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1. A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease

Author

Scott, Robert A, Freitag, Daniel F, Li, Li, Chu, Audrey Y, Surendran, Praveen, Young, Robin, Grarup, Niels, Stancáková, Alena, Chen, Yuning, Varga, Tibor V, Yaghootkar, Hanieh, Luan, Jian’an, Zhao, Jing Hua, Willems, Sara M, Wessel, Jennifer, Wang, Shuai, Maruthur, Nisa, Michailidou, Kyriaki, Pirie, Ailith, van der Lee, Sven J, Gillson, Christopher, Al Olama, Ali Amin, Amouyel, Philippe, Arriola, Larraitz, Arveiler, Dominique, Aviles-Olmos, Iciar, Balkau, Beverley, Barricarte, Aurelio, Barroso, Inês, Garcia, Sara Benlloch, Bis, Joshua C, Blankenberg, Stefan, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Borecki, Ingrid B, Bork-Jensen, Jette, Bowden, Sarah, Caldas, Carlos, Caslake, Muriel, consortium, The CVD50, Cupples, L Adrienne, Cruchaga, Carlos, Czajkowski, Jacek, Hoed, Marcel den, Dunn, Janet A, Earl, Helena M, Ehret, Georg B, Ferrannini, Ele, Ferrieres, Jean, Foltynie, Thomas, Ford, Ian, Forouhi, Nita G, Gianfagna, Francesco, Gonzalez, Carlos, Grioni, Sara, Hiller, Louise, Jansson, Jan-Håkan, Jørgensen, Marit E, Jukema, J Wouter, Kaaks, Rudolf, Kee, Frank, Kerrison, Nicola D, Key, Timothy J, Kontto, Jukka, Kote-Jarai, Zsofia, Kraja, Aldi T, Kuulasmaa, Kari, Kuusisto, Johanna, Linneberg, Allan, Liu, Chunyu, Marenne, Gaëlle, Mohlke, Karen L, Morris, Andrew P, Muir, Kenneth, Müller-Nurasyid, Martina, Munroe, Patricia B, Navarro, Carmen, Nielsen, Sune F, Nilsson, Peter M, Nordestgaard, Børge G, Packard, Chris J, Palli, Domenico, Panico, Salvatore, Peloso, Gina M, Perola, Markus, Peters, Annette, Poole, Christopher J, Quirós, J Ramón, Rolandsson, Olov, Sacerdote, Carlotta, Salomaa, Veikko, Sánchez, María-José, Sattar, Naveed, Sharp, Stephen J, Sims, Rebecca, Slimani, Nadia, Smith, Jennifer A, Thompson, Deborah J, and Trompet, Stella

Subjects
Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Clinical Research, Diabetes, Human Genome, Cardiovascular, Prevention, Obesity, Genetics, Heart Disease, Heart Disease - Coronary Heart Disease, Clinical Trials and Supportive Activities, Aetiology, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, 2.1 Biological and endogenous factors, Metabolic and endocrine, Good Health and Well Being, Alleles, Coronary Disease, Diabetes Mellitus, Type 2, Dipeptidyl Peptidase 4, Genotype, Glucagon-Like Peptide-1 Receptor, Humans, Receptor, Cannabinoid, CB2, Receptor, Serotonin, 5-HT2C, Receptors, Somatostatin, Sodium-Glucose Transporter 1, CVD50 consortium, GERAD_EC Consortium, Neurology Working Group of the Cohorts for Heart, Aging Research in Genomic Epidemiology, Alzheimer’s Disease Genetics Consortium, Pancreatic Cancer Cohort Consortium, European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease, EPIC-InterAct, CHARGE consortium, CHD Exome+ Consortium, CARDIOGRAM Exome Consortium, Biological Sciences, Medical and Health Sciences, Medical biotechnology, Biomedical engineering
Abstract

Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.

Published
2016

2. Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use

Author

Surendran, Praveen, Young, Robin, Barnes, Daniel R., Nielsen, Sune Fallgaard, Rasheed, Asif, Samuel, Maria, Zhao, Wei, Kontto, Jukka, Perola, Markus, Caslake, Muriel, de Craen, Anton J.M., Trompet, Stella, Uria-Nickelsen, Maria, Malarstig, Anders, Reily, Dermot F., Hoek, Maarten, Vogt, Thomas, Jukema, J. Wouter, Sattar, Naveed, Ford, Ian, Packard, Chris J., Alam, Dewan S., Majumder, Abdulla al Shafi, Di Angelantonio, Emanuele, Chowdhury, Rajiv, Amouyel, Philippe, Arveiler, Dominique, Blankenberg, Stefan, Ferrières, Jean, Kee, Frank, Kuulasmaa, Kari, Müller-Nurasyid, Martina, Veronesi, Giovanni, Virtamo, Jarmo, EPIC-CVD Consortium, Frossard, Philippe, Nordestgaard, Børge Grønne, Saleheen, Danish, Danesh, John, Butterworth, Adam S., Howson, Joanna M.M., Erzurumluoglu, A. Mesut, Jackson, Victoria E., Melbourne, Carl A., Varga, Tibor V., Warren, Helen R., Tragante, Vinicius, Tachmazidou, Ioanna, Harris, Sarah E., Evangelou, Evangelos, Marten, Jonathan, Zhang, Weihua, Altmaier, Elisabeth, Luan, Jian’an, Langenberg, Claudia, Scott, Robert A., Yaghootkar, Hanieh, Stirrups, Kathleen, Kanoni, Stavroula, Marouli, Eirini, Karpe, Fredrik, Dominiczak, Anna F., Sever, Peter, Poulter, Neil, Rolandsson, Olov, Baumbach, Clemens, Afaq, Saima, Chambers, John C., Kooner, Jaspal S., Wareham, Nicholas J., Renström, Frida, Hallmans, Göran, Marioni, Riccardo E., Corley, Janie, Starr, John M., Verweij, Niek, de Boer, Rudolf A., van der Meer, Peter, Yavas, Ersin, Vaartjes, Ilonca, Bots, Michiel L., Asselbergs, Folkert W., Grabe, Hans J., Völzke, Henry, Nauck, Matthias, Weiss, Stefan, Pharoah, Paul D.P., Dunning, Alison M., Dennis, Joe G., Thompson, Deborah J., Michailidou, Kyriaki, Easton, Douglas F., Antoniou, Antonis C., Tyrrell, Jessica, Mihailov, Evelin, Samani, Nilesh J., Zhou, Kaixin, Neville, Matthew J., Metspalu, Andres, Palmer, Colin N.A., Hall, Ian P., Strachan, David P., Deary, Ian J., Frayling, Tim M., Hayward, Caroline, van der Harst, Pim, Zeggini, Eleftheria, Understanding Society Scientific Group, Munroe, Patricia B., Jansson, Jan-Håkan, Franks, Paul W., Deloukas, Panos, Caulfield, Mark J., Wain, Louise V., Tobin, Martin D., Brazel, David M., Jiang, Yu, Hughey, Jordan M., Turcot, Valérie, Zhan, Xiaowei, Gong, Jian, Batini, Chiara, Weissenkampen, J. Dylan, Liu, MengZhen, Bertelsen, Sarah, Chou, Yi-Ling, Faul, Jessica D., Haessler, Jeff, Hammerschlag, Anke R., Hsu, Chris, Kapoor, Manav, Lai, Dongbing, Le, Nhung, de Leeuw, Christiaan A., Loukola, Anu, Mangino, Massimo, Pistis, Giorgio, Qaiser, Beenish, Rohde, Rebecca, Shao, Yaming, Stringham, Heather, Wetherill, Leah, Agrawal, Arpana, Bierut, Laura, Chen, Chu, Eaton, Charles B., Goate, Alison, Haiman, Christopher, Heath, Andrew, Iacono, William G., Martin, Nicholas G., Polderman, Tinca J., Reiner, Alex, Rice, John, Schlessinger, David, Scholte, H. Steven, Smith, Jennifer A., Tardif, Jean-Claude, Tindle, Hilary A., van der Leij, Andries R., Boehnke, Michael, Chang-Claude, Jenny, Cucca, Francesco, David, Sean P., Foroud, Tatiana, Kardia, Sharon L.R., Kooperberg, Charles, Laakso, Markku, Lettre, Guillaume, Madden, Pamela, McGue, Matt, North, Kari, Posthuma, Danielle, Spector, Timothy, Stram, Daniel, Weir, David R., Kaprio, Jaakko, Abecasis, Gonçalo R., Liu, Dajiang J., and Vrieze, Scott

Published
2019
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5. Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use

