike, Hennige, Anita, Dings, Christiane, Lehr, Thorsten, Scherer, Nina, Sihinecich, Iryna, Pattou, Francois, Raverdi, Violeta, Caiazzo, Robert, Torres, Fanelly, Verkindt, Helene, Mari, Andrea, Tura, Andrea, Giorgino, Toni, Bizzotto, Roberto, Froguel, Philippe, Bonneford, Amelie, Canouil, Mickael, Dhennin, Veronique, Brorsson, Caroline, Brunak, Soren, De Masi, Federico, Gudmundsdóttir, Valborg, Pedersen, Helle, Banasik, Karina, Thomas, Cecilia, Sackett, Peter, Staerfeldt, Hans-Henrik, Lundgaard, Agnete, Nilsson, Birgitte, Nielsen, Agnes, Mazzoni, Gianluca, Karaderi, Tugce, Rasmussen, Simon, Johansen, Joachim, Allesøe, Rosa, Fritsche, Andreas, Thorand, Barbara, Adamski, Jurek, Grallert, Harald, Haid, Mark, Sharma, Sapna, Troll, Martina, Adam, Jonathan, Ferrer, Jorge, Eriksen, Heather, Frost, Gary, Haussler, Ragna, Hong, Mun-gwan, Schwenk, Jochen, Uhlen, Mathias, Nicolay, Claudia, Pavo, Imre, Steckel-Hamann, Birgit, Thomas, Melissa, Adragni, Kofi, Wu, Han, Hart, Leen't, Roderick, Slieker, van Leeuwen, Nienke, Dekkers, Koen, Frau, Francesca, Gassenhuber, Johann, Jablonka, Bernd, Musholt, Petra, Ruetten, Hartmut, Tillner, Joachim, Baltauss, Tania, Bernard Poenaru, Oana, de Preville, Nathalie, Rodriquez, Marianne, Arumugam, Manimozhiyan, Allin, Kristine, Engelbrechtsen, Line, Hansen, Torben, Hansen, Tue, Forman, Annemette, Jonsson, Anna, Pedersen, Oluf, Dutta, Avirup, Vogt, Josef, Vestergaard, Henrik, Laakso, Markku, Kokkola, Tarja, Kuulasmaa, Teemu, Franks, Paul, Giordano, Nick, Pomares-Millan, Hugo, Fitipaldi, Hugo, Mutie, Pascal, Klintenberg, Maria, Bergstrom, Margit, Groop, Leif, Ridderstrale, Martin, Atabaki Pasdar, Naeimeh, Deshmukh, Harshal, Heggie, Alison, Wake, Dianne, McEvoy, Donna, McVittie, Ian, Walker, Mark, Hattersley, Andrew, Hill, Anita, Jones, Angus, McDonald, Timothy, Perry, Mandy, Nice, Rachel, Hudson, Michelle, Thorne, Claire, Dermitzakis, Emmanouil, Viñuela, Ana, Cabrelli, Louise, Loftus, Heather, Dawed, Adem, Donnelly, Louise, Forgie, Ian, Pearson, Ewan, Palmer, Colin, Brown, Andrew, Koivula, Robert, Wesolowska-Andersen, Agata, Abdalla, Moustafa, McRobert, Nicky, Fernandez, Juan, Jiao, Yunlong, Robertson, Neil, Gough, Stephen, Kaye, Jane, Mourby, Miranda, Mahajan, Anubha, McCarthy, Mark, Shah, Nisha, Teare, Harriet, Holl, Reinhard, Koopman, Anitra, Rutters, Femke, Beulens, Joline, Groeneveld, Lenka, Bell, Jimmy, Thomas, Louise, Whitcher, Brandon, Wilman, Henry R., Parisinos, Constantinos A., Atabaki-Pasdar, Naeimeh, Kelly, Matt, Thomas, E. Louise, Neubauer, Stefan, Hingorani, Aroon D., Patel, Riyaz S., Hemingway, Harry, Franks, Paul W., Bell, Jimmy D., Banerjee, Rajarshi, and Yaghootkar, Hanieh

Published
2019
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7. Genetics of Plasma Bilirubin and Associations between Bilirubin and Cardiometabolic Risk Profiles in Danish Children and Adolescents

Author

Ullah, Asmat, primary, Stankevic, Evelina, additional, Holm, Louise Aas, additional, Stinson, Sara E., additional, Juel, Helene Bæk, additional, Fonvig, Cilius E., additional, Lund, Morten A. V., additional, Trier, Cæcilie, additional, Engelbrechtsen, Line, additional, Ängquist, Lars, additional, Jonsson, Anna E., additional, Pedersen, Oluf, additional, Grarup, Niels, additional, Holm, Jens-Christian, additional, and Hansen, Torben, additional

Published
2023
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9. Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide

Author

Andrikopoulos, Petros, Aron-Wisnewsky, Judith, Chakaroun, Rima, Myridakis, Antonis, Forslund, Sofia K., Nielsen, Trine, Adriouch, Solia, Holmes, Bridget, Chilloux, Julien, Vieira-Silva, Sara, Falony, Gwen, Salem, Joe Elie, Andreelli, Fabrizio, Belda, Eugeni, Kieswich, Julius, Chechi, Kanta, Puig-Castellvi, Francesc, Chevalier, Mickael, Le Chatelier, Emmanuelle, Olanipekun, Michael T., Hoyles, Lesley, Alves, Renato, Helft, Gerard, Isnard, Richard, Køber, Lars, Coelho, Luis Pedro, Rouault, Christine, Gauguier, Dominique, Gøtze, Jens Peter, Prifti, Edi, Froguel, Philippe, Alili, Rohia, Galijatovic, Ehm Astrid Andersson, Barthelemy, Olivier, Bastard, Jean Philippe, Batisse, Jean Paul, Bel-Lassen, Pierre, Berland, Magalie, Bittar, Randa, Blottière, Hervé, Bosquet, Frederic, Boubrit, Rachid, Bourron, Olivier, Camus, Mickael, Ciangura, Cecile, Collet, Jean Philippe, Dietrich, Arne, Djebbar, Morad, Doré, Angélique, Engelbrechtsen, Line, Fezeu, Leopold, Fromentin, Sebastien, Pons, Nicolas, Graine, Marianne, Grünemann, Caroline, Hartemann, Agnes, Hartmann, Bolette, Hornbak, Malene, Jaqueminet, Sophie, Jørgensen, Niklas Rye, Julienne, Hanna, Justesen, Johanne, Kammer, Judith, Karup, Nikolaj, Kozlowski, Ruby, Kuhn, Michael, Lejard, Véronique, Letunic, Ivica, Levenez, Florence, Marko, Lajos, Martinez-Gili, Laura, Massey, Robin, Maziers, Nicolas, Moitinho-Silva, Lucas, Montalescot, Gilles, Neves, Ana Luisa, Le Pavin, Laetitia Pasero, Pousset, Francoise, Rodriguez-Martinez, Andrea, Schmidt, Sebastien, Schütz, Tatjana, Silva, Lucas, Silvain, Johanne, Svendstrup, Mathilde, Swartz, Timothy D., Vanduyvenboden, Thierry, Verger, Eric O., Walther, Stefanie, Zucker, Jean Daniel, Bäckhed, Fredrik, Vestergaard, Henrik, Hansen, Torben, Oppert, Jean Michel, Blüher, Matthias, Nielsen, Jens, Raes, Jeroen, Bork, Peer, Yaqoob, Muhammad M., Stumvoll, Michael, Pedersen, Oluf, Ehrlich, S. Dusko, Clément, Karine, Dumas, Marc Emmanuel, Andrikopoulos, Petros, Aron-Wisnewsky, Judith, Chakaroun, Rima, Myridakis, Antonis, Forslund, Sofia K., Nielsen, Trine, Adriouch, Solia, Holmes, Bridget, Chilloux, Julien, Vieira-Silva, Sara, Falony, Gwen, Salem, Joe Elie, Andreelli, Fabrizio, Belda, Eugeni, Kieswich, Julius, Chechi, Kanta, Puig-Castellvi, Francesc, Chevalier, Mickael, Le Chatelier, Emmanuelle, Olanipekun, Michael T., Hoyles, Lesley, Alves, Renato, Helft, Gerard, Isnard, Richard, Køber, Lars, Coelho, Luis Pedro, Rouault, Christine, Gauguier, Dominique, Gøtze, Jens Peter, Prifti, Edi, Froguel, Philippe, Alili, Rohia, Galijatovic, Ehm Astrid Andersson, Barthelemy, Olivier, Bastard, Jean Philippe, Batisse, Jean Paul, Bel-Lassen, Pierre, Berland, Magalie, Bittar, Randa, Blottière, Hervé, Bosquet, Frederic, Boubrit, Rachid, Bourron, Olivier, Camus, Mickael, Ciangura, Cecile, Collet, Jean Philippe, Dietrich, Arne, Djebbar, Morad, Doré, Angélique, Engelbrechtsen, Line, Fezeu, Leopold, Fromentin, Sebastien, Pons, Nicolas, Graine, Marianne, Grünemann, Caroline, Hartemann, Agnes, Hartmann, Bolette, Hornbak, Malene, Jaqueminet, Sophie, Jørgensen, Niklas Rye, Julienne, Hanna, Justesen, Johanne, Kammer, Judith, Karup, Nikolaj, Kozlowski, Ruby, Kuhn, Michael, Lejard, Véronique, Letunic, Ivica, Levenez, Florence, Marko, Lajos, Martinez-Gili, Laura, Massey, Robin, Maziers, Nicolas, Moitinho-Silva, Lucas, Montalescot, Gilles, Neves, Ana Luisa, Le Pavin, Laetitia Pasero, Pousset, Francoise, Rodriguez-Martinez, Andrea, Schmidt, Sebastien, Schütz, Tatjana, Silva, Lucas, Silvain, Johanne, Svendstrup, Mathilde, Swartz, Timothy D., Vanduyvenboden, Thierry, Verger, Eric O., Walther, Stefanie, Zucker, Jean Daniel, Bäckhed, Fredrik, Vestergaard, Henrik, Hansen, Torben, Oppert, Jean Michel, Blüher, Matthias, Nielsen, Jens, Raes, Jeroen, Bork, Peer, Yaqoob, Muhammad M., Stumvoll, Michael, Pedersen, Oluf, Ehrlich, S. Dusko, Clément, Karine, and Dumas, Marc Emmanuel

