Search

Your search keyword '"Caslake, Muriel"' showing total 435 results
Start Over Author "Caslake, Muriel"
435 results on '"Caslake, Muriel"'

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
Full Text
View/download PDF

3. Studies on the structural and metabolic heterogeneity in low density lipoprotein

Author

Caslake, Muriel

Subjects
572, Heart disease, Cholesterol
Abstract

This thesis sought to investigate the relationship between structural and metabolic heterogeneity in LDL and examine the influence of plasma triglyceride on the properties of this lipoprotein. A technique to quantify individual LDL subfractions was developed which was superior to previously published methods and was employed to characterise three LDL subfractions in normals and in subjects with coronary disease, primary hyperlipidaemia and the secondary hyperlipidaemia observed in non insulin dependent diabetes mellitus and the nephrotic syndrome. In a case controlled study, a sevenfold increased risk of myocardial infarction was found to be associated with a concentration of small dense LDL III > 100mg/100ml. Subjects with hypertriglyceridaemia, combined hyperlipidaemia and the secondary hyperlipidaemia were found to exhibit an atherogenic lipoprotein phenotype of raised plasma triglyceride, low HDL cholesterol and a preponderance of small dense LDL. The data in the entire cohort was pooled and multivariate analysis revealed that plasma triglyceride was the most important independent predictor of LDL III. Pharmacological modulation of the LDL profile was investigated in normals and in a variety of hyperlipidaemic states using the main classes of lipid lowering drugs- resins, nicotinic acid derivatives, fibrates and statins. Those drugs which act through the lowering of plasma triglyceride reduced the concentrations of LDL III and those whose mode of action is by activation of the LDL receptor, reduced the concentrations of the larger LDL I and LDL II species. An important finding was in the unexpected beneficial effect of statins in combined hyperlipidaemia when LDL III concentrations were lower than expected for the plasma triglyceride level. Kinetic heterogeneity of LDL was studied by undertaking radioactive turnovers in normals and hypercholesterolaemic subjects who were given triglyceride lowering therapy. A two pool model for plasma LDL was developed to explain the radioactive decay curves of plasma and urine. One pool (pool A) was rapidly removed by the LDL receptor while the other (pool B) was more slowly removed and its synthesis was positively related to plasma triglyceride. The kinetics of apo-LDL were further examined in subjects with moderate hypertriglyceridaemia. Here it was necessary to expand the model to a third plasma pool (pool C) to account for an LDL species which was rapidly catabolised by receptor- independent mechanisms. A high level of receptor-independent catabolism was associated with an increased ratio of LDL III to LDL II. Pool C was seen in subjects with plasma triglyceride >2.5mmol/l in whom there was the presence of an abnormally small, dense LDL. On the basis of these observations and published VLDL metabolic studies, a model was postulated in which pool A LDL was produced from the delipidation of hepatic lipoproteins secreted in the Sf 0-60 density range and circulated m the form LDL I and LDL II. Pool B LDL, on the other hand, was derived from large triglyceride-rich VLDL of Sf 60-400 and circulates in most subjects in the form of LDL II. Neutral lipid exchange and lipolysis via the agency of hepatic lipase converts a proportion of pool B LDL II to LDL III, depending on the level of plasma triglyceride and the activity of the lipase enzyme. The data presented in this thesis are in line with current concepts of the atherogenicity of small dense LDL and provide evidence that it is an independent risk factor for coronary disease. It demonstrates that the properties of LDL are strongly influenced by its pedigree. Furthermore it shows that there are currently available drugs that are capable of altering not only the quantity of LDL but also its quality and offer hope in the continuing problem of tackling coronary heart disease.