Author

Brazel, David M., Jiang, Yu, Hughey, Jordan M., Turcot, Valerie, Zhan, Xiaowei, Gong, Jian, Batini, Chiara, Weissenkampen, J. Dylan, Liu, MengZhen, Barnes, Daniel R., Bertelsen, Sarah, Chou, Yi-Ling, Erzurumluoglu, A. Mesut, Faul, Jessica D., Haessler, Jeff, Hammerschlag, Anke R., Hsu, Chris, Kapoor, Manav, Lai, Dongbing, Le, Nhung, de Leeuw, Christiaan A., Loukola, Anu, Mangino, Massimo, Melbourne, Carl A., Pistis, Giorgio, Qaiser, Beenish, Rohde, Rebecca, Shao, Yaming, Stringham, Heather, Wetherill, Leah, Zhao, Wei, Agrawal, Arpana, Bierut, Laura, Chen, Chu, Eaton, Charles B., Goate, Alison, Haiman, Christopher, Heath, Andrew, Iacono, William G., Martin, Nicholas G., Polderman, Tinca J., Reiner, Alex, Rice, John, Schlessinger, David, Scholte, H. Steven, Smith, Jennifer A., Tardif, Jean-Claude, Tindle, Hilary A., van der Leij, Andries R., Boehnke, Michael, Chang-Claude, Jenny, Cucca, Francesco, David, Sean P., Foroud, Tatiana, Howson, Joanna M. M., Kardia, Sharon L. R., Kooperberg, Charles, Laakso, Markku, Lettre, Guillaume, Madden, Pamela, Mcgue, Matt, North, Kari, Posthuma, Danielle, Spector, Timothy, Stram, Daniel, Tobin, Martin D., Weir, David R., Kaprio, Jaakko, Abecasis, Goncalo R., Liu, Dajiang J., Vrieze, Scott, Surendran, Praveen, Young, Robin, Nielsen, Sune Fallgaard, Rasheed, Asif, Samuel, Maria, Kontto, Jukka, Perola, Markus, Caslake, Muriel, de Craen, Anton J. M., Trompet, Stella, Uria-Nickelsen, Maria, Malarstig, Anders, Reily, Dermot F., Hoek, Maarten, Vogt, Thomas, Jukema, J. Wouter, Sattar, Naveed, Ford, Ian, Packard, Chris J., Alam, Dewan S., Majumder, Abdulla al Shafi, Di Ange-Lantonio, Emanuele, Chowdhury, Rajiv, Amouyel, Philippe, Arveiler, Dominique, Blankenberg, Stefan, Ferrieres, Jean, Kee, Frank, Kuulasmaa, Kari, Mueller-Nurasyid, Martina, Veronesi, Giovanni, Virtamo, Jarmo, Frossard, Philippe, Nordestgaard, Borge Gronne, Saleheen, Danish, Danesh, John, Butterworth, Adam S., Jackson, Victoria E., Varga, Tibor V., Warren, Helen R., Tragante, Vinicius, Tachmazidou, Ioanna, Harris, Sarah E., Evangelou, Evangelos, Marten, Jonathan, Zhang, Weihua, Altmaier, Elisabeth, Luan, Jian'an, Langenberg, Claudia, Scott, Robert A., Yaghootkar, Hanieh, Stirrups, Kathleen, Kanoni, Stavroula, Marouli, Eirini, Karpe, Fredrik, Dominiczak, Anna F., Sever, Peter, Poulter, Neil, Rolandsson, Olov, Baumbach, Clemens, Afaq, Saima, Chambers, John C., Kooner, Jaspal S., Wareham, Nicholas J., Renstrom, Frida, Hallmans, Goran, Marioni, Riccardo E., Corley, Janie, Starr, John M., Verweij, Niek, de Boer, Rudolf A., van der Meer, Peter, Yavas, Ersin, Vaartjes, Ilonca, Bots, Michiel L., Asselbergs, Folkert W., Grabe, Hans J., Volzke, Henry, Nauck, Matthias, Weiss, Stefan, Pharoah, Paul D. P., Dunning, Alison M., Dennis, Joe G., Thompson, Deborah J., Michailidou, Kyriaki, Easton, Douglas F., Antoniou, Antonis C., Tyrrell, Jessica, Mihailov, Evelin, Samani, Nilesh J., Zhou, Kaixin, Neville, Matthew J., Metspalu, Andres, Palmer, Colin N. A., Hall, Ian P., Strachan, David P., Deary, Ian J., Frayling, Tim M., Hayward, Caroline, van der Harst, Pim, Zeggini, Eleftheria, Munroe, Patricia B., Jansson, Jan-Hakan, Franks, Paul W., Deloukas, Panos, Caulfield, Mark J., Wain, Louise V., Brazel, David M., Jiang, Yu, Hughey, Jordan M., Turcot, Valerie, Zhan, Xiaowei, Gong, Jian, Batini, Chiara, Weissenkampen, J. Dylan, Liu, MengZhen, Barnes, Daniel R., Bertelsen, Sarah, Chou, Yi-Ling, Erzurumluoglu, A. Mesut, Faul, Jessica D., Haessler, Jeff, Hammerschlag, Anke R., Hsu, Chris, Kapoor, Manav, Lai, Dongbing, Le, Nhung, de Leeuw, Christiaan A., Loukola, Anu, Mangino, Massimo, Melbourne, Carl A., Pistis, Giorgio, Qaiser, Beenish, Rohde, Rebecca, Shao, Yaming, Stringham, Heather, Wetherill, Leah, Zhao, Wei, Agrawal, Arpana, Bierut, Laura, Chen, Chu, Eaton, Charles B., Goate, Alison, Haiman, Christopher, Heath, Andrew, Iacono, William G., Martin, Nicholas G., Polderman, Tinca J., Reiner, Alex, Rice, John, Schlessinger, David, Scholte, H. Steven, Smith, Jennifer A., Tardif, Jean-Claude, Tindle, Hilary A., van der Leij, Andries R., Boehnke, Michael, Chang-Claude, Jenny, Cucca, Francesco, David, Sean P., Foroud, Tatiana, Howson, Joanna M. M., Kardia, Sharon L. R., Kooperberg, Charles, Laakso, Markku, Lettre, Guillaume, Madden, Pamela, Mcgue, Matt, North, Kari, Posthuma, Danielle, Spector, Timothy, Stram, Daniel, Tobin, Martin D., Weir, David R., Kaprio, Jaakko, Abecasis, Goncalo R., Liu, Dajiang J., Vrieze, Scott, Surendran, Praveen, Young, Robin, Nielsen, Sune Fallgaard, Rasheed, Asif, Samuel, Maria, Kontto, Jukka, Perola, Markus, Caslake, Muriel, de Craen, Anton J. M., Trompet, Stella, Uria-Nickelsen, Maria, Malarstig, Anders, Reily, Dermot F., Hoek, Maarten, Vogt, Thomas, Jukema, J. Wouter, Sattar, Naveed, Ford, Ian, Packard, Chris J., Alam, Dewan S., Majumder, Abdulla al Shafi, Di Ange-Lantonio, Emanuele, Chowdhury, Rajiv, Amouyel, Philippe, Arveiler, Dominique, Blankenberg, Stefan, Ferrieres, Jean, Kee, Frank, Kuulasmaa, Kari, Mueller-Nurasyid, Martina, Veronesi, Giovanni, Virtamo, Jarmo, Frossard, Philippe, Nordestgaard, Borge Gronne, Saleheen, Danish, Danesh, John, Butterworth, Adam S., Jackson, Victoria E., Varga, Tibor V., Warren, Helen R., Tragante, Vinicius, Tachmazidou, Ioanna, Harris, Sarah E., Evangelou, Evangelos, Marten, Jonathan, Zhang, Weihua, Altmaier, Elisabeth, Luan, Jian'an, Langenberg, Claudia, Scott, Robert A., Yaghootkar, Hanieh, Stirrups, Kathleen, Kanoni, Stavroula, Marouli, Eirini, Karpe, Fredrik, Dominiczak, Anna F., Sever, Peter, Poulter, Neil, Rolandsson, Olov, Baumbach, Clemens, Afaq, Saima, Chambers, John C., Kooner, Jaspal S., Wareham, Nicholas J., Renstrom, Frida, Hallmans, Goran, Marioni, Riccardo E., Corley, Janie, Starr, John M., Verweij, Niek, de Boer, Rudolf A., van der Meer, Peter, Yavas, Ersin, Vaartjes, Ilonca, Bots, Michiel L., Asselbergs, Folkert W., Grabe, Hans J., Volzke, Henry, Nauck, Matthias, Weiss, Stefan, Pharoah, Paul D. P., Dunning, Alison M., Dennis, Joe G., Thompson, Deborah J., Michailidou, Kyriaki, Easton, Douglas F., Antoniou, Antonis C., Tyrrell, Jessica, Mihailov, Evelin, Samani, Nilesh J., Zhou, Kaixin, Neville, Matthew J., Metspalu, Andres, Palmer, Colin N. A., Hall, Ian P., Strachan, David P., Deary, Ian J., Frayling, Tim M., Hayward, Caroline, van der Harst, Pim, Zeggini, Eleftheria, Munroe, Patricia B., Jansson, Jan-Hakan, Franks, Paul W., Deloukas, Panos, Caulfield, Mark J., and Wain, Louise V.

Published
2019

6. miR‐34a−/− mice are susceptible to diet‐induced obesity

Author

Lavery, Christopher A., Kurowska‐Stolarska, Mariola, Holmes, William M., Donnelly, Iona, Caslake, Muriel, Collier, Andrew, Baker, Andrew H., and Miller, Ashley M.

Subjects
Tumor Necrosis Factor-alpha, Adipose Tissue, White, Macrophages, Original Articles, Diet, High-Fat, Interleukin-10, Mice, Inbred C57BL, Mice, MicroRNAs, Adipose Tissue, Adipose Tissue, Brown, Liver, Animals, Original Article, Obesity Biology and Integrated Physiology, Obesity
Abstract

Objective MicroRNA (miR)−34a regulates inflammatory pathways, and increased transcripts have been observed in serum and subcutaneous adipose of subjects who have obesity and type 2 diabetes. Therefore, the role of miR‐34a in adipose tissue inflammation and lipid metabolism in murine diet‐induced obesity was investigated. Methods Wild‐type (WT) and miR‐34a−/− mice were fed chow or high‐fat diet (HFD) for 24 weeks. WT and miR‐34a−/− bone marrow‐derived macrophages were cultured in vitro with macrophage colony‐stimulating factor (M‐CSF). Brown and white preadipocytes were cultured from the stromal vascular fraction (SVF) of intrascapular brown and epididymal white adipose tissue (eWAT), with rosiglitazone. Results HFD‐fed miR‐34a−/− mice were significantly heavier with a greater increase in eWAT weight than WT. miR‐34a−/− eWAT had a smaller adipocyte area, which significantly increased with HFD. miR‐34a−/− eWAT showed basal increases in Cd36, Hmgcr, Lxrα, Pgc1α, and Fasn. miR‐34a−/− intrascapular brown adipose tissue had basal reductions in c/ebpα and c/ebpβ, with in vitro miR‐34a−/− white adipocytes showing increased lipid content. An F4/80high macrophage population was present in HFD miR‐34a−/− eWAT, with increased IL‐10 transcripts and serum IL‐5 protein. Finally, miR‐34a−/− bone marrow‐derived macrophages showed an ablated CXCL1 response to tumor necrosis factor‐α. Conclusions These findings suggest a multifactorial role of miR‐34a in controlling susceptibility to obesity, by regulating inflammatory and metabolic pathways.

