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1. 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

2. 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

3. 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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4. 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
R1
Abstract

Objectives: \ud \ud 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.\ud \ud Methods: \ud \ud 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.\ud \ud Results: \ud \ud 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).\ud \ud Conclusions: \ud \ud 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

5. miR-34a-/- mice are susceptible to diet-induced obesity

Author

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

Abstract

Objective:\ud \ud 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.\ud Methods:\ud \ud 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.\ud Results:\ud \ud 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.\ud Conclusions:\ud \ud These findings suggest a multifactorial role of miR-34a in controlling susceptibility to obesity, by regulating inflammatory and metabolic pathways.

Published
2016

6. 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, 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

Subjects
Journal Article
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

7. 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, CVD50 consortium, 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, and Trompet, Stella

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

8. 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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9. 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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10. 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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11. 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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12. C-Reactive Protein, Fibrinogen, and Cardiovascular Disease Prediction

Author

Emerging Risk Factors Collaboration, Kaptoge, Stephen, Di Angelantonio, Emanuele, Pennells, Lisa, Wood, Angela M, White, Ian R, Gao, Pei, Walker, Matthew, Thompson, Alexander, Sarwar, Nadeem, Caslake, Muriel, Butterworth, Adam S, Amouyel, Philippe, Assmann, Gerd, Bakker, Stephan JL, Barr, Elizabeth LM, Barrett-Connor, Elizabeth, Benjamin, Emelia J, Björkelund, Cecilia, Brenner, Hermann, Brunner, Eric, Clarke, Robert, Cooper, Jackie A, Cremer, Peter, Cushman, Mary, Dagenais, Gilles R, D'Agostino, Ralph B, Dankner, Rachel, Davey-Smith, George, Deeg, Dorly, Dekker, Jacqueline M, Engström, Gunnar, Folsom, Aaron R, Fowkes, F Gerry R, Gallacher, John, Gaziano, J Michael, Giampaoli, Simona, Gillum, Richard F, Hofman, Albert, Howard, Barbara V, Ingelsson, Erik, Iso, Hiroyasu, Jørgensen, Torben, Kiechl, Stefan, Kitamura, Akihiko, Kiyohara, Yutaka, Koenig, Wolfgang, Kromhout, Daan, Kuller, Lewis H, Lawlor, Debbie A, Meade, Tom W, Nissinen, Aulikki, Nordestgaard, Børge G, Onat, Altan, Panagiotakos, Demosthenes B, Psaty, Bruce M, Rodriguez, Beatriz, Rosengren, Annika, Salomaa, Veikko, Kauhanen, Jussi, Salonen, Jukka T, Shaffer, Jonathan A, Shea, Steven, Ford, Ian, Stehouwer, Coen DA, Strandberg, Timo E, Tipping, Robert W, Tosetto, Alberto, Wassertheil-Smoller, Sylvia, Wennberg, Patrik, Westendorp, Rudi G, Whincup, Peter H, Wilhelmsen, Lars, Woodward, Mark, Lowe, Gordon DO, Wareham, Nicholas J, Khaw, Kay-Tee, Sattar, Naveed, Packard, Chris J, Gudnason, Vilmundur, Ridker, Paul M, Pepys, Mark B, Thompson, Simon G, and Danesh, John

Abstract

BACKGROUND: There is debate about the value of assessing levels of C-reactive protein (CRP) and other biomarkers of inflammation for the prediction of first cardiovascular events. METHODS: We analyzed data from 52 prospective studies that included 246,669 participants without a history of cardiovascular disease to investigate the value of adding CRP or fibrinogen levels to conventional risk factors for the prediction of cardiovascular risk. We calculated measures of discrimination and reclassification during follow-up and modeled the clinical implications of initiation of statin therapy after the assessment of CRP or fibrinogen. RESULTS: The addition of information on high-density lipoprotein cholesterol to a prognostic model for cardiovascular disease that included age, sex, smoking status, blood pressure, history of diabetes, and total cholesterol level increased the C-index, a measure of risk discrimination, by 0.0050. The further addition to this model of information on CRP or fibrinogen increased the C-index by 0.0039 and 0.0027, respectively (P