Published
1996

16. Microsomal triglyceride transfer protein -493T variant reduces IDL plus LDL apoB production and the plasma concentration of large LDL particles

Author

Lundahl, Bjorn, Skoglund-Andersson, Camilla, Caslake, Muriel, Bedford, Dorothy, Stewart, Philip, Hamsten, Anders, Packard, Christopher J., and Karpe, Fredrik

Subjects
Lipoproteins -- Research, Lipoproteins -- Analysis, Proteolipids -- Research, Proteolipids -- Analysis, Lipids -- Research, Biological sciences
Abstract

The microsomal triglyceride transfer protein (MTP) is essential for the synthesis and secretion of apolipoprotein B (apoB)-containing lipoproteins. We investigated the role the MTP -493G/T gene polymorphism in determining the apoB-100 secretion pattern and LDL heterogeneity in healthy human subjects. Groups of carriers of the T and the G variants (n = 6 each) were recruited from a cohort of healthy 50-yr-old men. Kinetic studies were performed by endogenous [[sup.2][H.sub.3]]leucine labeling of apoB and subsequent quantification of the stable isotope incorporation, apoB production rates, metabolic conversions, and eliminations were calculated by multicompartmental modeling (SAAM-II). LDL subfraction distribution was analyzed in the entire cohort (n = 377). Carriers of the MTP -493T allele had lower plasma LDL apoB and lower concentration of large LDL particles [LDL-I: 136 [+ or -] 57 (TT) vs. 175 [+ or -] 55 (GG) mg/l, P < 0.01]. Kinetic modeling suggested that MTP -493T homozygotes had a 60% lower direct production rate of intermediate-density lipoprotein (IDL) plus LDL compared with homozygotes for the G allele (P < 0.05). No differences were seen in production rates of large and small VLDL, nor were there any differences in metabolic conversion or elimination rates of apoB between the genotype groups. This study shows that a polymorphism in the MTP gene affects the spectrum of endogenous apoB-containing lipoprotein particles produced in humans. Reduced direct production of LDL plus IDL appears to be related to lower plasma concentrations of large LDL particles. intermediate-density lipoprotein; low-density lipoprotein; apolipoprotein B; very-low-density lipoprotein secretion; lipidation; microsomal triglyceride transfer protein

Published
2006

17. CD36 and SR-BI Are Involved in Cellular Uptake of Provitamin A Carotenoids by Caco-2 and HEK Cells, and Some of Their Genetic Variants Are Associated with Plasma Concentrations of These Micronutrients in Humans1-3

Author

Borel, Patrick, Lietz, Georg, Goncalves, Aurélie, de Edelenyi, Fabien Szabo, Lecompte, Sophie, Curtis, Peter, Goumidi, Louisa, Caslake, Muriel J., Miles, Elizabeth A., Packard, Christopher, Calder, Philip C., Mathers, John C., Minihane, Anne M., Tourniaire, Franck, Kesse-Guyot, Emmanuelle, Galan, Pilar, Hercberg, Serge, Breidenassel, Christina, Gross, Marcela González, Moussa, Myriam, Meirhaeghe, Aline, and Reboul, Emmanuelle

Published
2013
Full Text
View/download PDF

18. Genetic Associations with Valvular Calcification and Aortic Stenosis

Author

Thanassoulis, George, Campbell, Catherine Y., Owens, David S., Smith, J. Gustav, Smith, Albert V., Peloso, Gina M., Kerr, Kathleen F., Pechlivanis, Sonali, Budoff, Matthew J., Harris, Tamara B., Malhotra, Rajeev, OʼBrien, Kevin D., Kamstrup, Pia R., Nordestgaard, Børge G., Tybjaerg-Hansen, Anne, Allison, Matthew A., Aspelund, Thor, Criqui, Michael H., Heckbert, Susan R., Hwang, Shih-Jen, Liu, Yongmei, Sjogren, Marketa, van der Pals, Jesper, Kälsch, Hagen, Mühleisen, Thomas W., Nöthen, Markus M., Cupples, L. Adrienne, Caslake, Muriel, Di Angelantonio, Emanuele, Danesh, John, Rotter, Jerome I., Sigurdsson, Sigurdur, Wong, Quenna, Erbel, Raimund, Kathiresan, Sekar, Melander, Olle, Gudnason, Vilmundur, OʼDonnell, Christopher J., and Post, Wendy S.