Published
2016

7. Genetic invalidation of Lp-PLA2 as a therapeutic target: Large-scale study of five functional Lp-PLA2-lowering alleles

Author

Gregson, John M, Freitag, Daniel F, Surendran, Praveen, Stitziel, Nathan O, Chowdhury, Rajiv, Burgess, Stephen, Kaptoge, Stephen, Gao, Pei, Staley, James R, Willeit, Peter, Nielsen, Sune F, Caslake, Muriel, Trompet, Stella, Polfus, Linda M, Kuulasmaa, Kari, Kontto, Jukka, Perola, Markus, Blankenberg, Stefan, Veronesi, Giovanni, Gianfagna, Francesco, Männistö, Satu, Kimura, Akinori, Lin, Honghuang, Reilly, Dermot F, Gorski, Mathias, Mijatovic, Vladan, Munroe, Patricia B, Ehret, Georg B, Thompson, Alex, Uria-Nickelsen, Maria, Malarstig, Anders, Dehghan, Abbas, Vogt, Thomas F, Sasaoka, Taishi, Takeuchi, Fumihiko, Kato, Norihiro, Yamada, Yoshiji, Kee, Frank, Müller-Nurasyid, Martina, Ferrières, Jean, Arveiler, Dominique, Amouyel, Philippe, Salomaa, Veikko, Boerwinkle, Eric, Thompson, Simon G, Ford, Ian, Wouter Jukema, J, Sattar, Naveed, Packard, Chris J, Shafi Majumder, Abdulla al, Alam, Dewan S, Deloukas, Panos, Schunkert, Heribert, Samani, Nilesh J, Kathiresan, Sekar, Nordestgaard, Børge G, Saleheen, Danish, Howson, Joanna MM, Di Angelantonio, Emanuele, Butterworth, Adam S, and Danesh, John

Published
2017

9. Genetic invalidation of Lp-PLA2 as a therapeutic target:Large-scale study of five functional Lp-PLA2-lowering alleles

Author

Gregson, John M, Freitag, Daniel F, Surendran, Praveen, Stitziel, Nathan O, Chowdhury, Rajiv, Burgess, Stephen, Kaptoge, Stephen, Gao, Pei, Staley, James R, Willeit, Peter, Nielsen, Sune F, Caslake, Muriel, Trompet, Stella, Polfus, Linda M, Kuulasmaa, Kari, Kontto, Jukka, Perola, Markus, Blankenberg, Stefan, Veronesi, Giovanni, Gianfagna, Francesco, Männistö, Satu, Kimura, Akinori, Lin, Honghuang, Reilly, Dermot F, Gorski, Mathias, Mijatovic, Vladan, Munroe, Patricia B, Ehret, Georg B, Thompson, Alex, Uria-Nickelsen, Maria, Malarstig, Anders, Dehghan, Abbas, Vogt, Thomas F, Sasaoka, Taishi, Takeuchi, Fumihiko, Kato, Norihiro, Yamada, Yoshiji, Kee, Frank, Müller-Nurasyid, Martina, Ferrières, Jean, Arveiler, Dominique, Amouyel, Philippe, Salomaa, Veikko, Boerwinkle, Eric, Thompson, Simon G, Ford, Ian, Wouter Jukema, J, Sattar, Naveed, Packard, Chris J, Shafi Majumder, Abdulla Al, Alam, Dewan S, Deloukas, Panos, Schunkert, Heribert, Samani, Nilesh J, Kathiresan, Sekar, Nordestgaard, Børge G, Saleheen, Danish, Howson, Joanna Mm, Di Angelantonio, Emanuele, Butterworth, Adam S, Danesh, John, Gregson, John M, Freitag, Daniel F, Surendran, Praveen, Stitziel, Nathan O, Chowdhury, Rajiv, Burgess, Stephen, Kaptoge, Stephen, Gao, Pei, Staley, James R, Willeit, Peter, Nielsen, Sune F, Caslake, Muriel, Trompet, Stella, Polfus, Linda M, Kuulasmaa, Kari, Kontto, Jukka, Perola, Markus, Blankenberg, Stefan, Veronesi, Giovanni, Gianfagna, Francesco, Männistö, Satu, Kimura, Akinori, Lin, Honghuang, Reilly, Dermot F, Gorski, Mathias, Mijatovic, Vladan, Munroe, Patricia B, Ehret, Georg B, Thompson, Alex, Uria-Nickelsen, Maria, Malarstig, Anders, Dehghan, Abbas, Vogt, Thomas F, Sasaoka, Taishi, Takeuchi, Fumihiko, Kato, Norihiro, Yamada, Yoshiji, Kee, Frank, Müller-Nurasyid, Martina, Ferrières, Jean, Arveiler, Dominique, Amouyel, Philippe, Salomaa, Veikko, Boerwinkle, Eric, Thompson, Simon G, Ford, Ian, Wouter Jukema, J, Sattar, Naveed, Packard, Chris J, Shafi Majumder, Abdulla Al, Alam, Dewan S, Deloukas, Panos, Schunkert, Heribert, Samani, Nilesh J, Kathiresan, Sekar, Nordestgaard, Børge G, Saleheen, Danish, Howson, Joanna Mm, Di Angelantonio, Emanuele, Butterworth, Adam S, and Danesh, John

Published
2017

10. High-Sensitivity Cardiac Troponin, Statin Therapy, and Risk of Coronary Heart Disease

Author

Ford, Ian, Shah, Anoop S.V., Zhang, Ruiqi, McAllister, David A., Strachan, Fiona E., Caslake, Muriel, Newby, David E., Packard, Chris J., and Mills, Nicholas L.

Subjects
Cardiology and Cardiovascular Medicine
Abstract

Background Cardiac troponin is an independent predictor of cardiovascular mortality in individuals without symptoms or signs of cardiovascular disease. The mechanisms for this association are uncertain, and a role for troponin testing in the prevention of coronary heart disease has yet to be established. Objectives This study sought to determine whether troponin concentration could predict coronary events, be modified by statins, and reflect response to therapy in a primary prevention population. Methods WOSCOPS (West of Scotland Coronary Prevention Study) randomized men with raised low-density lipoprotein cholesterol and no history of myocardial infarction to pravastatin 40 mg once daily or placebo for 5 years. Plasma cardiac troponin I concentration was measured with a high-sensitivity assay at baseline and at 1 year in 3,318 participants. Results Baseline troponin was an independent predictor of myocardial infarction or death from coronary heart disease (hazard ratio [HR]: 2.3; 95% confidence interval [CI]: 1.4 to 3.7) for the highest (≥5.2 ng/l) versus lowest (≤3.1 ng/l) quarter of troponin (p < 0.001). There was a 5-fold greater reduction in coronary events when troponin concentrations decreased by more than a quarter, rather than increased by more than a quarter, for both placebo (HR: 0.29; 95% CI: 0.12 to 0.72 vs. HR: 1.95; 95% CI: 1.09 to 3.49; p < 0.001 for trend) and pravastatin (HR: 0.23; 95% CI: 0.10 to 0.53 vs. HR: 1.08; 95% CI: 0.53 to 2.21; p < 0.001 for trend). Pravastatin reduced troponin concentration by 13% (10% to 15%; placebo adjusted, p < 0.001) and doubled the number of men whose troponin fell more than a quarter (p < 0.001), which identified them as having the lowest risk for future coronary events (1.4% over 5 years). Conclusions Troponin concentration predicts coronary events, is reduced by statin therapy, and change at 1 year is associated with future coronary risk independent of cholesterol lowering. Serial troponin measurements have major potential to assess cardiovascular risk and monitor the impact of therapeutic interventions.

Published
2016
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11. Additional file 2: of Towards onset prevention of cognition decline in adults with Down syndrome (The TOP-COG study): A pilot randomised controlled trial

Author

Sally-Ann Cooper, Temitope Ademola, Caslake, Muriel, Douglas, Elizabeth, Evans, Jonathan, Greenlaw, Nicola, Haig, Caroline, Hassiotis, Angela, Jahoda, Andrew, McConnachie, Alex, Morrison, Jill, Ring, Howard, Starr, John, Stiles, Ciara, Chammy Sirisena, and Sullivan, Frank

Abstract

TOP-COG cognitive assessment tasks. (DOCX 15 kb)

Published
2016
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12. Additional file 3: of Towards onset prevention of cognition decline in adults with Down syndrome (The TOP-COG study): A pilot randomised controlled trial

Author

Sally-Ann Cooper, Temitope Ademola, Caslake, Muriel, Douglas, Elizabeth, Evans, Jonathan, Greenlaw, Nicola, Haig, Caroline, Hassiotis, Angela, Jahoda, Andrew, McConnachie, Alex, Morrison, Jill, Ring, Howard, Starr, John, Stiles, Ciara, Chammy Sirisena, and Sullivan, Frank

Abstract

CONSORT 2010 flow diagram. (DOC 48 kb)

Published
2016
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13. Additional file 1: of Towards onset prevention of cognition decline in adults with Down syndrome (The TOP-COG study): A pilot randomised controlled trial

Author

Sally-Ann Cooper, Temitope Ademola, Caslake, Muriel, Douglas, Elizabeth, Evans, Jonathan, Greenlaw, Nicola, Haig, Caroline, Hassiotis, Angela, Jahoda, Andrew, McConnachie, Alex, Morrison, Jill, Ring, Howard, Starr, John, Stiles, Ciara, Chammy Sirisena, and Sullivan, Frank

Abstract

CONSORT 2010 checklist. (DOC 218 kb)

Published
2016
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14. Additional file 4: of Towards onset prevention of cognition decline in adults with Down syndrome (The TOP-COG study): A pilot randomised controlled trial

Author

Sally-Ann Cooper, Temitope Ademola, Caslake, Muriel, Douglas, Elizabeth, Evans, Jonathan, Greenlaw, Nicola, Haig, Caroline, Hassiotis, Angela, Jahoda, Andrew, McConnachie, Alex, Morrison, Jill, Ring, Howard, Starr, John, Stiles, Ciara, Chammy Sirisena, and Sullivan, Frank

Abstract

Illustrative quotes from the nested qualitative study. (DOCX 16 kb)

Published
2016
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16. Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension

