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1. Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease

Author

Zhao, Wei, Rasheed, Asif, Tikkanen, Emmi, Lee, Jung-Jin, Butterworth, Adam S, Howson, Joanna MM, Assimes, Themistocles L, Chowdhury, Rajiv, Orho-Melander, Marju, Damrauer, Scott, Small, Aeron, Asma, Senay, Imamura, Minako, Yamauch, Toshimasa, Chambers, John C, Chen, Peng, Sapkota, Bishwa R, Shah, Nabi, Jabeen, Sehrish, Surendran, Praveen, Lu, Yingchang, Zhang, Weihua, Imran, Atif, Abbas, Shahid, Majeed, Faisal, Trindade, Kevin, Qamar, Nadeem, Mallick, Nadeem Hayyat, Yaqoob, Zia, Saghir, Tahir, Rizvi, Syed Nadeem Hasan, Memon, Anis, Rasheed, Syed Zahed, Memon, Fazal-ur-Rehman, Mehmood, Khalid, Ahmed, Naveeduddin, Qureshi, Irshad Hussain, Tanveer-us-Salam, Iqbal, Wasim, Malik, Uzma, Mehra, Narinder, Kuo, Jane Z, Sheu, Wayne H-H, Guo, Xiuqing, Hsiung, Chao A, Juang, Jyh-Ming J, Taylor, Kent D, Hung, Yi-Jen, Lee, Wen-Jane, Quertermous, Thomas, Lee, I-Te, Hsu, Chih-Cheng, Bottinger, Erwin P, Ralhan, Sarju, Teo, Yik Ying, Wang, Tzung-Dau, Alam, Dewan S, Di Angelantonio, Emanuele, Epstein, Steve, Nielsen, Sune F, Nordestgaard, Børge G, Tybjaerg-Hansen, Anne, Young, Robin, Benn, Marianne, Frikke-Schmidt, Ruth, Kamstrup, Pia R, Jukema, J Wouter, Sattar, Naveed, Smit, Roelof, Chung, Ren-Hua, Liang, Kae-Woei, Anand, Sonia, Sanghera, Dharambir K, Ripatti, Samuli, Loos, Ruth JF, Kooner, Jaspal S, Tai, E Shyong, Rotter, Jerome I, Chen, Yii-Der Ida, Frossard, Philippe, Maeda, Shiro, Kadowaki, Takashi, Reilly, Muredach, Pare, Guillaume, Melander, Olle, Salomaa, Veikko, Rader, Daniel J, Danesh, John, Voight, Benjamin F, and Saleheen, Danish

Subjects
Biological Sciences, Genetics, Obesity, Human Genome, Heart Disease - Coronary Heart Disease, Clinical Research, Heart Disease, Diabetes, Cardiovascular, 2.1 Biological and endogenous factors, Aetiology, Metabolic and endocrine, Asia, Asian People, Biomarkers, Comorbidity, Coronary Disease, Diabetes Mellitus, Type 2, Europe, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, HLA-DRB5 Chains, Humans, Metabolic Networks and Pathways, Metabolic Syndrome, Molecular Targeted Therapy, Mutation, Missense, Polymorphism, Single Nucleotide, Risk Factors, White People, CHD Exome+ Consortium, EPIC-CVD Consortium, EPIC-Interact Consortium, Michigan Biobank, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

To evaluate the shared genetic etiology of type 2 diabetes (T2D) and coronary heart disease (CHD), we conducted a genome-wide, multi-ancestry study of genetic variation for both diseases in up to 265,678 subjects for T2D and 260,365 subjects for CHD. We identify 16 previously unreported loci for T2D and 1 locus for CHD, including a new T2D association at a missense variant in HLA-DRB5 (odds ratio (OR) = 1.29). We show that genetically mediated increase in T2D risk also confers higher CHD risk. Joint T2D-CHD analysis identified eight variants-two of which are coding-where T2D and CHD associations appear to colocalize, including a new joint T2D-CHD association at the CCDC92 locus that also replicated for T2D. The variants associated with both outcomes implicate new pathways as well as targets of existing drugs, including icosapent ethyl and adipocyte fatty-acid-binding protein.