Abstract

The host-microbiota co-metabolite trimethylamine N-oxide (TMAO) is linked to increased cardiovascular risk but how its circulating levels are regulated remains unclear. We applied “explainable” machine learning, univariate, multivariate and mediation analyses of fasting plasma TMAO concentration and a multitude of phenotypes in 1,741 adult Europeans of the MetaCardis study. Here we show that next to age, kidney function is the primary variable predicting circulating TMAO, with microbiota composition and diet playing minor, albeit significant, roles. Mediation analysis suggests a causal relationship between TMAO and kidney function that we corroborate in preclinical models where TMAO exposure increases kidney scarring. Consistent with our findings, patients receiving glucose-lowering drugs with reno-protective properties have significantly lower circulating TMAO when compared to propensity-score matched control individuals. Our analyses uncover a bidirectional relationship between kidney function and TMAO that can potentially be modified by reno-protective anti-diabetic drugs and suggest a clinically actionable intervention for decreasing TMAO-associated excess cardiovascular risk.

Published
2023

10. Genetics of Plasma Bilirubin and Associations between Bilirubin and Cardiometabolic Risk Profiles in Danish Children and Adolescents

Author

Ullah, Asmat, Stankevic, Evelina, Holm, Louise Aas, Stinson, Sara E., Juel, Helene Bæk, Fonvig, Cilius E., Lund, Morten A.V., Trier, Cæcilie, Engelbrechtsen, Line, Ängquist, Lars, Jonsson, Anna E., Pedersen, Oluf, Grarup, Niels, Holm, Jens Christian, Hansen, Torben, Ullah, Asmat, Stankevic, Evelina, Holm, Louise Aas, Stinson, Sara E., Juel, Helene Bæk, Fonvig, Cilius E., Lund, Morten A.V., Trier, Cæcilie, Engelbrechtsen, Line, Ängquist, Lars, Jonsson, Anna E., Pedersen, Oluf, Grarup, Niels, Holm, Jens Christian, and Hansen, Torben

Abstract

Bilirubin is the end product of heme catabolism, mainly produced by the breakdown of mature red blood cells. Due to its anti-inflammatory, antioxidant, antidiabetic, and antilipemic properties, circulating bilirubin concentrations are inversely associated with the risk of cardiovascular disease, type 2 diabetes, and all-cause mortality in adults. Some genetic loci associated with circulating bilirubin concentrations have been identified by genome-wide association studies in adults. We aimed to examine the relationship between circulating bilirubin, cardiometabolic risk factors, and inflammation in children and adolescents and the genetic architecture of plasma bilirubin concentrations. We measured fasting plasma bilirubin, cardiometabolic risk factors, and inflammatory markers in a sample of Danish children and adolescents with overweight or obesity (n = 1530) and in a population-based sample (n = 1820) of Danish children and adolescents. Linear and logistic regression analyses were performed to analyze the associations between bilirubin, cardiometabolic risk factors, and inflammatory markers. A genome-wide association study (GWAS) of fasting plasma concentrations of bilirubin was performed in children and adolescents with overweight or obesity and in a population-based sample. Bilirubin is associated inversely and significantly with a number of cardiometabolic risk factors, including body mass index (BMI) standard deviation scores (SDS), waist circumference, high-sensitivity C-reactive protein (hs-CRP), homeostatic model assessment for insulin resistance (HOMA-IR), hemoglobin A1c (HbA1c), low-density lipoprotein cholesterol (LDL-C), triglycerides, and the majority of measured inflammatory markers. In contrast, bilirubin was positively associated with fasting plasma concentrations of alanine transaminase (ALT), high-density lipoprotein cholesterol (HDL-C), systolic blood pressure (SDS), and the inflammatory markers GH, PTX3, THBS2, TNFRSF9, PGF, PAPPA, GT, CCL23

Published
2023

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

Author

Brown, Andrew A., Fernandez-Tajes, Juan J., Hong, Mun gwan, Brorsson, Caroline A., Koivula, Robert W., Davtian, David, Dupuis, Théo, Sartori, Ambra, Michalettou, Theodora Dafni, Forgie, Ian M., Adam, Jonathan, Allin, Kristine H., Caiazzo, Robert, Cederberg, Henna, De Masi, Federico, Elders, Petra J.M., Giordano, Giuseppe N., Haid, Mark, Hansen, Torben, Hansen, Tue H., Hattersley, Andrew T., Heggie, Alison J., Howald, Cédric, Jones, Angus G., Kokkola, Tarja, Laakso, Markku, Mahajan, Anubha, Mari, Andrea, McDonald, Timothy J., McEvoy, Donna, Mourby, Miranda, Musholt, Petra B., Nilsson, Birgitte, Pattou, Francois, Penet, Deborah, Raverdy, Violeta, Ridderstråle, Martin, Romano, Luciana, Rutters, Femke, Sharma, Sapna, Teare, Harriet, ‘t Hart, Leen, Tsirigos, Konstantinos D., Vangipurapu, Jagadish, Vestergaard, Henrik, Brunak, Søren, Franks, Paul W., Frost, Gary, Grallert, Harald, Jablonka, Bernd, McCarthy, Mark I., Pavo, Imre, Pedersen, Oluf, Ruetten, Hartmut, Walker, Mark, Adragni, Kofi, Allesøe, Rosa Lundbye L., Artati, Anna A., Arumugam, Manimozhiyan, Atabaki-Pasdar, Naeimeh, Baltauss, Tania, Banasik, Karina, Barnett, Anna L., Baum, Patrick, Bell, Jimmy D., Beulens, Joline W., Bianzano, Susanna B., Bizzotto, Roberto, Bonnefond, Amelie, Cabrelli, Louise, Dale, Matilda, Dawed, Adem Y., de Preville, Nathalie, Dekkers, Koen F., Deshmukh, Harshal A., Dings, Christiane, Donnelly, Louise, Dutta, Avirup, Ehrhardt, Beate, Engelbrechtsen, Line, Eriksen, Rebeca, Fan, Yong, Ferrer, Jorge, Fitipaldi, Hugo, Forman, Annemette, Fritsche, Andreas, Froguel, Philippe, Gassenhuber, Johann, Gough, Stephen, Graefe-Mody, Ulrike, Grempler, Rolf, Groeneveld, Lenka, Groop, Leif, Gudmundsdóttir, Valborg, Gupta, Ramneek, Hennige, Anita M.H., Hill, Anita V., Holl, Reinhard W., Hudson, Michelle, Jacobsen, Ulrik Plesner, Jennison, Christopher, Johansen, Joachim, Jonsson, Anna, Karaderi, Tugce, Kaye, Jane, Kennedy, Gwen, Klintenberg, Maria, Kuulasmaa, Teemu, Lehr, Thorsten, Loftus, Heather, Lundgaard, Agnete Troen T., Mazzoni, Gianluca, McRobert, Nicky, McVittie, Ian, Nice, Rachel, Nicolay, Claudia, Nijpels, Giel, Palmer, Colin N., Pedersen, Helle K., Perry, Mandy H., Pomares-Millan, Hugo, Prehn, Cornelia P., Ramisch, Anna, Rasmussen, Simon, Robertson, Neil, Rodriquez, Marianne, Sackett, Peter, Scherer, Nina, Shah, Nisha, Sihinevich, Iryna, Slieker, Roderick C., Sondertoft, Nadja B., Steckel-Hamann, Birgit, Thomas, Melissa K., Thomas, Cecilia Engel E., Thomas, Elizabeth Louise L., Thorand, Barbara, Thorne, Claire E., Tillner, Joachim, Tura, Andrea, Uhlen, Mathias, van Leeuwen, Nienke, van Oort, Sabine, Verkindt, Helene, Vogt, Josef, Wad Sackett, Peter W., Wesolowska-Andersen, Agata, Whitcher, Brandon, White, Margaret W., Adamski, Jerzy, Schwenk, Jochen M., Pearson, Ewan R., Dermitzakis, Emmanouil T., Viñuela, Ana, Brown, Andrew A., Fernandez-Tajes, Juan J., Hong, Mun gwan, Brorsson, Caroline A., Koivula, Robert W., Davtian, David, Dupuis, Théo, Sartori, Ambra, Michalettou, Theodora Dafni, Forgie, Ian M., Adam, Jonathan, Allin, Kristine H., Caiazzo, Robert, Cederberg, Henna, De Masi, Federico, Elders, Petra J.M., Giordano, Giuseppe N., Haid, Mark, Hansen, Torben, Hansen, Tue H., Hattersley, Andrew T., Heggie, Alison J., Howald, Cédric, Jones, Angus G., Kokkola, Tarja, Laakso, Markku, Mahajan, Anubha, Mari, Andrea, McDonald, Timothy J., McEvoy, Donna, Mourby, Miranda, Musholt, Petra B., Nilsson, Birgitte, Pattou, Francois, Penet, Deborah, Raverdy, Violeta, Ridderstråle, Martin, Romano, Luciana, Rutters, Femke, Sharma, Sapna, Teare, Harriet, ‘t Hart, Leen, Tsirigos, Konstantinos D., Vangipurapu, Jagadish, Vestergaard, Henrik, Brunak, Søren, Franks, Paul W., Frost, Gary, Grallert, Harald, Jablonka, Bernd, McCarthy, Mark I., Pavo, Imre, Pedersen, Oluf, Ruetten, Hartmut, Walker, Mark, Adragni, Kofi, Allesøe, Rosa Lundbye L., Artati, Anna A., Arumugam, Manimozhiyan, Atabaki-Pasdar, Naeimeh, Baltauss, Tania, Banasik, Karina, Barnett, Anna L., Baum, Patrick, Bell, Jimmy D., Beulens, Joline W., Bianzano, Susanna B., Bizzotto, Roberto, Bonnefond, Amelie, Cabrelli, Louise, Dale, Matilda, Dawed, Adem Y., de Preville, Nathalie, Dekkers, Koen F., Deshmukh, Harshal A., Dings, Christiane, Donnelly, Louise, Dutta, Avirup, Ehrhardt, Beate, Engelbrechtsen, Line, Eriksen, Rebeca, Fan, Yong, Ferrer, Jorge, Fitipaldi, Hugo, Forman, Annemette, Fritsche, Andreas, Froguel, Philippe, Gassenhuber, Johann, Gough, Stephen, Graefe-Mody, Ulrike, Grempler, Rolf, Groeneveld, Lenka, Groop, Leif, Gudmundsdóttir, Valborg, Gupta, Ramneek, Hennige, Anita M.H., Hill, Anita V., Holl, Reinhard W., Hudson, Michelle, Jacobsen, Ulrik Plesner, Jennison, Christopher, Johansen, Joachim, Jonsson, Anna, Karaderi, Tugce, Kaye, Jane, Kennedy, Gwen, Klintenberg, Maria, Kuulasmaa, Teemu, Lehr, Thorsten, Loftus, Heather, Lundgaard, Agnete Troen T., Mazzoni, Gianluca, McRobert, Nicky, McVittie, Ian, Nice, Rachel, Nicolay, Claudia, Nijpels, Giel, Palmer, Colin N., Pedersen, Helle K., Perry, Mandy H., Pomares-Millan, Hugo, Prehn, Cornelia P., Ramisch, Anna, Rasmussen, Simon, Robertson, Neil, Rodriquez, Marianne, Sackett, Peter, Scherer, Nina, Shah, Nisha, Sihinevich, Iryna, Slieker, Roderick C., Sondertoft, Nadja B., Steckel-Hamann, Birgit, Thomas, Melissa K., Thomas, Cecilia Engel E., Thomas, Elizabeth Louise L., Thorand, Barbara, Thorne, Claire E., Tillner, Joachim, Tura, Andrea, Uhlen, Mathias, van Leeuwen, Nienke, van Oort, Sabine, Verkindt, Helene, Vogt, Josef, Wad Sackett, Peter W., Wesolowska-Andersen, Agata, Whitcher, Brandon, White, Margaret W., Adamski, Jerzy, Schwenk, Jochen M., Pearson, Ewan R., Dermitzakis, Emmanouil T., and Viñuela, Ana