Author

Surendran, Praveen, Drenos, Fotios, Young, Robin, Warren, Helen, Cook, James P., Manning, Alisa K., Grarup, Niels, Sim, Xueling, Barnes, Daniel R., Witkowska, Kate, Staley, James R., Tragante, Vinicius, Tukiainen, Taru, Yaghootkar, Hanieh, Masca, Nicholas, Freitag, Daniel F., Ferreira, Teresa, Giannakopoulou, Olga, Tinker, Andrew, Harakalova, Magdalena, Mihailov, Evelin, Liu, Chunyu, Kraja, Aldi T., Nielsen, Sune Fallgaard, Rasheed, Asif, Samue, Maria, Zhao, Wei, Bonnycastle, Lori L., Jackson, Anne U., Narisu, Narisu, Swift, Amy J., Southam, Lorraine, Marten, Jonathan, Huyghe, Jeroen R., Stancakova, Alena, Fava, Cristiano, Ohlsson, Therese, Matchan, Angela, Stirrups, Kathleen E., Bork-Jensen, Jette, Gjesing, Anette P., Kontto, Jukka, Perola, Markus, Shaw-Hawkins, Susan, Havulinna, Aki S., Zhang, He, Donnelly, Louise A., Groves, Christopher J., Rayner, N. William, Neville, Matt J., Robertson, Neil R., Yiorkas, Andrianos M., Herzig, Karl-Heinz, Kajantie, Eero, Zhang, Weihua, Willems, Sara M., Lannfelt, Lars, Malerba, Giovanni, Soranzo, Nicole, Trabetti, Elisabetta, Verweij, Niek, Evangelou, Evangelos, Moayyeri, Alireza, Vergnaud, Anne-Claire, Nelson, Christopher P., Poveda, Alaitz, Varga, Tibor V., Caslake, Muriel, de Craen, Anton J. M., Trompet, Stella, Luan, Jian'an, Scott, Robert A., Harris, Sarah E., Liewald, David C. M., Marioni, Riccardo, Menni, Cristina, Farmaki, Aliki-Eleni, Hallmans, Goran, Renstrom, Frida, Huffman, Jennifer E., Hassinen, Maija, Burgess, Stephen, Vasan, Ramachandran S., Felix, Janine F., Uria-Nickelsen, Maria, Malarstign, Anders, Reilly, Dermot F., Hoek, Maarten, Vogt, Thomas F., Lin, Honghuang, Lieb, Wolfgang, Traylor, Matthew, Markus, Hugh S., Highland, Heather M., Justice, Anne E., Marouli, Eirini, Lindstrom, Jaana, Uusitupa, Matti, Komulainen, Pirjo, Lakka, Timo A., Rauramaa, Rainer, Polasek, Ozren, Rudan, Igor, Rolandsson, Olov, Franks, Paul W., Dedoussis, George, Spector, Timothy D., Jousilahti, Pekka, Mannisto, Satu, Deary, Ian J., Starr, John M., Langenberg, Claudia, Wareham, Nick J., Brown, Morris J., Dominiczak, Anna F., Connell, John M., Jukema, J. Wouter, Sattar, Naveed, Ford, Ian, Packard, Chris J., Esko, Tonu, Magi, Reedik, Metspalu, Andres, de Boer, Rudolf A., van der Meer, Peter, van der Harst, Pim, Gambaro, Giovanni, Ingelsson, Erik, Lind, Lars, de Bakker, Paul I. W., Numans, Mattijs E., Brandslund, Ivan, Christensen, Cramer, Petersen, Eva R. B., Korpi-Hyovalti, Eeva, Oksa, Heikki, Chambers, John C., Kooner, Jaspal S., Blakemore, Alexandra I. F., Franks, Steve, Jarvelin, Marjo-Riitta, Husemoen, Lise L., Linneberg, Allan, Skaaby, Tea, Thuesen, Betina, Karpe, Fredrik, Tuomilehto, Jaakko, Doney, Alex S. F., Morris, Andrew D., Palmer, Colin N. A., Holmen, Oddgeir Lingaas, Hveem, Kristian, Willer, Cristen J., Tuomi, Tiinamaija, Groop, Leif, Karajamaki, AnneMari, Palotie, Aarno, Ripatti, Samuli, Salomaa, Veikko, Alam, Dewan S., Majmnder, Abdulla Al Shafi, Di Angelantonio, Emanuele, Chowdhury, Rajiv, McCarthy, Mark I., Poulter, Neil, Stanton, Alice V., Sever, Peter, Amouyel, Philippe, Arveiler, Dominique, Blankenberg, Stefan, Ferrieres, Jean, Kee, Frank, Kuulasmaa, Kari, Muller-Nurasyid, Martina, Veronesi, Giovanni, Virtamo, Jarmo, Deloukas, Panos, Elliott, Paul, Zeggini, Eleftheria, Kathiresan, Sekar, Melander, Olle, Kuusisto, Johanna, Laakso, Markku, Padmanabhan, Sandosh, Porteous, David J., Hayward, Caroline, Scotland, Generation, Collins, Francis S., Mohlke, Karen L., Hansen, Torben, Pedersen, Oluf, Boehnke, Michael, Stringham, Heather M., Frossard, Philippe, Newton-Cheh, Christopher, Tobin, Martin D., Nordestgaard, Borge Gronne, Caulfield, Mark J., Mahajan, Anubha, Morris, Andrew P., Tomaszewski, Maciej, Samani, Nilesh J., Saleheen, Danish, Asselbergs, Folkert W., Lindgren, Cecilia M., Danesh, John, Wain, Louise V., Butterworth, Adam S., Howson, Joanna M. M., Munroe, Patricia B., Surendran, Praveen, Drenos, Fotios, Young, Robin, Warren, Helen, Cook, James P., Manning, Alisa K., Grarup, Niels, Sim, Xueling, Barnes, Daniel R., Witkowska, Kate, Staley, James R., Tragante, Vinicius, Tukiainen, Taru, Yaghootkar, Hanieh, Masca, Nicholas, Freitag, Daniel F., Ferreira, Teresa, Giannakopoulou, Olga, Tinker, Andrew, Harakalova, Magdalena, Mihailov, Evelin, Liu, Chunyu, Kraja, Aldi T., Nielsen, Sune Fallgaard, Rasheed, Asif, Samue, Maria, Zhao, Wei, Bonnycastle, Lori L., Jackson, Anne U., Narisu, Narisu, Swift, Amy J., Southam, Lorraine, Marten, Jonathan, Huyghe, Jeroen R., Stancakova, Alena, Fava, Cristiano, Ohlsson, Therese, Matchan, Angela, Stirrups, Kathleen E., Bork-Jensen, Jette, Gjesing, Anette P., Kontto, Jukka, Perola, Markus, Shaw-Hawkins, Susan, Havulinna, Aki S., Zhang, He, Donnelly, Louise A., Groves, Christopher J., Rayner, N. William, Neville, Matt J., Robertson, Neil R., Yiorkas, Andrianos M., Herzig, Karl-Heinz, Kajantie, Eero, Zhang, Weihua, Willems, Sara M., Lannfelt, Lars, Malerba, Giovanni, Soranzo, Nicole, Trabetti, Elisabetta, Verweij, Niek, Evangelou, Evangelos, Moayyeri, Alireza, Vergnaud, Anne-Claire, Nelson, Christopher P., Poveda, Alaitz, Varga, Tibor V., Caslake, Muriel, de Craen, Anton J. M., Trompet, Stella, Luan, Jian'an, Scott, Robert A., Harris, Sarah E., Liewald, David C. M., Marioni, Riccardo, Menni, Cristina, Farmaki, Aliki-Eleni, Hallmans, Goran, Renstrom, Frida, Huffman, Jennifer E., Hassinen, Maija, Burgess, Stephen, Vasan, Ramachandran S., Felix, Janine F., Uria-Nickelsen, Maria, Malarstign, Anders, Reilly, Dermot F., Hoek, Maarten, Vogt, Thomas F., Lin, Honghuang, Lieb, Wolfgang, Traylor, Matthew, Markus, Hugh S., Highland, Heather M., Justice, Anne E., Marouli, Eirini, Lindstrom, Jaana, Uusitupa, Matti, Komulainen, Pirjo, Lakka, Timo A., Rauramaa, Rainer, Polasek, Ozren, Rudan, Igor, Rolandsson, Olov, Franks, Paul W., Dedoussis, George, Spector, Timothy D., Jousilahti, Pekka, Mannisto, Satu, Deary, Ian J., Starr, John M., Langenberg, Claudia, Wareham, Nick J., Brown, Morris J., Dominiczak, Anna F., Connell, John M., Jukema, J. Wouter, Sattar, Naveed, Ford, Ian, Packard, Chris J., Esko, Tonu, Magi, Reedik, Metspalu, Andres, de Boer, Rudolf A., van der Meer, Peter, van der Harst, Pim, Gambaro, Giovanni, Ingelsson, Erik, Lind, Lars, de Bakker, Paul I. W., Numans, Mattijs E., Brandslund, Ivan, Christensen, Cramer, Petersen, Eva R. B., Korpi-Hyovalti, Eeva, Oksa, Heikki, Chambers, John C., Kooner, Jaspal S., Blakemore, Alexandra I. F., Franks, Steve, Jarvelin, Marjo-Riitta, Husemoen, Lise L., Linneberg, Allan, Skaaby, Tea, Thuesen, Betina, Karpe, Fredrik, Tuomilehto, Jaakko, Doney, Alex S. F., Morris, Andrew D., Palmer, Colin N. A., Holmen, Oddgeir Lingaas, Hveem, Kristian, Willer, Cristen J., Tuomi, Tiinamaija, Groop, Leif, Karajamaki, AnneMari, Palotie, Aarno, Ripatti, Samuli, Salomaa, Veikko, Alam, Dewan S., Majmnder, Abdulla Al Shafi, Di Angelantonio, Emanuele, Chowdhury, Rajiv, McCarthy, Mark I., Poulter, Neil, Stanton, Alice V., Sever, Peter, Amouyel, Philippe, Arveiler, Dominique, Blankenberg, Stefan, Ferrieres, Jean, Kee, Frank, Kuulasmaa, Kari, Muller-Nurasyid, Martina, Veronesi, Giovanni, Virtamo, Jarmo, Deloukas, Panos, Elliott, Paul, Zeggini, Eleftheria, Kathiresan, Sekar, Melander, Olle, Kuusisto, Johanna, Laakso, Markku, Padmanabhan, Sandosh, Porteous, David J., Hayward, Caroline, Scotland, Generation, Collins, Francis S., Mohlke, Karen L., Hansen, Torben, Pedersen, Oluf, Boehnke, Michael, Stringham, Heather M., Frossard, Philippe, Newton-Cheh, Christopher, Tobin, Martin D., Nordestgaard, Borge Gronne, Caulfield, Mark J., Mahajan, Anubha, Morris, Andrew P., Tomaszewski, Maciej, Samani, Nilesh J., Saleheen, Danish, Asselbergs, Folkert W., Lindgren, Cecilia M., Danesh, John, Wain, Louise V., Butterworth, Adam S., Howson, Joanna M. M., and Munroe, Patricia B.