Published
2012

13. Lipoprotein-associated phospholipase A(2) and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies

Author

Thompson, Alexander, Gao, Pei, Orfei, Lia, Watson, Sarah, Di Angelantonio, Emanuele, Kaptoge, Stephen, Ballantyne, Christie, Cannon, Christopher P., Criqui, Michael, Cushman, Mary, Hofman, Albert, Packard, Chris, Thompson, Simon G., Collins, Rory, Danesh, John, Willeit, Johann, Kiechl, Stefan, Wiedemann, Christian, Psaty, Bruce, Furberg, Curt, Khaw, Kay-Tee, Sandhu, Manjinder, Benjamin, Emelia J., Vasan, Ramachandran S., Schnabel, Renate B., Oldgren, Jonas, Rossi, Gian Paolo, Cesari, Maurizio, Lenzini, Livia, Zanchetta, Mario, James, Stefan K., Rimm, Eric, Hatoum, Ida, Anderson, Jeffrey L., May, Heidi T., Home, Benjamin D., Carlquist, John F., Muhlestein, Joseph B., Koenig, Wolfgang, Hermann Brenner, Rothenbacher, Dietrich, Maerz, Winfried, Boehm, Bernhard, Winkelmann, Bernhard R., Winkler, Karl, Berglund, Goran, Persson, Margaretha, Roger, Veronique, Gerber, Yariv, Berger, Peter B., Brilakis, Emmanouil S., Mcconnell, Joseph P., Meisinger, Christa, Sacco, Ralph, Elkind, Mitchell, Talmud, Philippa J., O Donoghue, Michelle, Sabatine, Marc S., Morrow, David A., Caslake, Muriel, Braunwald, Eugene, Barrett-Connor, Elizabeth, Daniels, Lori B., Laughlin, Gail A., Kardys, Isabella, Witteman, Jacqueline C. M., Corsetti, James P., Rainwater, David L., Moss, Arthur J., Wassertheil-Smoller, Sylvia, Ridker, Paul, Nelson, Jeanenne J., Zariffa, Nevine, Zalewski, Andrew, and Walker, Mat

Subjects
Male, medicine.medical_specialty, Heart disease, Systole, Blood Pressure, Coronary Disease, 030204 cardiovascular system & hematology, Risk Assessment, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Darapladib, Internal medicine, medicine, Fast track — Articles, Humans, Myocardial infarction, Prospective Studies, Risk factor, Particle Size, 030304 developmental biology, Apolipoproteins B, 0303 health sciences, Framingham Risk Score, business.industry, Vascular disease, Lipoprotein-associated phospholipase A2, General Medicine, Middle Aged, medicine.disease, Lipids, 3. Good health, Lipoproteins, LDL, Stroke, Blood pressure, 1-Alkyl-2-acetylglycerophosphocholine Esterase, Cardiology, Linear Models, lipids (amino acids, peptides, and proteins), Female, business, Biomarkers
Abstract

Background Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), an inflammatory enzyme expressed in atherosclerotic plaques, is a therapeutic target being assessed in trials of vascular disease prevention. We investigated associations of circulating Lp-PLA(2) mass and activity with risk of coronary heart disease, stroke, and mortality under different circumstances. Methods With use of individual records from 79 036 participants in 32 prospective studies (yielding 17 722 incident fatal or non-fatal outcomes during 474 976 person-years at risk), we did a meta-analysis of within-study regressions to calculate risk ratios (RRs) per 1 SD higher value of Lp-PLA(2) or other risk factor. The primary outcome was coronary heart disease. Findings Lp-PLA(2) activity and mass were associated with each other (r=0.51, 95% CI 0.47-0.56) and proatherogenic lipids. We noted roughly log-linear associations of Lp-PLA(2) activity and mass with risk of coronary heart disease and vascular death. RRs, adjusted for conventional risk factors, were: 1.10 (95% CI 1.05-1.16) with Lp-PLA(2) activity and 1.11 (1.07-1.16) with Lp-PLA(2) mass for coronary heart disease; 1.08 (0.97-1.20) and 1.14 (1.02-1.27) for ischaemic stroke; 1.16 (1.09-1.24) and 1.13 (1.05-1.22) for vascular mortality; and 1.10 (1.04-1.17) and 1.10 (1.03-1.18) for non-vascular mortality, respectively. RRs with Lp-PLA(2) did not differ significantly in people with and without initial stable vascular disease, apart from for vascular death with Lp-PLA(2) mass. Adjusted RRs for coronary heart disease were 1.10 (1.02-1.18) with non-HDL cholesterol and 1.10 (1.00-1.21) with systolic blood pressure. Interpretation Lp-PLA(2) activity and mass each show continuous associations with risk of coronary heart disease, similar in magnitude to that with non-HDL cholesterol or systolic blood pressure in this population. Associations of Lp-PLA(2) mass and activity are not exclusive to vascular outcomes, and the vascular associations depend at least partly on lipids. Funding UK Medical Research Council, GlaxoSmithKline, and British Heart Foundation.