Published
2013
Full Text
View/download PDF

23. Lipoprotein-associated phospholipase A(sub 2) as an independent predictor of coronary heart disease

Author

Packard, Chris J., O'Reilly, Denis S.J., Caslake, Muriel J., McMahon, Alex D., Ford, Ian, Cooney, Josephine, Macphee, Colin H., Suckling, Keith E., Krishna, Mala, Wilkinson, Francis E., Rumley, Ann, and Lowe, Gordon D.O.

Subjects
Phospholipases -- Health aspects, Coronary heart disease -- Patient outcomes, Heart attack -- Risk factors
Abstract

Elevated blood levels of lipoprotein-associated phospholipase A(sub 2) may predict which men will have a heart attack or die from coronary artery disease. This enzyme may modify low-density lipoproteins inside coronary arteries.

Published
2000

29. Association Between Apolipoprotein E4 and Cognitive Decline in Elderly Adults

Author

Packard, Chris J., Westendorp, Rudi G.J., Stott, David J., Caslake, Muriel J., Murray, Heather M., Shepherd, James, Blauw, Gerard J., Murphy, Michael B., Bollen, Edward L.E.M., Buckley, Brendan M., Cobbe, Stuart M., Ford, Ian, Gaw, Allan, Hyland, Michael, Jukema, J. Wouter, Kamper, Adriaan M., Macfarlane, Peter W., Jolles, Jellemer, Perry, Ivan J., Sweeney, Brian J., and Twomey, Cillian

Published
2007

35. 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

40. Effects of dietary monounsaturated fatty acids on lipoprotein concentrations, compositions, and subfraction distributions and on VLDL apolipoprotein B kinetics: dose-dependent effects on LDL

Author

Gill, Jason MR, Brown, Jacqueline C, Caslake, Muriel J, Wright, Dawn M, Cooney, Josephine, Bedford, Dorothy, Hughes, David A, Stanley, John C, and Packard, Chris J

Subjects
Saturated fatty acids -- Health aspects, Monounsaturated fatty acids -- Physiological aspects, Cholesterol, LDL -- Physiological aspects, Food/cooking/nutrition, Health
Abstract

Background: Replacing dietary saturated fatty acids (SFAs) with monounsaturated fatty acids (MUFAs) lowers LDL cholesterol, but the underlying mechanisms remain unclear. Objective: We assessed the effects of replacing dietary SFAs with MUFAs on concentrations and subclass distributions of VLDL, intermediate-density lipoprotein, LDL, and HDL and on VLDL apolipoprotein B kinetics. Design: Thirty-five moderately hypercholesterolemic, middle-aged volunteers consumed for 6 wk, in random order, diets containing low (L-MUFA; 7.8% of energy from MUFAs), moderate (M-MUFA; 10.3% from MUFAs), or high (H-MUFA; 13.7% from MUFAs) amounts of MUFAs. Fasting blood samples were taken from all subjects after each intervention. VLDL apolipoprotein B kinetic studies were performed in a subgroup after the L-MUFA and H-MUFA diets. Results: Plasma cholesterol concentrations decreased in a dose-dependent manner with increasing intakes of dietary MUFAs. This change was entirely accounted for by reduced LDL cholesterol (-0.20 and -0.49 mmol/L after the M-MUFA and H-MUFA diets, respectively, compared with the concentration after the L-MUFA diet; P for trend < 0.01). Plasma triacylglycerol and HDL cholesterol were not significantly affected by the dietary intervention, nor were the concentrations of [VLDL.sub.1] ([S.sub.f] 60-400), [VLDL.sub.2] ([S.sub.f] 20-60), or intermediate-density lipoprotein ([S.sub.f] 12-20). Production and catabolic rates for [VLDL.sub.1] and [VLDL.sub.2] were also unaffected. HDL and LDL subclass distributions were not significantly altered, but as a consequence of the overall LDL lowering, concentrations of atherogenic LDL-III were 25% lower after the H-MUFA diet than after the L-MUFA diet (P = 0.02). Conclusion: The effects of replacing dietary SFAs with MUFAs on lipoprotein metabolism appear to be almost exclusively limited to the LDL density class. KEY WORDS Monounsaturated fatty acids, saturated fatty acids, LDL, VLDL, lipoprotein subfractions, cholesterol