Abstract

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low frequency and common genetic variants in up to 192,763 individuals and used similar to 155,063 samples for independent replication. We identified 30 new blood pressure- or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention.

Published
2016
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17. A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease

Author

Scott, Robert A., Freitag, Daniel F., Li, Li, Chu, Audrey Y., Surendran, Praveen, Young, Robin, Grarup, Niels, Stancakova, Alena, Chen, Yuning, Varga, Tibor V., Yaghootkar, Hanieh, Luan, Jian'an, Zhao, Jing Hua, Willems, Sara M., Wessel, Jennifer, Wang, Shuai, Maruthur, Nisa, Michailidou, Kyriaki, Pirie, Ailith, van der Lee, Sven J., Gillson, Christopher, Al Olama, Ali Amin, Amouyel, Philippe, Arriola, Larraitz, Arveiler, Dominique, Aviles-Olmos, Iciar, Balkau, Beverley, Barricarte, Aurelio, Barroso, Ines, Garcia, Sara Benlloch, Bis, Joshua C., Blankenberg, Stefan, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Borecki, Ingrid B., Bork-Jensen, Jette, Bowden, Sarah, Caldas, Carlos, Caslake, Muriel, Cupples, L. Adrienne, Cruchaga, Carlos, Czajkowski, Jacek, den Hoed, Marcel, Dunn, Janet A., Earl, Helena M., Ehret, Georg B., Ferrannini, Ele, Ferrieres, Jean, Foltynie, Thomas, Ford, Ian, Forouhi, Nita G., Gianfagna, Francesco, Gonzalez, Carlos, Grioni, Sara, Hiller, Louise, Jansson, Jan-Håkan, Jorgensen, Marit E., Jukema, J. Wouter, Kaaks, Rudolf, Kee, Frank, Kerrison, Nicola D., Key, Timothy J., Kontto, Jukka, Kote-Jarai, Zsofia, Kraja, Aldi T., Kuulasmaa, Kari, Kuusisto, Johanna, Linneberg, Allan, Liu, Chunyu, Marenne, Galle, Mohlke, Karen L., Morris, Andrew P., Muir, Kenneth, Mueller-Nurasyid, Martina, Munroe, Patricia B., Navarro, Carmen, Nielsen, Sune F., Nilsson, Peter M., Nordestgaard, Borge G., Packard, Chris J., Palli, Domenico, Panico, Salvatore, Peloso, Gina M., Perola, Markus, Peters, Annette, Poole, Christopher J., Quiros, J. Ramn, Rolandsson, Olov, Sacerdote, Carlotta, Salomaa, Veikko, Sanchez, Mara-Jose, Sattar, Naveed, Sharp, Stephen J., Sims, Rebecca, Slimani, Nadia, Smith, Jennifer A., Thompson, Deborah J., Trompet, Stella, Tumino, Rosario, van der A, Daphne L., van der Schouw, Yvonne T., Virtamo, Jarmo, Walker, Mark, Walter, Klaudia, Abraham, Jean E., Amundadottir, Laufey T., Aponte, Jennifer L., Butterworth, Adams., Dupuis, Josee, Easton, Douglas F., Eeles, Rosalind A., Erdmann, Jeanette, Franks, Paul W., Frayling, Timothy M., Hansen, Torben, Howson, Joanna M. M., Jorgensen, Torben, Kooner, Jaspal, Laakso, Markku, Langenberg, Claudia, McCarthy, Mark I., Pankow, James S., Pedersen, Oluf, Riboli, Elio, Rotter, Jerome I., Saleheen, Danish, Samani, Nilesh J., Schunkert, Heribert, Vollenweider, Peter, O'Rahilly, Stephen, Deloukas, Panos, Danesh, John, Goodarzi, Mark O., Kathiresan, Sekar, Meigs, James B., Ehm, Margaret G., Wareham, Nicholas J., Waterworth, Dawn M., Scott, Robert A., Freitag, Daniel F., Li, Li, Chu, Audrey Y., Surendran, Praveen, Young, Robin, Grarup, Niels, Stancakova, Alena, Chen, Yuning, Varga, Tibor V., Yaghootkar, Hanieh, Luan, Jian'an, Zhao, Jing Hua, Willems, Sara M., Wessel, Jennifer, Wang, Shuai, Maruthur, Nisa, Michailidou, Kyriaki, Pirie, Ailith, van der Lee, Sven J., Gillson, Christopher, Al Olama, Ali Amin, Amouyel, Philippe, Arriola, Larraitz, Arveiler, Dominique, Aviles-Olmos, Iciar, Balkau, Beverley, Barricarte, Aurelio, Barroso, Ines, Garcia, Sara Benlloch, Bis, Joshua C., Blankenberg, Stefan, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Borecki, Ingrid B., Bork-Jensen, Jette, Bowden, Sarah, Caldas, Carlos, Caslake, Muriel, Cupples, L. Adrienne, Cruchaga, Carlos, Czajkowski, Jacek, den Hoed, Marcel, Dunn, Janet A., Earl, Helena M., Ehret, Georg B., Ferrannini, Ele, Ferrieres, Jean, Foltynie, Thomas, Ford, Ian, Forouhi, Nita G., Gianfagna, Francesco, Gonzalez, Carlos, Grioni, Sara, Hiller, Louise, Jansson, Jan-Håkan, Jorgensen, Marit E., Jukema, J. Wouter, Kaaks, Rudolf, Kee, Frank, Kerrison, Nicola D., Key, Timothy J., Kontto, Jukka, Kote-Jarai, Zsofia, Kraja, Aldi T., Kuulasmaa, Kari, Kuusisto, Johanna, Linneberg, Allan, Liu, Chunyu, Marenne, Galle, Mohlke, Karen L., Morris, Andrew P., Muir, Kenneth, Mueller-Nurasyid, Martina, Munroe, Patricia B., Navarro, Carmen, Nielsen, Sune F., Nilsson, Peter M., Nordestgaard, Borge G., Packard, Chris J., Palli, Domenico, Panico, Salvatore, Peloso, Gina M., Perola, Markus, Peters, Annette, Poole, Christopher J., Quiros, J. Ramn, Rolandsson, Olov, Sacerdote, Carlotta, Salomaa, Veikko, Sanchez, Mara-Jose, Sattar, Naveed, Sharp, Stephen J., Sims, Rebecca, Slimani, Nadia, Smith, Jennifer A., Thompson, Deborah J., Trompet, Stella, Tumino, Rosario, van der A, Daphne L., van der Schouw, Yvonne T., Virtamo, Jarmo, Walker, Mark, Walter, Klaudia, Abraham, Jean E., Amundadottir, Laufey T., Aponte, Jennifer L., Butterworth, Adams., Dupuis, Josee, Easton, Douglas F., Eeles, Rosalind A., Erdmann, Jeanette, Franks, Paul W., Frayling, Timothy M., Hansen, Torben, Howson, Joanna M. M., Jorgensen, Torben, Kooner, Jaspal, Laakso, Markku, Langenberg, Claudia, McCarthy, Mark I., Pankow, James S., Pedersen, Oluf, Riboli, Elio, Rotter, Jerome I., Saleheen, Danish, Samani, Nilesh J., Schunkert, Heribert, Vollenweider, Peter, O'Rahilly, Stephen, Deloukas, Panos, Danesh, John, Goodarzi, Mark O., Kathiresan, Sekar, Meigs, James B., Ehm, Margaret G., Wareham, Nicholas J., and Waterworth, Dawn M.

Abstract

Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.

Published
2016
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18. A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease

Author

JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Circulatory Health, Cardiovasculaire Epidemiologie, Scott, Robert A, Freitag, Daniel F, Li, Li, Chu, Audrey Y, Surendran, Praveen, Young, Robin, Grarup, Niels, Stancáková, Alena, Chen, Yuning, Varga, Tibor V, Yaghootkar, Hanieh, Luan, Jian'an, Zhao, Jing Hua, Willems, Sara M, Wessel, Jennifer, Wang, Shuai, Maruthur, Nisa, Michailidou, Kyriaki, Pirie, Ailith, van der Lee, Sven J, Gillson, Christopher, Al Olama, Ali Amin, Amouyel, Philippe, Arriola, Larraitz, Arveiler, Dominique, Aviles-Olmos, Iciar, Balkau, Beverley, Barricarte, Aurelio, Barroso, Inês, Garcia, Sara Benlloch, Bis, Joshua C, Blankenberg, Stefan, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Borecki, Ingrid B, Bork-Jensen, Jette, Bowden, Sarah, Caldas, Carlos, Caslake, Muriel, Cupples, L Adrienne, Cruchaga, Carlos, Czajkowski, Jacek, den Hoed, Marcel, Dunn, Janet A, Earl, Helena M, Ehret, Georg B, Ferrannini, Ele, Ferrieres, Jean, van der Schouw, Yvonne T, CVD50 consortium, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Circulatory Health, Cardiovasculaire Epidemiologie, Scott, Robert A, Freitag, Daniel F, Li, Li, Chu, Audrey Y, Surendran, Praveen, Young, Robin, Grarup, Niels, Stancáková, Alena, Chen, Yuning, Varga, Tibor V, Yaghootkar, Hanieh, Luan, Jian'an, Zhao, Jing Hua, Willems, Sara M, Wessel, Jennifer, Wang, Shuai, Maruthur, Nisa, Michailidou, Kyriaki, Pirie, Ailith, van der Lee, Sven J, Gillson, Christopher, Al Olama, Ali Amin, Amouyel, Philippe, Arriola, Larraitz, Arveiler, Dominique, Aviles-Olmos, Iciar, Balkau, Beverley, Barricarte, Aurelio, Barroso, Inês, Garcia, Sara Benlloch, Bis, Joshua C, Blankenberg, Stefan, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Borecki, Ingrid B, Bork-Jensen, Jette, Bowden, Sarah, Caldas, Carlos, Caslake, Muriel, Cupples, L Adrienne, Cruchaga, Carlos, Czajkowski, Jacek, den Hoed, Marcel, Dunn, Janet A, Earl, Helena M, Ehret, Georg B, Ferrannini, Ele, Ferrieres, Jean, van der Schouw, Yvonne T, and CVD50 consortium