Abstract

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

Published
2023

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

Author

Allesøe, Rosa Lundbye, Lundgaard, Agnete Troen, Hernández Medina, Ricardo, Aguayo-Orozco, Alejandro, Johansen, Joachim, Nissen, Jakob Nybo, Brorsson, Caroline, Mazzoni, Gianluca, Niu, Lili, Biel, Jorge Hernansanz, Brasas, Valentas, Webel, Henry, Benros, Michael Eriksen, Pedersen, Anders Gorm, Chmura, Piotr Jaroslaw, Jacobsen, Ulrik Plesner, Mari, Andrea, Koivula, Robert, Mahajan, Anubha, Vinuela, Ana, Tajes, Juan Fernandez, Sharma, Sapna, Haid, Mark, Hong, Mun-Gwan, Musholt, Petra B., de Masi, Federico, Vogt, Josef, Pedersen, Helle Krogh, Gudmundsdottir, Valborg, Jones, Angus, Kennedy, Gwen, Bell, Jimmy, Thomas, E. Louise, Frost, Gary, Thomsen, Henrik, Hansen, Elizaveta, Hansen, Tue Haldor, Vestergaard, Henrik, Muilwijk, Mirthe, Blom, Marieke T., ‘t Hart, Leen M., Pattou, Francois, Raverdy, Violeta, Brage, Soren, Kokkola, Tarja, Heggie, Alison, McEvoy, Donna, Mourby, Miranda, Kaye, Jane, Hattersley, Andrew, McDonald, Timothy, Ridderstråle, Martin, Walker, Mark, Forgie, Ian, Giordano, Giuseppe N., Pavo, Imre, Ruetten, Hartmut, Pedersen, Oluf, Hansen, Torben, Dermitzakis, Emmanouil, Franks, Paul W., Schwenk, Jochen M., Adamski, Jerzy, McCarthy, Mark I., Pearson, Ewan, Banasik, Karina, Rasmussen, Simon, Brunak, S. ren, Froguel, Philippe, Thomas, Cecilia Engel, Haussler, Ragna, Beulens, Joline, Rutters, Femke, Nijpels, Giel, van Oort, Sabine, Groeneveld, Lenka, Elders, Petra, Giorgino, Toni, Rodriquez, Marianne, Nice, Rachel, Perry, Mandy, Bianzano, Susanna, Graefe-Mody, Ulrike, Hennige, Anita, Grempler, Rolf, Baum, Patrick, Stærfeldt, Hans-Henrik, Shah, Nisha, Teare, Harriet, Ehrhardt, Beate, Tillner, Joachim, Dings, Christiane, Lehr, Thorsten, Scherer, Nina, Sihinevich, Iryna, Cabrelli, Louise, Loftus, Heather, Bizzotto, Roberto, Tura, Andrea, Dekkers, Koen, van Leeuwen, Nienke, Groop, Leif, Slieker, Roderick, Ramisch, Anna, Jennison, Christopher, McVittie, Ian, Frau, Francesca, Steckel-Hamann, Birgit, Adragni, Kofi, Thomas, Melissa, Pasdar, Naeimeh Atabaki, Fitipaldi, Hugo, Kurbasic, Azra, Mutie, Pascal, Pomares-Millan, Hugo, Bonnefond, Amelie, Canouil, Mickael, Caiazzo, Robert, Verkindt, Helene, Holl, Reinhard, Kuulasmaa, Teemu, Deshmukh, Harshal, Cederberg, Henna, Laakso, Markku, Vangipurapu, Jagadish, Dale, Matilda, Thorand, Barbara, Nicolay, Claudia, Fritsche, Andreas, Hill, Anita, Hudson, Michelle, Thorne, Claire, Allin, Kristine, Arumugam, Manimozhiyan, Jonsson, Anna, Engelbrechtsen, Line, Forman, Annemette, Dutta, Avirup, Sondertoft, Nadja, Fan, Yong, Gough, Stephen, Robertson, Neil, McRobert, Nicky, Wesolowska-Andersen, Agata, Brown, Andrew, Davtian, David, Dawed, Adem, Donnelly, Louise, Palmer, Colin, White, Margaret, Ferrer, Jorge, Whitcher, Brandon, Artati, Anna, Prehn, Cornelia, Adam, Jonathan, Grallert, Harald, Gupta, Ramneek, Sackett, Peter Wad, Nilsson, Birgitte, Tsirigos, Konstantinos, Eriksen, Rebeca, Jablonka, Bernd, Uhlen, Mathias, Gassenhuber, Johann, Baltauss, Tania, de Preville, Nathalie, Klintenberg, Maria, Abdalla, Moustafa, Lundgaard, Agnete Troen [0000-0001-7447-6560], Hernández Medina, Ricardo [0000-0001-6373-2362], Johansen, Joachim [0000-0001-7052-1870], Niu, Lili [0000-0003-4571-4368], Biel, Jorge Hernansanz [0000-0002-3125-2951], Benros, Michael Eriksen [0000-0003-4939-9465], Pedersen, Anders Gorm [0000-0001-9650-8965], Jacobsen, Ulrik Plesner [0000-0001-9181-6854], Koivula, Robert [0000-0002-1646-4163], Vinuela, Ana [0000-0003-3771-8537], Haid, Mark [0000-0001-6118-1333], Hong, Mun-Gwan [0000-0001-8603-8293], Kennedy, Gwen [0000-0002-9856-3236], Thomas, E Louise [0000-0003-4235-4694], Frost, Gary [0000-0003-0529-6325], Hansen, Tue Haldor [0000-0001-5948-8993], Kaye, Jane [0000-0002-7311-4725], Hattersley, Andrew [0000-0001-5620-473X], Ridderstråle, Martin [0000-0002-3270-9167], Pedersen, Oluf [0000-0002-3321-3972], Hansen, Torben [0000-0001-8748-3831], Schwenk, Jochen M [0000-0001-8141-8449], Rasmussen, Simon [0000-0001-6323-9041], Brunak, Søren [0000-0003-0316-5866], Apollo - University of Cambridge Repository, Epidemiology and Data Science, ACS - Diabetes & metabolism, APH - Health Behaviors & Chronic Diseases, General practice, ACS - Heart failure & arrhythmias, APH - Aging & Later Life, Graduate School, and APH - Methodology