Published
2017

2. 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

3. Association ofLPAVariants With Risk of Coronary Disease and the Implications for Lipoprotein(a)-Lowering Therapies

Author

Burgess, Stephen, Ference, Brian A., Staley, James R., Freitag, Daniel F., Mason, Amy M., Nielsen, Sune F., Willeit, Peter, Young, Robin, Surendran, Praveen, Karthikeyan, Savita, Bolton, Thomas R., Peters, James E., Kamstrup, Pia, Tybjærg-Hansen, Anne, Benn, Marianne, Langsted, Anne, Schnohr, Peter, Vedel-Krogh, Signe, Kobylecki, Camilla J., Ford, Ian, Packard, Chris, Trompet, Stella, Jukema, J. Wouter, Sattar, Naveed, Di Angelantonio, Emanuele, Saleheen, Danish, Howson, Joanna M.M., Nordestgaard, Børge G., Butterworth, Adam S., Danesh, John, Bargess, Stephen, Overvad, Kim, Tjønneland, Anne, Clavel-Chapelon, Francoise, Kaaks, Rudolf, Boeing, Heiner, Trichopoulou, Antonia, Ferrari, Pietro, Palli, Domenico, Krogh, Vittorio, Panico, Salvatore, Tumino, Rosario, Matullo, Giuseppe, Boer, Jolanda, Van Der Schouw, Yvonne, Weiderpass, Elisabete, Quiros, J. Ramon, Sánchez, María José, Navarro, Carmen, Moreno-Iribas, Conchi, Arriola, Larraitz, Melander, Olle, Wennberg, Patrik, Wareham, Nicholas J., Key, Timothy J., Riboli, Elio, Burgess, Stephen [0000-0001-5365-8760], Mason, Amy [0000-0002-8019-0777], Surendran, Praveen [0000-0002-4911-6077], Karthikeyan, Savita [0000-0002-4798-5746], Di Angelantonio, Emanuele [0000-0001-8776-6719], Howson, Joanna [0000-0001-7618-0050], Butterworth, Adam [0000-0002-6915-9015], Danesh, John [0000-0003-1158-6791], and Apollo - University of Cambridge Repository

Subjects
Male, medicine.medical_specialty, Population, Coronary Disease, Coronary Artery Disease, 030204 cardiovascular system & hematology, Polymorphism, Single Nucleotide, Article, law.invention, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, Ezetimibe, Risk Factors, law, Internal medicine, medicine, Humans, Prospective Studies, 030212 general & internal medicine, Precision Medicine, Prospective cohort study, education, Hypolipidemic Agents, education.field_of_study, biology, Cholesterol, business.industry, Genetic Variation, Mendelian Randomization Analysis, Cholesterol, LDL, Lipoprotein(a), Odds ratio, Middle Aged, Prognosis, Phenotype, chemistry, biology.protein, Female, Cardiology and Cardiovascular Medicine, business, Biomarkers, Follow-Up Studies, medicine.drug
Abstract