Published
2016

19. Does high-density lipoprotein protect vascular function in healthy pregnancy?

Author

Sulaiman, Wan N Wan, Caslake, Muriel J, Delles, Christian, Karlsson, Helen, Mulder, Monique T, Graham, Delyth, Freeman, Dilys J, Sulaiman, Wan N Wan, Caslake, Muriel J, Delles, Christian, Karlsson, Helen, Mulder, Monique T, Graham, Delyth, and Freeman, Dilys J

Abstract

The maternal adaptation to pregnancy includes hyperlipidaemia, oxidative stress and chronic inflammation. In non-pregnant individuals, these processes are usually associated with poor vascular function. However, maternal vascular function is enhanced in pregnancy. It is not understood how this is achieved in the face of the adverse metabolic and inflammatory environment. Research into cardiovascular disease demonstrates that plasma HDL (high-density lipoprotein), by merit of its functionality rather than its plasma concentration, exerts protective effects on the vascular endothelium. HDL has vasodilatory, antioxidant, anti-thrombotic and anti-inflammatory effects, and can protect against endothelial cell damage. In pregnancy, the plasma HDL concentration starts to rise at 10 weeks of gestation, peaking at 20 weeks. The initial rise in plasma HDL occurs around the time of the establishment of the feto-placental circulation, a time when the trophoblast plugs in the maternal spiral arteries are released, generating oxidative stress. Thus there is the intriguing possibility that new HDL of improved function is synthesized around the time of the establishment of the feto-placental circulation. In obese pregnancy and, to a greater extent, in pre-eclampsia, plasma HDL levels are significantly decreased and maternal vascular function is reduced. Wire myography studies have shown an association between the plasma content of apolipoprotein AI, the major protein constituent of HDL, and blood vessel relaxation. These observations lead us to hypothesize that HDL concentration, and function, increases in pregnancy in order to protect the maternal vascular endothelium and that in pre-eclampsia this fails to occur., Funding agencies: Malaysian Ministry of Higher Education; grant EU-MASCARA from the European Commission [278249]; grant sysVASC from the European Commission [603288]

Published
2016
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22. Towards onset prevention of cognition decline in adults with Down syndrome (The TOP-COG study): A pilot randomised controlled trial

Author

Cooper, Sally-Ann, primary, Ademola, Temitope, additional, Caslake, Muriel, additional, Douglas, Elizabeth, additional, Evans, Jonathan, additional, Greenlaw, Nicola, additional, Haig, Caroline, additional, Hassiotis, Angela, additional, Jahoda, Andrew, additional, McConnachie, Alex, additional, Morrison, Jill, additional, Ring, Howard, additional, Starr, John, additional, Stiles, Ciara, additional, Sirisena, Chammy, additional, and Sullivan, Frank, additional

Published
2016
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26. Consumption of Fish Oil Providing Amounts of Eicosapentaenoic Acid and Docosahexaenoic Acid That Can Be Obtained from the Diet Reduces Blood Pressure in Adults with Systolic Hypertension: A Retrospective Analysis

Author

Minihane, Anne M, primary, Armah, Christopher K, additional, Miles, Elizabeth A, additional, Madden, Jacqueline M, additional, Clark, Allan B, additional, Caslake, Muriel J, additional, Packard, Chris J, additional, Kofler, Bettina M, additional, Lietz, Georg, additional, Curtis, Peter J, additional, Mathers, John C, additional, Williams, Christine M, additional, and Calder, Philip C, additional

Published
2016
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28. Genetic invalidation of Lp-PLA2 as a therapeutic target: Large-scale study of five functional Lp-PLA2-lowering alleles.

Author

Gregson, John M, Freitag, Daniel F, Surendran, Praveen, Stitziel, Nathan O, Chowdhury, Rajiv, Burgess, Stephen, Kaptoge, Stephen, Gao, Pei, Staley, James R, Willeit, Peter, Nielsen, Sune F, Caslake, Muriel, Trompet, Stella, Polfus, Linda M, Kuulasmaa, Kari, Kontto, Jukka, Perola, Markus, Blankenberg, Stefan, Veronesi, Giovanni, and Gianfagna, Francesco

Published
2017
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29. Genetic invalidation of Lp-PLA2as a therapeutic target: Large-scale study of five functional Lp-PLA2-lowering alleles

Author

Gregson, John M, Freitag, Daniel F, Surendran, Praveen, Stitziel, Nathan O, Chowdhury, Rajiv, Burgess, Stephen, Kaptoge, Stephen, Gao, Pei, Staley, James R, Willeit, Peter, Nielsen, Sune F, Caslake, Muriel, Trompet, Stella, Polfus, Linda M, Kuulasmaa, Kari, Kontto, Jukka, Perola, Markus, Blankenberg, Stefan, Veronesi, Giovanni, Gianfagna, Francesco, Männistö, Satu, Kimura, Akinori, Lin, Honghuang, Reilly, Dermot F, Gorski, Mathias, Mijatovic, Vladan, Munroe, Patricia B, Ehret, Georg B, Thompson, Alex, Uria-Nickelsen, Maria, Malarstig, Anders, Dehghan, Abbas, Vogt, Thomas F, Sasaoka, Taishi, Takeuchi, Fumihiko, Kato, Norihiro, Yamada, Yoshiji, Kee, Frank, Müller-Nurasyid, Martina, Ferrières, Jean, Arveiler, Dominique, Amouyel, Philippe, Salomaa, Veikko, Boerwinkle, Eric, Thompson, Simon G, Ford, Ian, Wouter Jukema, J, Sattar, Naveed, Packard, Chris J, Shafi Majumder, Abdulla al, Alam, Dewan S, Deloukas, Panos, Schunkert, Heribert, Samani, Nilesh J, Kathiresan, Sekar, Nordestgaard, Børge G, Saleheen, Danish, Howson, Joanna MM, Di Angelantonio, Emanuele, Butterworth, Adam S, and Danesh, John

Abstract

Aims Darapladib, a potent inhibitor of lipoprotein-associated phospholipase A2(Lp-PLA2), has not reduced risk of cardiovascular disease outcomes in recent randomized trials. We aimed to test whether Lp-PLA2enzyme activity is causally relevant to coronary heart disease.Methods In 72,657 patients with coronary heart disease and 110,218 controls in 23 epidemiological studies, we genotyped five functional variants: four rare loss-of-function mutations (c.109+2T > C (rs142974898), Arg82His (rs144983904), Val279Phe (rs76863441), Gln287Ter (rs140020965)) and one common modest-impact variant (Val379Ala (rs1051931)) in PLA2G7,the gene encoding Lp-PLA2. We supplemented de-novo genotyping with information on a further 45,823 coronary heart disease patients and 88,680 controls in publicly available databases and other previous studies. We conducted a systematic review of randomized trials to compare effects of darapladib treatment on soluble Lp-PLA2activity, conventional cardiovascular risk factors, and coronary heart disease risk with corresponding effects of Lp-PLA2-lowering alleles.Results Lp-PLA2activity was decreased by 64% (p= 2.4 × 10–25) with carriage of any of the four loss-of-function variants, by 45% (p< 10–300) for every allele inherited at Val279Phe, and by 2.7% (p= 1.9 × 10–12) for every allele inherited at Val379Ala. Darapladib 160 mg once-daily reduced Lp-PLA2activity by 65% (p< 10–300). Causal risk ratios for coronary heart disease per 65% lower Lp-PLA2activity were: 0.95 (0.88–1.03) with Val279Phe; 0.92 (0.74–1.16) with carriage of any loss-of-function variant; 1.01 (0.68–1.51) with Val379Ala; and 0.95 (0.89–1.02) with darapladib treatment.Conclusions In a large-scale human genetic study, none of a series of Lp-PLA2-lowering alleles was related to coronary heart disease risk, suggesting that Lp-PLA2is unlikely to be a causal risk factor.

Published
2017
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30. A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1Rvariant protective for coronary heart disease

Author

Scott, Robert A., Freitag, Daniel F., Li, Li, Chu, Audrey Y., Surendran, Praveen, Young, Robin, Grarup, Niels, Stancáková, Alena, Chen, Yuning, Varga, Tibor V., Yaghootkar, Hanieh, Luan, Jian’an, Zhao, Jing Hua, Willems, Sara M., Wessel, Jennifer, Wang, Shuai, Maruthur, Nisa, Michailidou, Kyriaki, Pirie, Ailith, van der Lee, Sven J., Gillson, Christopher, Al Olama, Ali Amin, Amouyel, Philippe, Arriola, Larraitz, Arveiler, Dominique, Aviles-Olmos, Iciar, Balkau, Beverley, Barricarte, Aurelio, Barroso, Inês, Garcia, Sara Benlloch, Bis, Joshua C., Blankenberg, Stefan, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Borecki, Ingrid B., Bork-Jensen, Jette, Bowden, Sarah, Caldas, Carlos, Caslake, Muriel, Cupples, L. Adrienne, Cruchaga, Carlos, Czajkowski, Jacek, den Hoed, Marcel, Dunn, Janet A., Earl, Helena M., Ehret, Georg B., Ferrannini, Ele, Ferrieres, Jean, Foltynie, Thomas, Ford, Ian, Forouhi, Nita G., Gianfagna, Francesco, Gonzalez, Carlos, Grioni, Sara, Hiller, Louise, Jansson, Jan-Håkan, Jørgensen, Marit E., Jukema, J. Wouter, Kaaks, Rudolf, Kee, Frank, Kerrison, Nicola D., Key, Timothy J., Kontto, Jukka, Kote-Jarai, Zsofia, Kraja, Aldi T., Kuulasmaa, Kari, Kuusisto, Johanna, Linneberg, Allan, Liu, Chunyu, Marenne, Gaëlle, Mohlke, Karen L., Morris, Andrew P., Muir, Kenneth, Müller-Nurasyid, Martina, Munroe, Patricia B., Navarro, Carmen, Nielsen, Sune F., Nilsson, Peter M., Nordestgaard, Børge G., Packard, Chris J., Palli, Domenico, Panico, Salvatore, Peloso, Gina M., Perola, Markus, Peters, Annette, Poole, Christopher J., Quirós, J. Ramón, Rolandsson, Olov, Sacerdote, Carlotta, Salomaa, Veikko, Sánchez, María-José, Sattar, Naveed, Sharp, Stephen J., Sims, Rebecca, Slimani, Nadia, Smith, Jennifer A., Thompson, Deborah J., Trompet, Stella, Tumino, Rosario, van der A, Daphne L., van der Schouw, Yvonne T., Virtamo, Jarmo, Walker, Mark, Walter, Klaudia, Abraham, Jean E., Amundadottir, Laufey T., Aponte, Jennifer L., Butterworth, Adam S., Dupuis, Josée, Easton, Douglas F., Eeles, Rosalind A., Erdmann, Jeanette, Franks, Paul W., Frayling, Timothy M., Hansen, Torben, Howson, Joanna M. M., Jørgensen, Torben, Kooner, Jaspal, Laakso, Markku, Langenberg, Claudia, McCarthy, Mark I., Pankow, James S., Pedersen, Oluf, Riboli, Elio, Rotter, Jerome I., Saleheen, Danish, Samani, Nilesh J., Schunkert, Heribert, Vollenweider, Peter, O’Rahilly, Stephen, Deloukas, Panos, Danesh, John, Goodarzi, Mark O., Kathiresan, Sekar, Meigs, James B., Ehm, Margaret G., Wareham, Nicholas J., and Waterworth, Dawn M.