Subjects
Biomedical Engineering, Type 2 diabetes, Bioengineering, Applied Microbiology and Biotechnology, Deep Learning, SDG 3 - Good Health and Well-being, Diabetes Mellitus, Type 2, Machine learning, Molecular Medicine, Humans, Data integration, IMI DIRECT Consortium, Systems biology, Algorithms, Biotechnology
Abstract

The application of multiple omics technologies in biomedical cohorts has the potential to reveal patient-level disease characteristics and individualized response to treatment. However, the scale and heterogeneous nature of multi-modal data makes integration and inference a non-trivial task. We developed a deep-learning-based framework, multi-omics variational autoencoders (MOVE), to integrate such data and applied it to a cohort of 789 people with newly diagnosed type 2 diabetes with deep multi-omics phenotyping from the DIRECT consortium. Using in silico perturbations, we identified drug–omics associations across the multi-modal datasets for the 20 most prevalent drugs given to people with type 2 diabetes with substantially higher sensitivity than univariate statistical tests. From these, we among others, identified novel associations between metformin and the gut microbiota as well as opposite molecular responses for the two statins, simvastatin and atorvastatin. We used the associations to quantify drug–drug similarities, assess the degree of polypharmacy and conclude that drug effects are distributed across the multi-omics modalities.

Published
2023
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13. Common variants in the hERG (KCNH2) voltage-gated potassium channel are associated with altered fasting and glucose-stimulated plasma incretin and glucagon responses

Author

Engelbrechtsen, Line, Mahendran, Yuvaraj, Jonsson, Anna, Gjesing, Anette Prior, Weeke, Peter E., Jørgensen, Marit E., Færch, Kristine, Witte, Daniel R., Holst, Jens J., Jørgensen, Torben, Grarup, Niels, Pedersen, Oluf, Vestergaard, Henrik, Torekov, Signe, Kanters, Jørgen K., and Hansen, Torben

Published
2018
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16. Microbially Produced Imidazole Propionate Is Associated With Heart Failure and Mortality

Author

Molinaro, Antonio, Nemet, Ina, Bel Lassen, Pierre, Chakaroun, Rima, Nielsen, Trine, Aron-Wisnewsky, Judith, Bergh, Per-Olof, Li, Lin, Henricsson, Marcus, Køber, Lars, Isnard, Richard, Helft, Gerard, Stumvoll, Michael, Pedersen, Oluf, Smith, J. Gustav, Tang, W.H. Wilson, Clément, Karine, Hazen, Stanley L., Bäckhed, Fredrik, Alves, Renato, Amouyal, Chloe, Andersson Galijatovic, Ehm Astrid, Andreelli, Fabrizio, Barthelemy, Olivier, Bastard, Jean-Philippe, Batisse, Jean-Paul, Berland, Magalie, Bittar, Randa, Blüher, Matthias, Bork, Peer, Bourron, Olivier, Camus, Mickael, Cassuto, Dominique, Ciangura, Cecile, Coelho, Luis Pedro, Collet, Jean-Philippe, Dumas, Marc-Emmanuel, Ehrlich, S. Dusko, Engelbrechtsen, Line, Fezeu, Leopold, Forslund, Sofia, Fromentin, Sebastien, Galan, Pilar, Giral, Philippe, Gøtze, Jens Peter, Hansen, Torben, Hansen, Tue H., Hartemann, Agnes, Hartmann, Bolette, Hercberg, Serge, Holmes, Bridget, Holst, Jens Juul, Hornbak, Malene, Hoyles, Lesley, Hulot, Jean-Sebastien, Jaqueminet, Sophie, Kerneis, Mathieu, Khemis, Jean, Kozlowski, Ruby, Pedersen, Helle Krogh, Kuhn, Michael, Mannerås-Holm, Louise, Marko, Lajos, Martinez-Gili Robin Massey, Laura, Maziers, Nicolas, Medina-Stamminger, Jonathan, Moitinho-Silva, Lucas, Montalescot, Gilles, Moutel, Sandrine, Neves, Ana Luisa, Olanipekun, Michael, Oppert, Jean-Michel, Poitou, Christine, Pousset, Francoise, Pouzoulet, Laurence, Rouault, Christine, Silvain, Johanne, and Vestergaard, Henrik

Abstract

Over the past years, it has become clear that the microbial ecosystem in the gut has a profound capacity to interact with the host through the production of a wide range of bioactive metabolites. The microbially produced metabolite imidazole propionate (ImP) is clinically and mechanistically linked with insulin resistance and type 2 diabetes, but it is unclear how ImP is associated with heart failure.

Published
2023
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17. Non-linear interaction between physical activity and polygenic risk score of body mass index in Danish and Russian populations

Author

Borisevich, Dmitrii, primary, Schnurr, Theresia M., additional, Engelbrechtsen, Line, additional, Rakitko, Alexander, additional, Ängquist, Lars, additional, Ilinsky, Valery, additional, Aadahl, Mette, additional, Grarup, Niels, additional, Pedersen, Oluf, additional, Sørensen, Thorkild I. A., additional, and Hansen, Torben, additional

Published
2021
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18. RNA profiles reveal signatures of future health and disease in pregnancy

Author

Rasmussen, Morten, Reddy, Mitsu, Nolan, Rory, Camunas-Soler, Joan, Khodursky, Arkady, Scheller, Nikolai M., Cantonwine, David E., Engelbrechtsen, Line, Mi, Jia Dai, Dutta, Arup, Brundage, Tiffany, Siddiqui, Farooq, Thao, Mainou, Gee, Elaine P. S., La, Johnny, Baruch-Gravett, Courtney, Santillan, Mark K., Deb, Saikat, Ame, Shaali M., Ali, Said M., Adkins, Melanie, DePristo, Mark A., Lee, Manfred, Namsaraev, Eugeni, Gybel-Brask, Dorte Jensen, Skibsted, Lillian, Litch, James A., Santillan, Donna A., Sazawal, Sunil, Tribe, Rachel M., Roberts, James M., Jain, Maneesh, Høgdall, Estrid, Holzman, Claudia, Quake, Stephen R., Elovitz, Michal A., and McElrath, Thomas F.

Subjects
EXPRESSION, Multidisciplinary, MOUSE, Predictive markers, Sensitivity and Specificity, Article, KIDNEY, Pre-Eclampsia, Predictive Value of Tests, Pregnancy, CELLS, Humans, RNA, Female, Gene expression, GESTATIONAL-AGE, Cell-Free Nucleic Acids, FETAL, Retrospective Studies
Abstract

Maternal morbidity and mortality continue to rise, and pre-eclampsia is a major driver of this burden1. Yet the ability to assess underlying pathophysiology before clinical presentation to enable identification of pregnancies at risk remains elusive. Here we demonstrate the ability of plasma cell-free RNA (cfRNA) to reveal patterns of normal pregnancy progression and determine the risk of developing pre-eclampsia months before clinical presentation. Our results centre on comprehensive transcriptome data from eight independent prospectively collected cohorts comprising 1,840 racially diverse pregnancies and retrospective analysis of 2,539 banked plasma samples. The pre-eclampsia data include 524 samples (72 cases and 452 non-cases) from two diverse independent cohorts collected 14.5 weeks (s.d., 4.5 weeks) before delivery. We show that cfRNA signatures from a single blood draw can track pregnancy progression at the placental, maternal and fetal levels and can robustly predict pre-eclampsia, with a sensitivity of 75% and a positive predictive value of 32.3% (s.d., 3%), which is superior to the state-of-the-art method2. cfRNA signatures of normal pregnancy progression and pre-eclampsia are independent of clinical factors, such as maternal age, body mass index and race, which cumulatively account for less than 1% of model variance. Further, the cfRNA signature for pre-eclampsia contains gene features linked to biological processes implicated in the underlying pathophysiology of pre-eclampsia., Expression signatures from cell-free RNA of pregnant women can be used to reveal normal biology of pregnancy and predict development of pre-eclampsia.