Importance: Human genetic studies have indicated that plasma lipoprotein(a) (Lp[a]) is causally associated with the risk of coronary heart disease (CHD), but randomized trials of several therapies that reduce Lp(a) levels by 25% to 35% have not provided any evidence that lowering Lp(a) level reduces CHD risk.Objective: To estimate the magnitude of the change in plasma Lp(a) levels needed to have the same evidence of an association with CHD risk as a 38.67-mg/dL (ie, 1-mmol/L) change in low-density lipoprotein cholesterol (LDL-C) level, a change that has been shown to produce a clinically meaningful reduction in the risk of CHD.Design, Setting, and Participants: A mendelian randomization analysis was conducted using individual participant data from 5 studies and with external validation using summarized data from 48 studies. Population-based prospective cohort and case-control studies featured 20 793 individuals with CHD and 27 540 controls with individual participant data, whereas summarized data included 62 240 patients with CHD and 127 299 controls. Data were analyzed from November 2016 to March 2018.Exposures: Genetic LPA score and plasma Lp(a) mass concentration.Main Outcomes and Measures: Coronary heart disease.Results: Of the included study participants, 53% were men, all were of white European ancestry, and the mean age was 57.5 years. The association of genetically predicted Lp(a) with CHD risk was linearly proportional to the absolute change in Lp(a) concentration. A 10-mg/dL lower genetically predicted Lp(a) concentration was associated with a 5.8% lower CHD risk (odds ratio [OR], 0.942; 95% CI, 0.933-0.951; P = 3 × 10-37), whereas a 10-mg/dL lower genetically predicted LDL-C level estimated using an LDL-C genetic score was associated with a 14.5% lower CHD risk (OR, 0.855; 95% CI, 0.818-0.893; P = 2 × 10-12). Thus, a 101.5-mg/dL change (95% CI, 71.0-137.0) in Lp(a) concentration had the same association with CHD risk as a 38.67-mg/dL change in LDL-C level. The association of genetically predicted Lp(a) concentration with CHD risk appeared to be independent of changes in LDL-C level owing to genetic variants that mimic the relationship of statins, PCSK9 inhibitors, and ezetimibe with CHD risk.Conclusions and Relevance: The clinical benefit of lowering Lp(a) is likely to be proportional to the absolute reduction in Lp(a) concentration. Large absolute reductions in Lp(a) of approximately 100 mg/dL may be required to produce a clinically meaningful reduction in the risk of CHD similar in magnitude to what can be achieved by lowering LDL-C level by 38.67 mg/dL (ie, 1 mmol/L).

Published
2018

4. Glycated hemoglobin measurement and prediction of cardiovascular disease

Author

Emerging Risk Factors Collaboration, Di Angelantonio, Emanuele, Gao, Pei, Khan, Hassan, Butterworth, Adam, Wormser, David, Kaptoge, Stephen, Kondapally Seshasai, Sreenivasa Rao, Thompson, Alex, Sarwar, Nadeem, Willeit, Peter, Ridker, Paul M, Barr, Elizabeth LM, Khaw, Kay-Tee, Psaty, Bruce M, Brenner, Hermann, Balkau, Beverley, Dekker, Jacqueline M, Lawlor, Debbie A, Daimon, Makoto, Willeit, Johann, Njølstad, Inger, Nissinen, Aulikki, Brunner, Eric J, Kuller, Lewis H, Price, Jackie F, Sundström, Johan, Knuiman, Matthew W, Feskens, Edith JM, Verschuren, WMM, Wald, Nicholas, Bakker, Stephan JL, Whincup, Peter H, Ford, Ian, Goldbourt, Uri, Gómez-De-La-Cámara, Agustín, Gallacher, John, Simons, Leon A, Rosengren, Annika, Sutherland, Susan E, Björkelund, Cecilia, Blazer, Dan G, Wassertheil-Smoller, Sylvia, Onat, Altan, Marín Ibañez, Alejandro, Casiglia, Edoardo, Jukema, J Wouter, Simpson, Lara M, Giampaoli, Simona, Nordestgaard, Børge G, Selmer, Randi, Wennberg, Patrik, Kauhanen, Jussi, Salonen, Jukka T, Dankner, Rachel, Barrett-Connor, Elizabeth, Kavousi, Maryam, Gudnason, Vilmundur, Evans, Denis, Wallace, Robert B, Cushman, Mary, D'Agostino, Ralph B, Umans, Jason G, Kiyohara, Yutaka, Nakagawa, Hidaeki, Sato, Shinichi, Gillum, Richard F, Folsom, Aaron R, Van Der Schouw, Yvonne T, Moons, Karel G, Griffin, Simon, Sattar, Naveed, Wareham, Nicholas, Selvin, Elizabeth, Thompson, Simon, and Danesh, John

Subjects
Male, Emerging Risk Factors Collaboration, Glycated Hemoglobin A, Cholesterol, HDL, Coronary Disease, Middle Aged, Risk Assessment, 3. Good health, Stroke, C-Reactive Protein, Predictive Value of Tests, Diabetes Mellitus, Humans, Female, Prospective Studies, Aged
Abstract

IMPORTANCE: The value of measuring levels of glycated hemoglobin (HbA1c) for the prediction of first cardiovascular events is uncertain. OBJECTIVE: To determine whether adding information on HbA1c values to conventional cardiovascular risk factors is associated with improvement in prediction of cardiovascular disease (CVD) risk. DESIGN, SETTING, AND PARTICIPANTS: Analysis of individual-participant data available from 73 prospective studies involving 294,998 participants without a known history of diabetes mellitus or CVD at the baseline assessment. MAIN OUTCOMES AND MEASURES: Measures of risk discrimination for CVD outcomes (eg, C-index) and reclassification (eg, net reclassification improvement) of participants across predicted 10-year risk categories of low (

5. 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.