Abstract

A missense variant in GLP1R associated with lower fasting glucose levels and protective against T2D is associated with lower risk of coronary heart disease, suggesting that GLP1R agonists are not associated with an unacceptable increase in cardiovascular risk.

Published
2016
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31. A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease

Author

Nicola D. Kerrison, Carlos González, Mark Walker, Adam S. Butterworth, Martina Müller-Nurasyid, Mark I. McCarthy, Jarmo Virtamo, Nilesh J. Samani, Daniel F. Freitag, Jennifer Wessel, Inês Barroso, Jette Bork-Jensen, Marit E. Jørgensen, Torben Hansen, Nita G. Forouhi, Jennifer A. Smith, Peter Vollenweider, Douglas F. Easton, Heiner Boeing, Helena M. Earl, Laufey T. Amundadottir, Annette Peters, Ingrid B. Borecki, L. Adrienne Cupples, Li Li, Josée Dupuis, Sara Benlloch Garcia, J. Wouter Jukema, Shuai Wang, Veikko Salomaa, Jukka Kontto, Timothy J. Key, Yuning Chen, Sune F. Nielsen, Robin Young, Jing Hua Zhao, Andrew P. Morris, Larraitz Arriola, Claudia Langenberg, Joshua C. Bis, Nisa M. Maruthur, Ele Ferrannini, Joanna M. M. Howson, Marcel den Hoed, Jeanette Erdmann, Rosalind A. Eeles, Daphne L. van der A, Panos Deloukas, Eric Boerwinkle, Sara M. Willems, Elio Riboli, Markku Laakso, Gina M. Peloso, Muriel J. Caslake, Nadia Slimani, Zsofia Kote-Jarai, Paul W. Franks, EPIC-InterAct, Dominique Arveiler, Sarah Bowden, Janet A. Dunn, Jan-Håkan Jansson, Carlos Cruchaga, Audrey Y. Chu, James S. Pankow, Rudolf Kaaks, Jerome I. Rotter, Jaspal S. Kooner, Ailith Pirie, Johanna Kuusisto, Hanieh Yaghootkar, Niels Grarup, Danish Saleheen, Thomas Foltynie, Jean Abraham, Stefan Blankenberg, Mark O. Goodarzi, Markus Perola, Olov Rolandsson, Chris J. Packard, Praveen Surendran, Allan Linneberg, Beverley Balkau, Christopher J. Poole, Frank Kee, Carmen Navarro, Nicholas J. Wareham, Oluf Pedersen, Heribert Schunkert, Domenico Palli, Patricia B. Munroe, Sven J. van der Lee, Chunyu Liu, Rebecca Sims, Georg Ehret, Michael Boehnke, Stephen J. Sharp, Peter M. Nilsson, Salvatore Panico, Børge G. Nordestgaard, Aldi T. Kraja, Sara Grioni, Sekar Kathiresan, Dawn M. Waterworth, Francesco Gianfagna, Jacek Czajkowski, Naveed Sattar, Margaret G. Ehm, Christopher J. Gillson, Karen L. Mohlke, Stella Trompet, John Danesh, Carlotta Sacerdote, Gaëlle Marenne, Jian'an Luan, Timothy M. Frayling, J. Ramón Quirós, Iciar Aviles-Olmos, Robert A. Scott, Yvonne T. van der Schouw, Jennifer L. Aponte, María José Sánchez, Deborah J. Thompson, Klaudia Walter, James B. Meigs, Tibor V. Varga, Kari Kuulasmaa, Torben Jørgensen, Rosario Tumino, Kyriaki Michailidou, Kenneth Muir, Philippe Amouyel, Ian Ford, Aurelio Barricarte, Stephen O'Rahilly, Ali Amin Al Olama, Louise Hiller, Alena Stančáková, Carlos Caldas, Jean Ferrières, Scott, Robert A, Freitag, Daniel F, Li, Li, Chu, Audrey Y, Surendran, Praveen, Young, Robin, Grarup, Niel, Stancáková, Alena, Chen, Yuning, Varga, Tibor V, Yaghootkar, Hanieh, Luan, Jian'An, Zhao, Jing Hua, Willems, Sara M, Wessel, Jennifer, Wang, Shuai, Maruthur, Nisa, Michailidou, Kyriaki, Pirie, Ailith, van der Lee, Sven J, Gillson, Christopher, Al Olama, Ali Amin, Amouyel, Philippe, Arriola, Larraitz, Arveiler, Dominique, Aviles Olmos, Iciar, Balkau, Beverley, Barricarte, Aurelio, Barroso, Inê, Garcia, Sara Benlloch, Bis, Joshua C, Blankenberg, Stefan, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Borecki, Ingrid B, Bork Jensen, Jette, Bowden, Sarah, Caldas, Carlo, Caslake, Muriel, Cupples, L. Adrienne, Cruchaga, Carlo, Czajkowski, Jacek, den Hoed, Marcel, Dunn, Janet A, Earl, Helena M, Ehret, Georg B, Ferrannini, Ele, Ferrieres, Jean, Foltynie, Thoma, Ford, Ian, Forouhi, Nita G, Gianfagna, Francesco, Gonzalez, Carlo, Grioni, Sara, Hiller, Louise, Jansson, Jan Håkan, Jørgensen, Marit E, Jukema, J. Wouter, Kaaks, Rudolf, Kee, Frank, Kerrison, Nicola D, Key, Timothy J, Kontto, Jukka, Kote Jarai, Zsofia, Kraja, Aldi T, Kuulasmaa, Kari, Kuusisto, Johanna, Linneberg, Allan, Liu, Chunyu, Marenne, Gaëlle, Mohlke, Karen L, Morris, Andrew P, Muir, Kenneth, Müller Nurasyid, Martina, Munroe, Patricia B, Navarro, Carmen, Nielsen, Sune F, Nilsson, Peter M, Nordestgaard, Børge G, Packard, Chris J, Palli, Domenico, Panico, Salvatore, Peloso, Gina M, Perola, Marku, Peters, Annette, Poole, Christopher J, Quirós, J. Ramón, Rolandsson, Olov, Sacerdote, Carlotta, Salomaa, Veikko, Sánchez, María José, Sattar, Naveed, Sharp, Stephen J, Sims, Rebecca, Slimani, Nadia, Smith, Jennifer A, Thompson, Deborah J, Trompet, Stella, Tumino, Rosario, van der A, Daphne L, van der Schouw, Yvonne T, Virtamo, Jarmo, Walker, Mark, Walter, Klaudia, Abraham, Jean E, Amundadottir, Laufey T, Aponte, Jennifer L, Butterworth, Adam S, Dupuis, Josée, Easton, Douglas F, Eeles, Rosalind A, Erdmann, Jeanette, Franks, Paul W, Frayling, Timothy M, Hansen, Torben, Howson, Joanna M. M, Jørgensen, Torben, Kooner, Jaspal, Laakso, Markku, Langenberg, Claudia, Mccarthy, Mark I, Pankow, James S, Pedersen, Oluf, Riboli, Elio, Rotter, Jerome I, Saleheen, Danish, Samani, Nilesh J, Schunkert, Heribert, Vollenweider, Peter, O'Rahilly, Stephen, Deloukas, Pano, Danesh, John, Goodarzi, Mark O, Kathiresan, Sekar, Meigs, James B, Ehm, Margaret G, Wareham, Nicholas J, Waterworth, Dawn M., Surgery, Epidemiology, Ehret, Georg Benedikt, Surendran, Praveen [0000-0002-4911-6077], Luan, Jian'an [0000-0003-3137-6337], Barroso, Ines [0000-0001-5800-4520], Caldas, Carlos [0000-0003-3547-1489], Earl, Helena [0000-0003-1549-8094], Forouhi, Nita [0000-0002-5041-248X], Sharp, Stephen [0000-0003-2375-1440], Thompson, Deborah [0000-0003-1465-5799], Abraham, Jean [0000-0003-0688-4807], Butterworth, Adam [0000-0002-6915-9015], Easton, Douglas [0000-0003-2444-3247], Howson, Joanna [0000-0001-7618-0050], Langenberg, Claudia [0000-0002-5017-7344], O'Rahilly, Stephen [0000-0003-2199-4449], Danesh, John [0000-0003-1158-6791], Wareham, Nicholas [0000-0003-1422-2993], and Apollo - University of Cambridge Repository