Published
2021
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20. Non-linear interaction between physical activity and polygenic risk score of body mass index in Danish and Russian populations

Author

Borisevich, Dmitrii, Schnurr, Theresia M., Engelbrechtsen, Line, Rakitko, Alexander, Ängquist, Lars, Ilinsky, Valery, Aadahl, Mette, Grarup, Niels, Pedersen, Oluf, Sørensen, Thorkild I.A., Hansen, Torben, Borisevich, Dmitrii, Schnurr, Theresia M., Engelbrechtsen, Line, Rakitko, Alexander, Ängquist, Lars, Ilinsky, Valery, Aadahl, Mette, Grarup, Niels, Pedersen, Oluf, Sørensen, Thorkild I.A., and Hansen, Torben

Abstract

Body mass index (BMI) is a highly heritable polygenic trait. It is also affected by various environmental and behavioral risk factors. We used a BMI polygenic risk score (PRS) to study the interplay between the genetic and environmental factors defining BMI. First, we generated a BMI PRS that explained more variance than a BMI genetic risk score (GRS), which was using only genome-wide significant BMI-associated variants (R2 = 13.1% compared to 6.1%). Second, we analyzed interactions between BMI PRS and seven environmental factors. We found a significant interaction between physical activity and BMI PRS, even when the well-known effect of the FTO region was excluded from the PRS, using a small dataset of 6,179 samples. Third, we stratified the study population into two risk groups using BMI PRS. The top 22% of the studied populations were included in a high PRS risk group. Engagement in self-reported physical activity was associated with a 1.66 kg/m2 decrease in BMI in this group, compared to a 0.84 kg/m2 decrease in BMI in the rest of the population. Our results (i) confirm that genetic background strongly affects adult BMI in the general population, (ii) show a non-linear interaction between BMI genetics and physical activity, and (iii) provide a standardized framework for future gene-environment interaction analyses.

Published
2021

21. The influence of transmitted and non-transmitted parental BMI-associated alleles on the risk of overweight in childhood

Author

Schnurr, Theresia M., Morgen, Camilla S., Borisevich, Dmitrii, Beaumont, Robin N., Engelbrechtsen, Line, Ängquist, Lars, Have, Christian T., Freathy, Rachel M., Smith, George Davey, Nohr, Ellen A., Hansen, Torben, Sørensen, Thorkild I.A., Schnurr, Theresia M., Morgen, Camilla S., Borisevich, Dmitrii, Beaumont, Robin N., Engelbrechtsen, Line, Ängquist, Lars, Have, Christian T., Freathy, Rachel M., Smith, George Davey, Nohr, Ellen A., Hansen, Torben, and Sørensen, Thorkild I.A.

Abstract

Overweight in children is strongly associated with parental body mass index (BMI) and overweight. We assessed parental transmitted and non-transmitted genetic contributions to overweight in children from the Danish National Birth Cohort by constructing genetic risk scores (GRSs) from 941 common genetic variants associated with adult BMI and estimating associations of transmitted maternal/paternal and non-transmitted maternal GRS with child overweight. Maternal and paternal BMI (standard deviation (SD) units) had a strong association with childhood overweight [Odds ratio (OR): 2.01 (95% confidence interval (CI) 1.74; 2.34) and 1.64 (95% CI 1.43; 1.89)]. Maternal and paternal transmitted GRSs (SD-units) increased odds for child overweight equally [OR: 1.30 (95% CI 1.16; 1.46) and 1.30 (95% CI 1.16; 1.47)]. However, both the parental phenotypic and the GRS associations may depend on maternal BMI, being weaker among mothers with overweight. Maternal non-transmitted GRS was not associated with child overweight [OR 0.98 (95% CI 0.88; 1.10)] suggesting no specific influence of maternal adiposity as such. In conclusion, parental transmitted GRSs, based on adult BMI, contribute to child overweight, but in overweight mothers other genetic and environmental factors may play a greater role.

Published
2020

23. The influence of transmitted and non-transmitted parental BMI-associated alleles on the risk of overweight in childhood

Author

Schnurr, Theresia M., primary, Morgen, Camilla S., additional, Borisevich, Dmitrii, additional, Beaumont, Robin N., additional, Engelbrechtsen, Line, additional, Ängquist, Lars, additional, Have, Christian T., additional, Freathy, Rachel M., additional, Smith, George Davey, additional, Nohr, Ellen A., additional, Hansen, Torben, additional, and Sørensen, Thorkild I. A., additional

Published
2020
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24. Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration

Author

Wilman, Henry R., Parisinos, Constantinos A., Atabaki-Pasdar, Naeimeh, Kelly, Matt, Thomas, E. Louise, Neubauer, Stefan, Jennison, Christopher, Ehrhardt, Beate, Baum, Patrick, Schoelsch, Corinna, Freijer, Jan, Grempler, Rolf, Graefe-Mody, Ulrike, Hennige, Anita, Dings, Christiane, Lehr, Thorsten, Scherer, Nina, Sihinecich, Iryna, Pattou, Francois, Raverdi, Violeta, Caiazzo, Robert, Torres, Fanelly, Verkindt, Helene, Mari, Andrea, Tura, Andrea, Giorgino, Toni, Bizzotto, Roberto, Froguel, Philippe, Bonneford, Amelie, Canouil, Mickael, Dhennin, Veronique, Brorsson, Caroline, Brunak, Soren, De Masi, Federico, Gudmundsdóttir, Valborg, Pedersen, Helle, Banasik, Karina, Thomas, Cecilia, Sackett, Peter, Staerfeldt, Hans Henrik, Lundgaard, Agnete, Nilsson, Birgitte, Nielsen, Agnes, Mazzoni, Gianluca, Karaderi, Tugce, Rasmussen, Simon, Johansen, Joachim, Allesøe, Rosa, Fritsche, Andreas, Thorand, Barbara, Adamski, Jurek, Grallert, Harald, Haid, Mark, Sharma, Sapna, Troll, Martina, Adam, Jonathan, Ferrer, Jorge, Eriksen, Heather, Frost, Gary, Haussler, Ragna, Hong, Mun gwan, Schwenk, Jochen, Uhlen, Mathias, Nicolay, Claudia, Pavo, Imre, Steckel-Hamann, Birgit, Thomas, Melissa, Adragni, Kofi, Wu, Han, Hart, Leen't, Roderick, Slieker, van Leeuwen, Nienke, Dekkers, Koen, Frau, Francesca, Gassenhuber, Johann, Jablonka, Bernd, Musholt, Petra, Ruetten, Hartmut, Tillner, Joachim, Baltauss, Tania, Bernard Poenaru, Oana, de Preville, Nathalie, Rodriquez, Marianne, Arumugam, Manimozhiyan, Allin, Kristine, Engelbrechtsen, Line, Hansen, Torben, Hansen, Tue, Forman, Annemette, Jonsson, Anna, Pedersen, Oluf, Dutta, Avirup, Vogt, Josef, Vestergaard, Henrik, Laakso, Markku, Kokkola, Tarja, Kuulasmaa, Teemu, Franks, Paul, Giordano, Nick, and Pomares-Millan, Hugo

Subjects
Genome-wide association study, Magnetic resonance imaging, Metabolism, Iron, Genetics, Metabolic syndrome
Abstract

Background & Aims: Excess liver iron content is common and is linked to the risk of hepatic and extrahepatic diseases. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases. Methods: First, we performed a genome-wide association study (GWAS) in 8,289 individuals from UK Biobank, whose liver iron level had been quantified by magnetic resonance imaging, before validating our findings in an independent cohort (n = 1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 25 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 traits and disease outcomes. Results: We identified 3 independent genetic variants (rs1800562 [C282Y] and rs1799945 [H63D] in HFE and rs855791 [V736A] in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p

Published
2019
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25. Genetic determinants of blood pressure traits are associated with carotid arterial thickening and plaque formation in patients with type 2 diabetes

Author

Engelbrechtsen, Line, Appel, Vincent E., Schnurr, Theresia M., Lundby-Christensen, Louise, Skaaby, Thea, Linneberg, Allan, Drivsholm, Thomas, Witte, Daniel R., Jørgensen, Marit E., Grarup, Niels, Pedersen, Oluf, Hansen, Torben, Vestergaard, Henrik, Engelbrechtsen, Line, Appel, Vincent E., Schnurr, Theresia M., Lundby-Christensen, Louise, Skaaby, Thea, Linneberg, Allan, Drivsholm, Thomas, Witte, Daniel R., Jørgensen, Marit E., Grarup, Niels, Pedersen, Oluf, Hansen, Torben, and Vestergaard, Henrik

Published
2019

26. Additional file 1: of Common variants in the hERG (KCNH2) voltage-gated potassium channel are associated with altered fasting and glucose-stimulated plasma incretin and glucagon responses

Author

Engelbrechtsen, Line, Yuvaraj Mahendran, Jonsson, Anna, Gjesing, Anette, Weeke, Peter, Jørgensen, Marit, Færch, Kristine, Witte, Daniel, Holst, Jens, Jørgensen, Torben, Grarup, Niels, Pedersen, Oluf, Vestergaard, Henrik, Torekov, Signe, Kanters, Jørgen, and Hansen, Torben

Subjects
endocrine system, digestive, oral, and skin physiology, hormones, hormone substitutes, and hormone antagonists
Abstract

Calculations of AUC and iAUC. Information on how AUC and iAUC was calculated in the cohorts. Table S1: Participant characteristics in the ADDITION-PRO cohort and Inter99. Anthropometric measures of individuals in the ADDITION-PRO and Inter99 cohort. Table S2. Association of variants (rs36210421 and rs1805123) with QT interval and with metabolic and incretin levels in the Inter99 cohort (n = 5487). Table with measures of QTcF interval and glucose levels in the Inter99 cohort sorted by genetic variant and combined in a genetic risk score. Table S3. Association of KCNH2 variant rs36210421 with metabolic and incretin levels in ADDITION-PRO cohort (N = 1324) (Non diabetes and newly diagnosed T2D). Table with measures of glucose, insulin GIP, GLP-1 and glucagon levels according to carrier status for rs1805123 and rs36210421. Figure S1. Levels of incretins and glucagon according to number of risk alleles. Levels of GLP-1, GIP and Glucagon during an OGTT according to number of risk alleles in the GRS. (DOCX 122 kb)