6. Cardiovascular Risk Factors Associated With Venous Thromboembolism

Author

Gregson, John, Kaptoge, Stephen, Bolton, Thomas, Pennells, Lisa, Willeit, Peter, Burgess, Stephen, Bell, Steven, Sweeting, Michael, Rimm, Eric B, Kabrhel, Christopher, Zöller, Bengt, Assmann, Gerd, Gudnason, Vilmundur, Folsom, Aaron R, Arndt, Volker, Fletcher, Astrid, Norman, Paul E, Nordestgaard, Børge G, Kitamura, Akihiko, Mahmoodi, Bakhtawar K, Whincup, Peter H, Knuiman, Matthew, Salomaa, Veikko, Meisinger, Christa, Koenig, Wolfgang, Kavousi, Maryam, Völzke, Henry, Cooper, Jackie A, Ninomiya, Toshiharu, Casiglia, Edoardo, Rodriguez, Beatriz, Ben-Shlomo, Yoav, Després, Jean-Pierre, Simons, Leon, Barrett-Connor, Elizabeth, Björkelund, Cecilia, Notdurfter, Marlene, Kromhout, Daan, Price, Jackie, Sutherland, Susan E, Sundström, Johan, Kauhanen, Jussi, Gallacher, John, Beulens, Joline WJ, Dankner, Rachel, Cooper, Cyrus, Giampaoli, Simona, Deen, Jason F, Gómez De La Cámara, Agustín, Kuller, Lewis H, Rosengren, Annika, Svensson, Peter J, Nagel, Dorothea, Crespo, Carlos J, Brenner, Hermann, Albertorio-Diaz, Juan R, Atkins, Robert, Brunner, Eric J, Shipley, Martin, Njølstad, Inger, Lawlor, Deborah A, Van Der Schouw, Yvonne T, Selmer, Randi Marie, Trevisan, Maurizio, Verschuren, WM Monique, Greenland, Philip, Wassertheil-Smoller, Sylvia, Lowe, Gordon DO, Wood, Angela M, Butterworth, Adam S, Thompson, Simon G, Danesh, John, Di Angelantonio, Emanuele, Meade, Tom, and Emerging Risk Factors Collaboration

Subjects
2. Zero hunger, Adult, Male, Venous Thrombosis, Smoking, Coronary Disease, Venous Thromboembolism, Middle Aged, 16. Peace & justice, United Kingdom, 3. Good health, Body Mass Index, Cardiovascular Diseases, Risk Factors, Outcome Assessment, Health Care, Diabetes Mellitus, Humans, Female, Obesity, Prospective Studies, Pulmonary Embolism
Abstract