Published
2010

14. 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, CVD50 Consortium, 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, GERAD_EC Consortium, Neurology Working Group Of The Cohorts For Heart, Aging Research In Genomic Epidemiology (CHARGE), Alzheimer’s Disease Genetics Consortium, Pancreatic Cancer Cohort Consortium, European Prospective Investigation Into Cancer And Nutrition–Cardiovascular Disease (EPIC-CVD), EPIC-InterAct, 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 MM, 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, CHARGE Consortium, CHD Exome+ Consortium, CARDIOGRAM Exome Consortium, Deloukas, Panos, Danesh, John, Goodarzi, Mark O, Kathiresan, Sekar, Meigs, James B, Ehm, Margaret G, Wareham, Nicholas J, and Waterworth, Dawn M

Subjects
Receptor, Cannabinoid, CB2, Sodium-Glucose Transporter 1, Diabetes Mellitus, Type 2, Genotype, Dipeptidyl Peptidase 4, Receptor, Serotonin, 5-HT2C, Humans, Coronary Disease, Obesity, Receptors, Somatostatin, Alleles, Glucagon-Like Peptide-1 Receptor, 3. Good health
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.

15. 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, Fallgaard Nielsen, Sune, Rasheed, Asif, Samuel, Maria, Zhao, Wei, Bonnycastle, Lori L, Jackson, Anne U, Narisu, Narisu, Swift, Amy J, Southam, Lorraine, Marten, Jonathan, Huyghe, Jeroen R, Stančáková, 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 Jm, Trompet, Stella, Luan, Jian'an, Scott, Robert A, Harris, Sarah E, Liewald, David Cm, Marioni, Riccardo, Menni, Cristina, Farmaki, Aliki-Eleni, Hallmans, Göran, Renström, Frida, Huffman, Jennifer E, Hassinen, Maija, Burgess, Stephen, Vasan, Ramachandran S, Felix, Janine F, CHARGE-Heart Failure Consortium, Uria-Nickelsen, Maria, Malarstig, Anders, Reily, Dermot F, Hoek, Maarten, Vogt, Thomas, Lin, Honghuang, Lieb, Wolfgang, EchoGen Consortium, Traylor, Matthew, Markus, Hugh F, METASTROKE Consortium, Highland, Heather M, Justice, Anne E, Marouli, Eirini, GIANT Consortium, Lindström, Jaana, Uusitupa, Matti, Komulainen, Pirjo, Lakka, Timo A, Rauramaa, Rainer, Polasek, Ozren, Rudan, Igor, Rolandsson, Olov, Franks, Paul W, Dedoussis, George, Spector, Timothy D, EPIC-InterAct Consortium, Jousilahti, Pekka, Männistö, 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, Tõnu, Mägi, Reedik, Metspalu, Andres, De Boer, Rudolf A, Van Der Meer, Peter, Van Der Harst, Pim, Lifelines Cohort Study, Gambaro, Giovanni, Ingelsson, Erik, Lind, Lars, De Bakker, Paul Iw, Numans, Mattijs E, Brandslund, Ivan, Christensen, Cramer, Petersen, Eva Rb, Korpi-Hyövälti, Eeva, Oksa, Heikki, Chambers, John C, Kooner, Jaspal S, Blakemore, Alexandra If, Franks, Steve, Jarvelin, Marjo-Riitta, Husemoen, Lise L, Linneberg, Allan, Skaaby, Tea, Thuesen, Betina, Karpe, Fredrik, Tuomilehto, Jaakko, Doney, Alex Sf, Morris, Andrew D, Palmer, Colin Na, Holmen, Oddgeir Lingaas, Hveem, Kristian, Willer, Cristen J, Tuomi, Tiinamaija, Groop, Leif, Käräjämäki, AnneMari, Palotie, Aarno, Ripatti, Samuli, Salomaa, Veikko, Alam, Dewan S, Shafi Majumder, Abdulla Al, Di Angelantonio, Emanuele, Chowdhury, Rajiv, McCarthy, Mark I, Poulter, Neil, Stanton, Alice V, Sever, Peter, Amouyel, Philippe, Arveiler, Dominique, Blankenberg, Stefan, Ferrières, Jean, Kee, Frank, Kuulasmaa, Kari, Müller-Nurasyid, Martina, Veronesi, Giovanni, Virtamo, Jarmo, Deloukas, Panos, Wellcome Trust Case Control Consortium, Elliott, Paul, Understanding Society Scientific Group, Zeggini, Eleftheria, Kathiresan, Sekar, Melander, Olle, Kuusisto, Johanna, Laakso, Markku, Padmanabhan, Sandosh, Porteous, David, Hayward, Caroline, Scotland, Generation, Collins, Francis S, Mohlke, Karen L, Hansen, Torben, Pedersen, Oluf, Boehnke, Michael, Stringham, Heather M, EPIC-CVD Consortium, Frossard, Philippe, Newton-Cheh, Christopher, CHARGE+ Exome Chip Blood Pressure Consortium, Tobin, Martin D, Nordestgaard, Børge Grønne, T2D-GENES Consortium, GoT2DGenes Consortium, ExomeBP Consortium, CHD Exome+ Consortium, 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 Mm, and Munroe, Patricia B