Published
2018
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27. Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration

Author

Wilman, Henry R., primary, Parisinos, Constantinos A., additional, Atabaki-Pasdar, Naeimeh, additional, Kelly, Matt, additional, Thomas, E. Louise, additional, Neubauer, Stefan, additional, Mahajan, Anubha, additional, Hingorani, Aroon D., additional, Patel, Riyaz S., additional, Hemingway, Harry, additional, Franks, Paul W., additional, Bell, Jimmy D., additional, Banerjee, Rajarshi, additional, Yaghootkar, Hanieh, additional, Jennison, Christopher, additional, Ehrhardt, Beate, additional, Baum, Patrick, additional, Schoelsch, Corinna, additional, Freijer, Jan, additional, Grempler, Rolf, additional, Graefe-Mody, Ulrike, additional, Hennige, Anita, additional, Dings, Christiane, additional, Lehr, Thorsten, additional, Scherer, Nina, additional, Sihinecich, Iryna, additional, Pattou, Francois, additional, Raverdi, Violeta, additional, Caiazzo, Robert, additional, Torres, Fanelly, additional, Verkindt, Helene, additional, Mari, Andrea, additional, Tura, Andrea, additional, Giorgino, Toni, additional, Bizzotto, Roberto, additional, Froguel, Philippe, additional, Bonneford, Amelie, additional, Canouil, Mickael, additional, Dhennin, Veronique, additional, Brorsson, Caroline, additional, Brunak, Soren, additional, De Masi, Federico, additional, Gudmundsdóttir, Valborg, additional, Pedersen, Helle, additional, Banasik, Karina, additional, Thomas, Cecilia, additional, Sackett, Peter, additional, Staerfeldt, Hans-Henrik, additional, Lundgaard, Agnete, additional, Nilsson, Birgitte, additional, Nielsen, Agnes, additional, Mazzoni, Gianluca, additional, Karaderi, Tugce, additional, Rasmussen, Simon, additional, Johansen, Joachim, additional, Allesøe, Rosa, additional, Fritsche, Andreas, additional, Thorand, Barbara, additional, Adamski, Jurek, additional, Grallert, Harald, additional, Haid, Mark, additional, Sharma, Sapna, additional, Troll, Martina, additional, Adam, Jonathan, additional, Ferrer, Jorge, additional, Eriksen, Heather, additional, Frost, Gary, additional, Haussler, Ragna, additional, Hong, Mun-gwan, additional, Schwenk, Jochen, additional, Uhlen, Mathias, additional, Nicolay, Claudia, additional, Pavo, Imre, additional, Steckel-Hamann, Birgit, additional, Thomas, Melissa, additional, Adragni, Kofi, additional, Wu, Han, additional, Hart, Leen't, additional, Roderick, Slieker, additional, van Leeuwen, Nienke, additional, Dekkers, Koen, additional, Frau, Francesca, additional, Gassenhuber, Johann, additional, Jablonka, Bernd, additional, Musholt, Petra, additional, Ruetten, Hartmut, additional, Tillner, Joachim, additional, Baltauss, Tania, additional, Bernard Poenaru, Oana, additional, de Preville, Nathalie, additional, Rodriquez, Marianne, additional, Arumugam, Manimozhiyan, additional, Allin, Kristine, additional, Engelbrechtsen, Line, additional, Hansen, Torben, additional, Hansen, Tue, additional, Forman, Annemette, additional, Jonsson, Anna, additional, Pedersen, Oluf, additional, Dutta, Avirup, additional, Vogt, Josef, additional, Vestergaard, Henrik, additional, Laakso, Markku, additional, Kokkola, Tarja, additional, Kuulasmaa, Teemu, additional, Franks, Paul, additional, Giordano, Nick, additional, Pomares-Millan, Hugo, additional, Fitipaldi, Hugo, additional, Mutie, Pascal, additional, Klintenberg, Maria, additional, Bergstrom, Margit, additional, Groop, Leif, additional, Ridderstrale, Martin, additional, Atabaki Pasdar, Naeimeh, additional, Deshmukh, Harshal, additional, Heggie, Alison, additional, Wake, Dianne, additional, McEvoy, Donna, additional, McVittie, Ian, additional, Walker, Mark, additional, Hattersley, Andrew, additional, Hill, Anita, additional, Jones, Angus, additional, McDonald, Timothy, additional, Perry, Mandy, additional, Nice, Rachel, additional, Hudson, Michelle, additional, Thorne, Claire, additional, Dermitzakis, Emmanouil, additional, Viñuela, Ana, additional, Cabrelli, Louise, additional, Loftus, Heather, additional, Dawed, Adem, additional, Donnelly, Louise, additional, Forgie, Ian, additional, Pearson, Ewan, additional, Palmer, Colin, additional, Brown, Andrew, additional, Koivula, Robert, additional, Wesolowska-Andersen, Agata, additional, Abdalla, Moustafa, additional, McRobert, Nicky, additional, Fernandez, Juan, additional, Jiao, Yunlong, additional, Robertson, Neil, additional, Gough, Stephen, additional, Kaye, Jane, additional, Mourby, Miranda, additional, McCarthy, Mark, additional, Shah, Nisha, additional, Teare, Harriet, additional, Holl, Reinhard, additional, Koopman, Anitra, additional, Rutters, Femke, additional, Beulens, Joline, additional, Groeneveld, Lenka, additional, Bell, Jimmy, additional, Thomas, Louise, additional, and Whitcher, Brandon, additional

Published
2019
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28. Hypertension genetic risk score is associated with burden of coronary heart disease among patients referred for coronary angiography

Author

Krogager, Maria Lukacs, Skals, Regitze Kuhr, Appel, Emil Vincent R., Schnurr, Theresia Maria, Engelbrechtsen, Line, Have, Christian Theil, Pedersen, Oluf Borbye, Engstrøm, Thomas, Roden, Dan M., Gislason, Gunnar, Poulsen, Henrik Enghusen, Køber, Lars, Stender, Steen, Hansen, Torben, Grarup, Niels, Andersson, Charlotte, Torp-Pedersen, Christian, Weeke, Peter E., Krogager, Maria Lukacs, Skals, Regitze Kuhr, Appel, Emil Vincent R., Schnurr, Theresia Maria, Engelbrechtsen, Line, Have, Christian Theil, Pedersen, Oluf Borbye, Engstrøm, Thomas, Roden, Dan M., Gislason, Gunnar, Poulsen, Henrik Enghusen, Køber, Lars, Stender, Steen, Hansen, Torben, Grarup, Niels, Andersson, Charlotte, Torp-Pedersen, Christian, and Weeke, Peter E.

Published
2018

29. Treatment with liraglutide may improve markers of CVD reflected by reduced levels of apoB

Author

Engelbrechtsen, Line, Lundgren, J, Wewer Albrechtsen, Nicolai Jacob, Mahendran, Yuvaraj, Iepsen, Eva Pers Winning, Finocchietto, P., Jonsson, Anna Elisabet, Madsbad, Sten, Holst, Jens Juul, Vestergaard, Henrik, Hansen, T., and Torekov, Signe Sørensen

Subjects
Journal Article, lipids (amino acids, peptides, and proteins)
Abstract

Background: Dislipidaemia and increased levels of apolipoprotein B (apoB) in individuals with obesity are risk factors for development of cardiovascular disease (CVD). The aim of this study was to investigate the effect of weight loss and weight maintenance with and without liraglutide treatment on plasma lipid profiles and apoB.Methods: Fifty-eight individuals with obesity (body mass index 34.5 ± 3.0 kg/m2 [mean ± SD]) were included in this study. After 8 weeks on a very low-calorie diet (800 kcal/day), participants were randomized to weight maintenance with meal replacements with or without liraglutide (1.2 mg daily) for 1 year. Plasma samples from before and after weight loss and after 1 year of weight maintenance were subjected to nuclear magnetic resonance-based lipidomics analysis.Results: After an 8-week low-calorie diet, study participants lost 12.0 ± 2.9 kg (mean ± SD) of their body weight, which was reflected in their lipid profiles (80 out of 124 lipids changed significantly), including reduced levels of apoB, total cholesterol, free cholesterol, remnant cholesterol, triglycerides, low-density lipoprotein and very low-density lipoprotein subclasses. After 1 year of maintained weight loss, the majority of the lipids had returned to pre-weight loss levels even though weight loss was successfully maintained in both groups. Interestingly, apoB levels remained low in the liraglutide treated group (apoB change: 0.03 ± 0.02 mmol/L, p = 0.4) in contrast to an increase in the control group (apoB change: 0.06 ± 0.07 mmol/L, p = 0.02).Conclusion: An 8-week low-calorie diet, in individuals with obesity, reduced plasma levels of lipids and the atherogenic marker apoB. After 1 year of weight maintenance, only study participants treated with liraglutide maintained reduced levels of apoB, despite similar body weight maintenance. Treatment with liraglutide may therefore reduce apoB levels and thus reflect lower CVD risk. Including apoB measurements in clinical practice when monitoring patients with dislipidemia or CVD might prove to be useful.