Subjects
Type 2/genetics, 0301 basic medicine, Somatostatin/genetics, Heart disease, Epidemiology, CHARGE consortium, Obesity/genetics, RECEPTOR AGONIST LIXISENATIDE, Coronary Disease, Type 2 diabetes, Research & Experimental Medicine, Bioinformatics, PLACEBO-CONTROLLED TRIAL, Receptor, Cannabinoid, CB2, DOUBLE-BLIND, Dipeptidyl Peptidase 4/genetics, 0302 clinical medicine, ONCE-DAILY LIXISENATIDE, Receptors, Receptor, Serotonin, 5-HT2C, Receptors, Somatostatin, Exome sequencing, GLUCAGON-LIKE PEPTIDE-1, CHD Exome+ Consortium, Neurology Working Group of the Cohorts for Heart, General Medicine, 11 Medical And Health Sciences, RANDOMIZED CONTROLLED-TRIAL, 3. Good health, Coronary Disease/genetics, 5-HT2C/genetics, CVD50 consortium, Drug development, Medicine, Research & Experimental, EPIC-InterAct, Public Health, Life Sciences & Biomedicine, INCRETIN-BASED THERAPIES, Receptor, Serotonin, RM, European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease (EPIC-CVD), Genotype, Dipeptidyl Peptidase 4, CB2/genetics, TYPE-2 DIABETES-MELLITUS, 030209 endocrinology & metabolism, Article, Glucagon-Like Peptide-1 Receptor, 03 medical and health sciences, Sodium-Glucose Transporter 1, BETA-CELL FUNCTION, Diabetes mellitus, Diabetes Mellitus, Journal Article, medicine, Humans, Sodium-Glucose Transporter 1/genetics, Obesity, Cannabinoid, Alleles, Science & Technology, business.industry, Alzheimer’s Disease Genetics Consortium, Glucagon-Like Peptide-1 Receptor/genetics, GERAD_EC Consortium, Cell Biology, 06 Biological Sciences, medicine.disease, R1, Human genetics, CARDIOGRAM Exome Consortium, Clinical trial, Minor allele frequency, BODY-MASS INDEX, 030104 developmental biology, Diabetes Mellitus, Type 2, Aging Research in Genomic Epidemiology (CHARGE), business, RC, Pancreatic Cancer Cohort Consortium
Abstract

Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11, 806 individuals by targeted exome sequencing and follow-up in 39, 979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process. Copyright 2016 by the American Association for the Advancement of Science; all rights reserved.

Published
2016
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32. Genetic invalidation of Lp-PLA 2 as a therapeutic target: Large-scale study of five functional Lp-PLA 2 -lowering alleles.

Author

Gregson JM, Freitag DF, Surendran P, Stitziel NO, Chowdhury R, Burgess S, Kaptoge S, Gao P, Staley JR, Willeit P, Nielsen SF, Caslake M, Trompet S, Polfus LM, Kuulasmaa K, Kontto J, Perola M, Blankenberg S, Veronesi G, Gianfagna F, Männistö S, Kimura A, Lin H, Reilly DF, Gorski M, Mijatovic V, Munroe PB, Ehret GB, Thompson A, Uria-Nickelsen M, Malarstig A, Dehghan A, Vogt TF, Sasaoka T, Takeuchi F, Kato N, Yamada Y, Kee F, Müller-Nurasyid M, Ferrières J, Arveiler D, Amouyel P, Salomaa V, Boerwinkle E, Thompson SG, Ford I, Wouter Jukema J, Sattar N, Packard CJ, Shafi Majumder AA, Alam DS, Deloukas P, Schunkert H, Samani NJ, Kathiresan S, Nordestgaard BG, Saleheen D, Howson JM, Di Angelantonio E, Butterworth AS, and Danesh J

Subjects
1-Alkyl-2-acetylglycerophosphocholine Esterase drug effects, 1-Alkyl-2-acetylglycerophosphocholine Esterase genetics, Adult, Aged, Alleles, Case-Control Studies, Coronary Disease diagnosis, Female, Gene Expression Regulation, Genotype, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Randomized Controlled Trials as Topic, Reference Values, Reproducibility of Results, Risk Assessment, Treatment Outcome, Benzaldehydes therapeutic use, Coronary Disease drug therapy, Coronary Disease genetics, Molecular Targeted Therapy, Oximes therapeutic use, Phospholipase A2 Inhibitors therapeutic use
Abstract

Aims Darapladib, a potent inhibitor of lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ), has not reduced risk of cardiovascular disease outcomes in recent randomized trials. We aimed to test whether Lp-PLA 2 enzyme activity is causally relevant to coronary heart disease. Methods In 72,657 patients with coronary heart disease and 110,218 controls in 23 epidemiological studies, we genotyped five functional variants: four rare loss-of-function mutations (c.109+2T > C (rs142974898), Arg82His (rs144983904), Val279Phe (rs76863441), Gln287Ter (rs140020965)) and one common modest-impact variant (Val379Ala (rs1051931)) in PLA2G7, the gene encoding Lp-PLA 2 . We supplemented de-novo genotyping with information on a further 45,823 coronary heart disease patients and 88,680 controls in publicly available databases and other previous studies. We conducted a systematic review of randomized trials to compare effects of darapladib treatment on soluble Lp-PLA 2 activity, conventional cardiovascular risk factors, and coronary heart disease risk with corresponding effects of Lp-PLA 2 -lowering alleles. Results Lp-PLA 2 activity was decreased by 64% ( p = 2.4 × 10 -25 ) with carriage of any of the four loss-of-function variants, by 45% ( p < 10 -300 ) for every allele inherited at Val279Phe, and by 2.7% ( p = 1.9 × 10 -12 ) for every allele inherited at Val379Ala. Darapladib 160 mg once-daily reduced Lp-PLA 2 activity by 65% ( p < 10 -300 ). Causal risk ratios for coronary heart disease per 65% lower Lp-PLA 2 activity were: 0.95 (0.88-1.03) with Val279Phe; 0.92 (0.74-1.16) with carriage of any loss-of-function variant; 1.01 (0.68-1.51) with Val379Ala; and 0.95 (0.89-1.02) with darapladib treatment. Conclusions In a large-scale human genetic study, none of a series of Lp-PLA 2 -lowering alleles was related to coronary heart disease risk, suggesting that Lp-PLA 2 is unlikely to be a causal risk factor.

Published
2017
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33. Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension.

Author

Surendran P, Drenos F, Young R, Warren H, Cook JP, Manning AK, Grarup N, Sim X, Barnes DR, Witkowska K, Staley JR, Tragante V, Tukiainen T, Yaghootkar H, Masca N, Freitag DF, Ferreira T, Giannakopoulou O, Tinker A, Harakalova M, Mihailov E, Liu C, Kraja AT, Fallgaard Nielsen S, Rasheed A, Samuel M, Zhao W, Bonnycastle LL, Jackson AU, Narisu N, Swift AJ, Southam L, Marten J, Huyghe JR, Stančáková A, Fava C, Ohlsson T, Matchan A, Stirrups KE, Bork-Jensen J, Gjesing AP, Kontto J, Perola M, Shaw-Hawkins S, Havulinna AS, Zhang H, Donnelly LA, Groves CJ, Rayner NW, Neville MJ, Robertson NR, Yiorkas AM, Herzig KH, Kajantie E, Zhang W, Willems SM, Lannfelt L, Malerba G, Soranzo N, Trabetti E, Verweij N, Evangelou E, Moayyeri A, Vergnaud AC, Nelson CP, Poveda A, Varga TV, Caslake M, de Craen AJ, Trompet S, Luan J, Scott RA, Harris SE, Liewald DC, Marioni R, Menni C, Farmaki AE, Hallmans G, Renström F, Huffman JE, Hassinen M, Burgess S, Vasan RS, Felix JF, Uria-Nickelsen M, Malarstig A, Reily DF, Hoek M, Vogt T, Lin H, Lieb W, Traylor M, Markus HF, Highland HM, Justice AE, Marouli E, Lindström J, Uusitupa M, Komulainen P, Lakka TA, Rauramaa R, Polasek O, Rudan I, Rolandsson O, Franks PW, Dedoussis G, Spector TD, Jousilahti P, Männistö S, Deary IJ, Starr JM, Langenberg C, Wareham NJ, Brown MJ, Dominiczak AF, Connell JM, Jukema JW, Sattar N, Ford I, Packard CJ, Esko T, Mägi R, Metspalu A, de Boer RA, van der Meer P, van der Harst P, Gambaro G, Ingelsson E, Lind L, de Bakker PI, Numans ME, Brandslund I, Christensen C, Petersen ER, Korpi-Hyövälti E, Oksa H, Chambers JC, Kooner JS, Blakemore AI, Franks S, Jarvelin MR, Husemoen LL, Linneberg A, Skaaby T, Thuesen B, Karpe F, Tuomilehto J, Doney AS, Morris AD, Palmer CN, Holmen OL, Hveem K, Willer CJ, Tuomi T, Groop L, Käräjämäki A, Palotie A, Ripatti S, Salomaa V, Alam DS, Shafi Majumder AA, Di Angelantonio E, Chowdhury R, McCarthy MI, Poulter N, Stanton AV, Sever P, Amouyel P, Arveiler D, Blankenberg S, Ferrières J, Kee F, Kuulasmaa K, Müller-Nurasyid M, Veronesi G, Virtamo J, Deloukas P, Elliott P, Zeggini E, Kathiresan S, Melander O, Kuusisto J, Laakso M, Padmanabhan S, Porteous D, Hayward C, Scotland G, Collins FS, Mohlke KL, Hansen T, Pedersen O, Boehnke M, Stringham HM, Frossard P, Newton-Cheh C, Tobin MD, Nordestgaard BG, Caulfield MJ, Mahajan A, Morris AP, Tomaszewski M, Samani NJ, Saleheen D, Asselbergs FW, Lindgren CM, Danesh J, Wain LV, Butterworth AS, Howson JM, and Munroe PB

Subjects
Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Blood Pressure genetics, Genetic Variation, Hypertension genetics
Abstract

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used ∼155,063 samples for independent replication. We identified 30 new blood pressure- or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention., Competing Interests: Conflict of interests N. P. has received financial support from several pharmaceutical companies that manufacture either blood pressure lowering or lipid lowering agents, or both, and consultancy fees. S. K. has received Research Grant-Merck, Bayer, Aegerion; SAB-Catabasis, Regeneron Genetics Center, Merck, Celera; Equity-San Therapeutics, Catabasis; Consulting-Novartis, Aegerion, Bristol Myers-Squibb, Sanofi, AstraZeneca, Alnylam. P. Sever has received research awards from Pfizer Inc. A. Malarstig and M. Uria-Nickelsen are full time employees of Pfizer. D. Reily and M. Hoek are full time employees of Merck and co Inc. M.J. Caulfield is Chief Scientist for Genomics England a UK Government company. The authors declare no competing financial interest.

Published
2016
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