Subjects
Genotype, Hypertension, Genetic Variation, Humans, Blood Pressure, Genetic Predisposition to Disease, 3. Good health, Genome-Wide Association Study
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.

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

Author

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

Subjects
3. Good health
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 inform development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in 6 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 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 lower 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 randomised 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.

17. Lipoprotein-associated phospholipase A(2) and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies

Author

Thompson, Alexander, Pei Gao, Orfei, Lia, Watson, Sarah, Di Angelantonio, Emanuele, Kaptoge, Stephen, Ballantyne, Christie, Cannon, Christopher P., Criqui, Michael, Cushman, Mary, Hofman, Albert, Packard, Chris, Thompson, Simon G., Collins, Rory, Danesh, John, Willeit, Johann, Kiechl, Stefan, Wiedemann, Christian, Psaty, Bruce, Furberg, Curt, Khaw, Kay-Tee, Sandhu, Manjinder, Benjamin, Emelia J., Vasan, Ramachandran S., Schnabel, Renate B., Oldgren, Jonas, Rossi, Gian Paolo, Cesari, Maurizio, Lenzini, Livia, Zanchetta, Mario, James, Stefan K., Rimm, Eric, Hatoum, Ida, Anderson, Jeffrey L., May, Heidi T., Home, Benjamin D., Carlquist, John F., Muhlestein, Joseph B., Koenig, Wolfgang, Brenner, Herrnann, Rothenbacher, Dietrich, Maerz, Winfried, Boehm, Bernhard, Winkelmann, Bernhard R., Winkler, Karl, Berglund, Goran, Persson, Margaretha, Roger, Veronique, Gerber, Yariv, Berger, Peter B., Brilakis, Emmanouil S., Mcconnell, Joseph P., Meisinger, Christa, Sacco, Ralph, Elkind, Mitchell, Talmud, Philippa J., O Donoghue, Michelle, Sabatine, Marc S., Morrow, David A., Caslake, Muriel, Braunwald, Eugene, Barrett-Connor, Elizabeth, Daniels, Lori B., Laughlin, Gail A., Kardys, Isabella, Witteman, Jacqueline C. M., Corsetti, James P., Rainwater, David L., Moss, Arthur J., Wassertheil-Smoller, Sylvia, Ridker, Paul, Nelson, Jeanenne J., Zariffa, Nevine, Zalewski, Andrew, Walker, Mat, and Lp-PLA2 Studies Collaboration

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

Author

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

Subjects
3. Good health
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 ~192,000 individuals, and used ~155,063 samples for independent replication. We identified 31 novel blood pressure or hypertension associated genetic regions in the general population, including three rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5mmHg/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.

19. 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. 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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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