Published
2017
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30. Hypertension genetic risk score is associated with burden of coronary heart disease among patients referred for coronary angiography

Author

Lukács Krogager, Maria, primary, Skals, Regitze Kuhr, additional, Appel, Emil Vincent R., additional, Schnurr, Theresia M., additional, Engelbrechtsen, Line, additional, Have, Christian Theil, additional, Pedersen, Oluf, additional, Engstrøm, Thomas, additional, Roden, Dan M., additional, Gislason, Gunnar, additional, Poulsen, Henrik Enghusen, additional, Køber, Lars, additional, Stender, Steen, additional, Hansen, Torben, additional, Grarup, Niels, additional, Andersson, Charlotte, additional, Torp-Pedersen, Christian, additional, and Weeke, Peter E., additional

Published
2018
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31. Correction: Hypertension genetic risk score is associated with burden of coronary heart disease among patients referred for coronary angiography.

Author

Krogager, Maria Lukács, Skals, Regitze Kuhr, Appel, Emil Vincent R., Schnurr, Theresia M., Engelbrechtsen, Line, Have, Christian Theil, Pedersen, Oluf, Engstrøm, Thomas, Roden, Dan M., Gislason, Gunnar, Poulsen, Henrik Enghusen, Køber, Lars, Stender, Steen, Hansen, Torben, Grarup, Niels, Andersson, Charlotte, Torp-Pedersen, Christian, and Weeke, Peter E.

Subjects
CARDIAC patients, CORONARY disease, CORONARY angiography, HYPERTENSION, GENETIC risk score
Abstract

In the Ethics subsection of the Methods, there is an error in the paragraph. Reference 1 Lukács Krogager M, Skals RK, Appel EVR, Schnurr TM, Engelbrechtsen L, Have CT, et al. (2018) Hypertension genetic risk score is associated with burden of coronary heart disease among patients referred for coronary angiography. [Extracted from the article]

Published
2023
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33. Pharmacogenetics and individual responses to treatment of hyperglycemia in type 2 diabetes.

Author

Engelbrechtsen, Line, Galijatovic, Ehm Astrid Andersson, Roepstorff, Søren, Hansen, Torben, Vestergaard, Henrik, Engelbrechtsen, Line, Galijatovic, Ehm Astrid Andersson, Roepstorff, Søren, Hansen, Torben, and Vestergaard, Henrik

Abstract

The aim of this study was to summarize current knowledge and provide perspectives on the relationships between human genetic variants, type 2 diabetes, antidiabetic treatment, and disease progression. Type 2 diabetes is a complex disease with clear-cut diagnostic criteria and treatment guidelines. Yet, the interindividual response to therapy and slope of disease progression varies markedly among patients with type 2 diabetes. Gene–gene, gene–environment, and gene–treatment interactions may explain some of the variation in disease progression. Several genetic variants have been suggested to be associated with response to antidiabetic drugs. Some are present in drug receptors or drug metabolizers (OCT genes, KCNJ11, ABCC8, and CYP2C9). Numerous type 2 diabetes risk variants have been identified, but genetic risk score models applying these variants have failed to identify ‘disease progressors’ among patients with diabetes. Although genetic risk scores are based on a few known loci and only explain a fraction of the heritability of type 2 diabetes, it seems that the genes responsible for the development of diabetes may not be the same driving disease progression after the diagnosis has been made. Pharmacogenetic interactions explain some of the interindividual variation in responses to antidiabetic treatment and may provide the foundation for future genotype-based treatment standards.

Published
2015

34. Ashermans syndrom

Author

Istre, Olav, Engelbrechtsen, Line, Istre, Olav, and Engelbrechtsen, Line

Published
2015

36. Detection of triploidy at 11-14 weeks of gestation:A cohort study of 198,000 pregnant women

Author

Engelbrechtsen, Line, Brøndum-Nielsen, Karen, Ekelund, Charlotte Kvist, Tabor, Ann, and Skibsted, Lillian

Subjects
reproductive and urinary physiology
Abstract

OBJECTIVES: To assess the detection rate of triploidy at first-trimester screening for trisomy 21 and evaluate outcome in triploid pregnancies. METHODS: From 2008-2011, 198,427 patients women with singleton pregnancies underwent first-trimester screening (FTS) at 11+2 - 14+0 weeks of gestation. FTS included: Nuchal translucency (NT), maternal serum free β-human chorionic gonadotrophin (β-hCG) and pregnancy associated plasma protein-A (PAPP-A). In all triploid fetuses FTS parameters were re-evaluated. Karyotypes were established by invasive testing (CVS or AC) or post abortem and obtained from the Danish Cytogenetic Central Register and the Danish Fetal Medicine Database. RESULTS: A total of 30 triploid fetuses attended FTS. Twenty-five triploid fetuses were diagnosed as a result of abnormal FTS, a detection rate of 83%.Twenty-three fetuses were identified due to a high risk of trisomy 13, 18 or 21 and two fetuses due to structural abnormalities at FTS. The incidence of triploidy at FTS was 1:6614. A smaller CRL than estimated by last menstrual period was found in 95 % of the fetuses with the data available for evaluation. Eight fetuses had larger BPD than expected by gestational age. 69, XXX fetuses had significantly lower β-hCG MoM and PAPP-A MoM than 69, XXY fetuses (p=0.045 and p=0.02). No infants with triploidy were born in the study period. Among the triploid gestations, 80% of the women chose termination of pregnancy, 16 % had spontaneous miscarriages, and one was stillborn. CONCLUSION: First trimester screening for trisomy 21 also provides a high detection rate for triploidy.

Published
2013
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37. Cesarean section for the second twin: a population-based study of occurrence and outcome

Author

Engelbrechtsen, Line, Nielsen, Elise Hoffmann, Perin, Trine, Oldenburg, Anna, Tabor, Ann, Skibsted, Lillian, Bødker, Birgit, Ersbak, Vibeke, Holmskov, Anni, JØorgensen, Finn Stener, Larsen, Helle, Larsen, Torben, Laursen, Lone, Mogensen, Helle, Petersen, Olav Bjørn, Sperling, Lene, Stornes, Inger, and Zingenberg, Helle

Subjects
Adult, medicine.medical_specialty, Denmark, Population, Intrauterine growth restriction, Labor Presentation, Umbilical Cord, Cohort Studies, Pregnancy, Medicine, Humans, Registries, education, Twin Pregnancy, Retrospective Studies, education.field_of_study, business.industry, Vaginal delivery, Obstetrics, Cesarean Section, Infant, Newborn, Obstetrics and Gynecology, Gestational age, Neonatal outcome, Hydrogen-Ion Concentration, medicine.disease, Twin delivery, Combined delivery, Apgar Score, Pregnancy, Twin, Fetal presentation, Apgar score, Female, business, Cohort study
Abstract

Background: Although management of twin deliveries has been a topic ofdiscussion for decades, a consensus on how to deliver twins is lacking. The objective of thisstudy was to examine short-term neonatal outcome of the second twin delivered by cesareansection after vaginal delivery of the first-born twin (combined delivery) and to identifypredictors of combined delivery. Methods: This study was a 3-year, population-based,retrospective cohort investigation of 1,254 twin births in Denmark. The twin births weredivided into three groups: vaginal deliveries, planned cesarean deliveries, and combineddeliveries. Data were extracted from medical records, a fetal medicine software program(Astraia), and the National Birth Registry. Short-term poor neonatal outcome was measuredas a 5-minute Apgar score 7, umbilical cord pH 7.10, and admission to neonatalintensive care unit for more than 3 days. Results: Vertex-nonvertex fetal presentations weremore prevalent in combined deliveries than vaginal deliveries (OR 4.4, 2.5–7.8). Nonvertexsecond twins born by combined delivery had a higher risk of Apgar score 7 and umbilicalcord pH 7.10 compared with vaginal delivery, unadjusted OR 6.2 (2.1–18), andunadjusted OR 3.9 (1.6–9.5). Prenatal ultrasound scans were evaluated in combineddeliveries, of which 48 percent were vertex-vertex at the last ultrasound scan in pregnancy(mean gestational age 34 + 0) and 37 percent were vertex-vertex at birth. Conclusions:Vertex-nonvertex presenting twins have an increased risk of combined delivery. Combineddeliveries are associated with increased neonatal morbidity for the second twin. (BIRTH 40:1March 2013)Key words: combined delivery, fetal presentation, neonatal outcome, twin deliveryManagement of twin deliveries has been a topic ofdiscussion for decades, yet the lack of randomized tri-als on the subject still leaves unanswered the questionconcerning optimal mode of twin delivery. In Denmark,there is a consensus that vaginal delivery may beattempted in women with cephalic presenting twins ofsimilar size, no contraindications to trial of labor, andno intrauterine growth restriction of one or both twins.However, controversy on mode of delivery still remainswhen the second twin presents as nonvertex.