Published
2003

44. 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

47. Familial combined hyperlipidaemia linked to the apolipoprotein AI-CIII-AIV gene cluster on chromosome 11q23-q24

Author

Wojciechowski, Andrew P, Farrall, Martin, Cullen, Paul, Wilson, Teresa M E, Bayliss, Jayne D, Farren, Bernadette, Griffin, Bruce A, Caslake, Muriel J, Packard, Christopher J, Shepherd, James, Thakker, Rajesh, and Scott, James

Subjects
Familial diseases -- Genetic aspects, Hyperlipidemia -- Genetic aspects, Hyperlipidemia -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Familial combined hyperlipidemia (FCHL) is an inherited disorder of fat metabolism that causes as many as 10 percent of the cases of premature disease of the coronary arteries, which supply the heart with blood. One fifth of the patients with FCHL develop premature coronary heart disease. FCHL sufferers have elevated blood cholesterol and/or triglyceride levels, as well as abnormal low-density lipoproteins (forms in which fats are carried in the blood). To better characterize the gene defect associated with FCHL, members of eight FCHL families were studied. Techniques of DNA analysis and linkage analysis were used to identify the gene cluster associated with FCHL in the families evaluated. It was found to be the AI-CIII-AIV gene cluster, which contained the X2 allele in half the affected families. This region appears to carry a genetic defect that causes a metabolic disorder that in turn predisposes the individual to develop premature coronary heart disease. Further research is needed to identify the mutation present in people at risk. (Consumer Summary produced by Reliance Medical Information, Inc.)

Published
1991

48. Replication of LDL GWAs hits in PROSPER/PHASE as validation for future (pharmaco)genetic analyses

Author

Stott David J, Caslake Muriel, Sattar Naveed, Ford Ian, Postmus Iris, de Craen Anton JM, Trompet Stella, Buckley Brendan M, Sacks Frank, Devlin James J, Slagboom P, Westendorp Rudi GJ, and Jukema J

Subjects
Internal medicine, RC31-1245, Genetics, QH426-470
Abstract

Abstract Background The PHArmacogenetic study of Statins in the Elderly at risk (PHASE) is a genome wide association study in the PROspective Study of Pravastatin in the Elderly at risk for vascular disease (PROSPER) that investigates the genetic variation responsible for the individual variation in drug response to pravastatin. Statins lower LDL-cholesterol in general by 30%, however not in all subjects. Moreover, clinical response is highly variable and adverse effects occur in a minority of patients. In this report we first describe the rationale of the PROSPER/PHASE project and second show that the PROSPER/PHASE study can be used to study pharmacogenetics in the elderly. Methods The genome wide association study (GWAS) was conducted using the Illumina 660K-Quad beadchips following manufacturer's instructions. After a stringent quality control 557,192 SNPs in 5,244 subjects were available for analysis. To maximize the availability of genetic data and coverage of the genome, imputation up to 2.5 million autosomal CEPH HapMap SNPs was performed with MACH imputation software. The GWAS for LDL-cholesterol is assessed with an additive linear regression model in PROBABEL software, adjusted for age, sex, and country of origin to account for population stratification. Results Forty-two SNPs reached the GWAS significant threshold of p = 5.0e-08 in 5 genomic loci (APOE/APOC1; LDLR; FADS2/FEN1; HMGCR; PSRC1/CELSR5). The top SNP (rs445925, chromosome 19) with a p-value of p = 2.8e-30 is located within the APOC1 gene and near the APOE gene. The second top SNP (rs6511720, chromosome 19) with a p-value of p = 5.22e-15 is located within the LDLR gene. All 5 genomic loci were previously associated with LDL-cholesterol levels, no novel loci were identified. Replication in WOSCOPS and CARE confirmed our results. Conclusion With the GWAS in the PROSPER/PHASE study we confirm the previously found genetic associations with LDL-cholesterol levels. With this proof-of-principle study we show that the PROSPER/PHASE study can be used to investigate genetic associations in a similar way to population based studies. The next step of the PROSPER/PHASE study is to identify the genetic variation responsible for the variation in LDL-cholesterol lowering in response to statin treatment in collaboration with other large trials.

Published
2011
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results