Published
2012
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42. Cesarean Section for the Second Twin:A Population-Based Study of Occurrence and Outcome

Author

Engelbrechtsen, Line, Nielsen, Elise Hoffmann, Perin, Trine, Oldenburg, Anna, Tabor, Ann, Skibsted, Lillian, Bødker, Birgit, Ersbak, Vibeke, Holmskov, Anni, Petersen, Olav Bjørn, Sperling, Lene, Stornes, Inger, Zingenberg, Helle, Engelbrechtsen, Line, Nielsen, Elise Hoffmann, Perin, Trine, Oldenburg, Anna, Tabor, Ann, Skibsted, Lillian, Bødker, Birgit, Ersbak, Vibeke, Holmskov, Anni, Petersen, Olav Bjørn, Sperling, Lene, Stornes, Inger, and Zingenberg, Helle

Abstract

BACKGROUND: Although management of twin deliveries has been a topic of discussion for decades, a consensus on how to deliver twins is lacking. The objective of this study was to examine short-term neonatal outcome of the second twin delivered by cesarean section after vaginal delivery of the first-born twin (combined delivery) and to identify predictors of combined delivery.METHODS: This study was a 3-year, population-based, retrospective cohort investigation of 1,254 twin births in Denmark. The twin births were divided into three groups: vaginal deliveries, planned cesarean deliveries, and combined deliveries. Data were extracted from medical records, a fetal medicine software program (Astraia), and the National Birth Registry. Short-term poor neonatal outcome was measured as a 5-minute Apgar score ≤ 7, umbilical cord pH ≤ 7.10, and admission to neonatal intensive care unit for more than 3 days.RESULTS: Vertex-nonvertex fetal presentations were more prevalent in combined deliveries than vaginal deliveries (OR 4.4, 2.5-7.8). Nonvertex second twins born by combined delivery had a higher risk of Apgar score ≤ 7 and umbilical cord pH ≤ 7.10 compared with vaginal delivery, unadjusted OR 6.2 (2.1-18), and unadjusted OR 3.9 (1.6-9.5). Prenatal ultrasound scans were evaluated in combined deliveries, of which 48 percent were vertex-vertex at the last ultrasound scan in pregnancy (mean gestational age 34 + 0) and 37 percent were vertex-vertex at birth.CONCLUSIONS: Vertex-nonvertex presenting twins have an increased risk of combined delivery. Combined deliveries are associated with increased neonatal morbidity for the second twin.

Published
2013

43. Common variants in the <italic>hERG</italic> (<italic>KCNH2</italic>) voltage-gated potassium channel are associated with altered fasting and glucose-stimulated plasma incretin and glucagon responses.

Author

Engelbrechtsen, Line, Mahendran, Yuvaraj, Jonsson, Anna, Gjesing, Anette Prior, Weeke, Peter E., Jørgensen, Marit E., Færch, Kristine, Witte, Daniel R., Holst, Jens J., Jørgensen, Torben, Grarup, Niels, Pedersen, Oluf, Vestergaard, Henrik, Torekov, Signe, Kanters, Jørgen K., and Hansen, Torben

Subjects
GENETIC disorders, GLUCOSE metabolism, VOLTAGE-gated ion channels, ARRHYTHMIA, ALLELES, POTASSIUM channels, FASTING, GLUCAGON
Abstract

Background: Patients with long QT syndrome due to rare loss-of-function mutations in the human ether-á-go-go-related gene (hERG) have prolonged QT interval, risk of arrhythmias, increased secretion of insulin and incretins and impaired glucagon response to hypoglycemia. This is caused by a dysfunctional Kv11.1 voltage-gated potassium channel. Based on these findings in patients with rare variants in hERG, we hypothesized that common variants in hERG may also lead to alterations in glucose homeostasis. Subsequently, we aimed to evaluate the effect of two common gain-of-function variants in hERG (rs36210421 and rs1805123) on QT interval and plasma levels of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), insulin and glucagon during an oral glucose tolerance test (OGTT). We used two population-based cohorts for evaluation of the effect of common variants in hERG on QT-interval and circulation levels of incretins, insulin and glucagon. The Danish population-based Inter99 cohort (n = 5895) was used to assess the effect of common variants on QT-interval. The Danish ADDITION-PRO cohort was used (n = 1329) to study genetic associations with levels of GLP-1, GIP, insulin and glucagon during an OGTT. Results: Carriers of either the minor A-allele of rs36210421 or the minor G-allele of rs1805123 had ~ 2 ms shorter QT interval per risk allele (p = 0.025 and p = 1.9 × 10− 7). Additionally, both variants were associated with alterations in pancreatic and gut hormone release among carriers. The minor A- allele of rs36210421 was associated with increased GLP-1 and decreased GIP response to oral glucose stimulation, whereas the minor G-allele of rs1805123 is associated with decreased fasting plasma insulin and glucagon release. A genetic risk score combining the two gene variants revealed reductions in glucose-stimulated GIP, as well as suppressed glucagon response to increased glucose levels during an OGTT. Conclusions: Two common missense polymorphisms of the Kv11.1 voltage-gated hERG potassium channel are associated with alterations in circulating levels of GIP and glucagon, suggesting that hERG potassium channels play a role in fasting and glucose-stimulated release of GIP and glucagon. Trial registration: ClinicalTrials.gov (NCT00289237). Trial retrospectively registered at February 9, 2006. Studies were approved by the Ethical Committee of the Central Denmark Region (journal no. 20080229) and by the Copenhagen County Ethical Committee (KA 98155). [ABSTRACT FROM AUTHOR]

Published
2018
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45. Prophylactic progesterone and preterm birth.

Author

Madsen C, Ørsted AO, Rasmussen MB, Christensen MH, Engelbrechtsen L, Canning MM, Viuff MH, Storgaard L, and Lauenborg J

Subjects
Humans, Pregnancy, Female, Administration, Intravaginal, Risk Factors, Cervical Length Measurement, Cervix Uteri, Premature Birth prevention & control, Progesterone administration & dosage, Progesterone therapeutic use, Progestins administration & dosage, Progestins therapeutic use
Abstract

This review summarises the present knowledge of prophylactic progesterone and preterm birth. Preterm birth (less-than 37 weeks) is a leading cause of neonatal mortality and morbidity worldwide. The incidence varies globally but remains low in the Nordic countries (5-6%). Prediction and prevention are complicated due to diverse aetiology, but obstetric history and cervical length can improve prediction. Prophylactic vaginal progesterone initiated between 12 and 24 weeks of gestation is recommended to reduce preterm birth less-than 33-35 weeks in singleton pregnancies with a history of preterm birth or with a short cervix (less-than 25 mm) and can be considered for twin pregnancies with the same risk factors., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Published
2024
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46. Genetic determinants of blood pressure traits are associated with carotid arterial thickening and plaque formation in patients with type 2 diabetes.

Author

Engelbrechtsen L, Appel VE, Schnurr TM, Lundby-Christensen L, Skaaby T, Linneberg A, Drivsholm T, Witte DR, Jorgensen ME, Grarup N, Pedersen O, Hansen T, and Vestergaard H

Subjects
Aged, Carotid Artery Diseases diagnostic imaging, Case-Control Studies, Diabetes Mellitus, Type 2 diagnosis, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Hypertension diagnosis, Hypertension physiopathology, Male, Middle Aged, Phenotype, Predictive Value of Tests, Randomized Controlled Trials as Topic, Risk Assessment, Risk Factors, Blood Pressure genetics, Carotid Artery Diseases genetics, Carotid Intima-Media Thickness, Diabetes Mellitus, Type 2 genetics, Hypertension genetics, Plaque, Atherosclerotic, Quantitative Trait Loci, Quantitative Trait, Heritable
Abstract

Objectives: The aim of this study is to explore the contribution of genetically driven cardiometabolic risk factors for development of carotid arterial thickening in patients with type 2 diabetes., Methods: In total, 12 genetic risk scores for blood pressure, blood lipids and glycaemic traits were constructed. The genetic risk scores were tested for association with carotid intima-media thickness and plaques in patients with type 2 diabetes ( n = 401) and in non-diabetic individuals ( n = 648) and for association with glucose levels in two population-based cohorts ( n = 1328 and n = 6161)., Results: In patients with type 2 diabetes, the genetic risk scores for pulse pressure were positively associated with plaque formation ( β = 0.036 ± 0.01 standard deviation/allele, p = 0.003). The genetic risk score for diastolic blood pressure was negatively associated with carotid intima-media thickness ( β = -0.037 ± 0.01 standard deviation/allele, p = 0.005), although not significant after correction for multiple testing ( p < 0.0042). In a meta-analysis of individuals with and without type 2 diabetes, the high-density lipoprotein genetic risk scores showed a trend towards an inverse association with carotid intima-media thickness and plaques, while the low-density lipoprotein genetic risk scores showed a trend towards a positive association with plaque formation but did reach the statistical threshold., Conclusion: Genetic loci for pulse pressure are associated with plaque formation among patients with type 2 diabetes, suggesting an underlying genetic contribution to arterial stiffening and atherosclerosis.

Published
2019
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47. [Gallstones and gallstone-associated complications in patients treated with statin].

Author

Roepstorff S and Engelbrechtsen L

Subjects
Cholangitis prevention & control, Cholecystitis prevention & control, Cholesterol metabolism, Gallstones complications, Gallstones pathology, Humans, Pancreatitis prevention & control, Gallstones prevention & control, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use
Abstract

Statins are a widely used group of drugs which can lower cholesterol levels. Recently, there has been emerging evidence that statins may decrease the formation of cholesterol gallstones and several studies have reported invert association between symptomatic cholesterol gallstones and statin use. Subsequent evidence for decrease in gallstone-associated complications among statin users have not been clearly described. In this review we summarize current evidence for the association between statin use and the risk of gallstone-associated complications.

Published
2015

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