IMPORTANCE: It is uncertain to what extent established cardiovascular risk factors are associated with venous thromboembolism (VTE). OBJECTIVE: To estimate the associations of major cardiovascular risk factors with VTE, ie, deep vein thrombosis and pulmonary embolism. DESIGN, SETTING, AND PARTICIPANTS: This study included individual participant data mostly from essentially population-based cohort studies from the Emerging Risk Factors Collaboration (ERFC; 731 728 participants; 75 cohorts; years of baseline surveys, February 1960 to June 2008; latest date of follow-up, December 2015) and the UK Biobank (421 537 participants; years of baseline surveys, March 2006 to September 2010; latest date of follow-up, February 2016). Participants without cardiovascular disease at baseline were included. Data were analyzed from June 2017 to September 2018. EXPOSURES: A panel of several established cardiovascular risk factors. MAIN OUTCOMES AND MEASURES: Hazard ratios (HRs) per 1-SD higher usual risk factor levels (or presence/absence). Incident fatal outcomes in ERFC (VTE, 1041; coronary heart disease [CHD], 25 131) and incident fatal/nonfatal outcomes in UK Biobank (VTE, 2321; CHD, 3385). Hazard ratios were adjusted for age, sex, smoking status, diabetes, and body mass index (BMI). RESULTS: Of the 731 728 participants from the ERFC, 403 396 (55.1%) were female, and the mean (SD) age at the time of the survey was 51.9 (9.0) years; of the 421 537 participants from the UK Biobank, 233 699 (55.4%) were female, and the mean (SD) age at the time of the survey was 56.4 (8.1) years. Risk factors for VTE included older age (ERFC: HR per decade, 2.67; 95% CI, 2.45-2.91; UK Biobank: HR, 1.81; 95% CI, 1.71-1.92), current smoking (ERFC: HR, 1.38; 95% CI, 1.20-1.58; UK Biobank: HR, 1.23; 95% CI, 1.08-1.40), and BMI (ERFC: HR per 1-SD higher BMI, 1.43; 95% CI, 1.35-1.50; UK Biobank: HR, 1.37; 95% CI, 1.32-1.41). For these factors, there were similar HRs for pulmonary embolism and deep vein thrombosis in UK Biobank (except adiposity was more strongly associated with pulmonary embolism) and similar HRs for unprovoked vs provoked VTE. Apart from adiposity, these risk factors were less strongly associated with VTE than CHD. There were inconsistent associations of VTEs with diabetes and blood pressure across ERFC and UK Biobank, and there was limited ability to study lipid and inflammation markers. CONCLUSIONS AND RELEVANCE: Older age, smoking, and adiposity were consistently associated with higher VTE risk.

7. Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses

Author

Liam Gaziano, Luanluan Sun, Matthew Arnold, Steven Bell, Kelly Cho, Stephen K. Kaptoge, Rebecca J. Song, Stephen Burgess, Daniel C. Posner, Katja Mosconi, Cassianne Robinson-Cohen, Amy M. Mason, Thomas R. Bolton, Ran Tao, Elias Allara, Petra Schubert, Lingyan Chen, James R. Staley, Natalie Staplin, Servet Altay, Pilar Amiano, Volker Arndt, Johan Ärnlöv, Elizabeth L.M. Barr, Cecilia Björkelund, Jolanda M.A. Boer, Hermann Brenner, Edoardo Casiglia, Paolo Chiodini, Jackie A. Cooper, Josef Coresh, Mary Cushman, Rachel Dankner, Karina W. Davidson, Renate T. de Jongh, Chiara Donfrancesco, Gunnar Engström, Heinz Freisling, Agustín Gómez de la Cámara, Vilmundur Gudnason, Graeme J. Hankey, Per-Olof Hansson, Alicia K. Heath, Ewout J. Hoorn, Hironori Imano, Simerjot K. Jassal, Rudolf Kaaks, Verena Katzke, Jussi Kauhanen, Stefan Kiechl, Wolfgang Koenig, Richard A. Kronmal, Cecilie Kyrø, Deborah A. Lawlor, Börje Ljungberg, Conor MacDonald, Giovanna Masala, Christa Meisinger, Olle Melander, Conchi Moreno Iribas, Toshiharu Ninomiya, Dorothea Nitsch, Børge G. Nordestgaard, Charlotte Onland-Moret, Luigi Palmieri, Dafina Petrova, Jose Ramón Quirós Garcia, Annika Rosengren, Carlotta Sacerdote, Masaru Sakurai, Carmen Santiuste, Matthias B. Schulze, Sabina Sieri, Johan Sundström, Valérie Tikhonoff, Anne Tjønneland, Tammy Tong, Rosario Tumino, Ioanna Tzoulaki, Yvonne T. van der Schouw, W.M. Monique Verschuren, Henry Völzke, Robert B. Wallace, S. Goya Wannamethee, Elisabete Weiderpass, Peter Willeit, Mark Woodward, Kazumasa Yamagishi, Raul Zamora-Ros, Elvis A. Akwo, Saiju Pyarajan, David R. Gagnon, Philip S. Tsao, Sumitra Muralidhar, Todd L. Edwards, Scott M. Damrauer, Jacob Joseph, Lisa Pennells, Peter W.F. Wilson, Seamus Harrison, Thomas A. Gaziano, Michael Inouye, Colin Baigent, Juan P. Casas, Claudia Langenberg, Nick Wareham, Elio Riboli, J.Michael Gaziano, John Danesh, Adriana M. Hung, Adam S. Butterworth, Angela M. Wood, Emanuele Di Angelantonio, Anna Koettgen, Jonathan Shaw, Robert Atkins, Paul Zimmet, Peter Whincup, Johann Willeit, Christoph Leitner, Anne Tybjaerg-Hansen, Peter Schnohr, Shoaib Afzal, David Lora Pablos, Cristina Martin Arriscado, Carmen Romero Ferreiro, Hannah Stocker, Ben Schöttker, Bernd Holleczek, Angela Chetrit, Lennart Welin, Kurt Svärdsudd, Lauren Lissner, Dominique Hange, Kirsten Mehlig, Dorothea Nagel, Paul E. Norman, Osvaldo Almeida, Leon Flicker, Jun Hata, Takanori Honda, Yoshihiko Furuta, Hiroyasu Iso, Akihiko Kitamura, Isao Muraki, Jukka T. Salonen, Tomi-Pekka Tuomainen, E. M. van Zutphen, N. M. van Schoor, Cinzia Lo Noce, Richard Kronmal, Georg Lappas, Peter M. Nilsson, Bo Hedblad, Jonathan Shaffer, Joseph Schwartz, Daichi Shimbo, Shinichi Sato, Mina Hayama-Terada, Simerjot Jassal, Thor Aspelund, Bolli Thorsson, Gunnar Sigurdsson, Layal Chaker, Kamran M. Ikram, Maryam Kavousi, Hugh Tunstall-Pedoe, Günay Can, Hüsniye Yüksel, Uğur Özkan, Hideaki Nakagawa, Yuko Morikawa, Masao Ishizaki, Edith Feskens, Johanna M Geleijnse, Daan Kromhout, Internal Medicine, Neurology, Epidemiology, Bell, Steven [0000-0001-6774-3149], Posner, Daniel C [0000-0002-3056-6924], Mason, Amy M [0000-0002-8019-0777], Allara, Elias [0000-0002-1634-8330], Staplin, Natalie [0000-0003-4482-4418], Arndt, Volker [0000-0001-9320-8684], Ärnlöv, Johan [0000-0002-6933-4637], Barr, Elizabeth LM [0000-0003-4284-1716], Boer, Jolanda MA [0000-0002-9714-4304], Brenner, Hermann [0000-0002-6129-1572], Casiglia, Edoardo [0000-0002-0003-3289], Chiodini, Paolo [0000-0003-0139-2264], Coresh, Josef [0000-0002-4598-0669], Cushman, Mary [0000-0002-7871-6143], Davidson, Karina W [0000-0002-9162-477X], de Jongh, Renate T [0000-0001-8414-3938], Engström, Gunnar [0000-0002-8618-9152], de la Cámara, Agustín Gómez [0000-0001-6827-6319], Gudnason, Vilmundur [0000-0001-5696-0084], Hankey, Graeme J [0000-0002-6044-7328], Hansson, Per-Olof [0000-0001-6323-0506], Heath, Alicia K [0000-0001-6517-1300], Hoorn, Ewout J [0000-0002-8738-3571], Imano, Hironori [0000-0002-6661-4254], Katzke, Verena [0000-0002-6509-6555], Kiechl, Stefan [0000-0002-9836-2514], Koenig, Wolfgang [0000-0002-2064-9603], Kronmal, Richard A [0000-0002-9897-7076], Kyrø, Cecilie [0000-0002-9083-8960], Ljungberg, Börje [0000-0002-4121-3753], MacDonald, Conor [0000-0002-4989-803X], Masala, Giovanna [0000-0002-5758-9069], Ninomiya, Toshiharu [0000-0003-1345-9032], Nordestgaard, Børge G [0000-0002-1954-7220], Onland-Moret, Charlotte [0000-0002-2360-913X], Palmieri, Luigi [0000-0002-4298-2642], Rosengren, Annika [0000-0002-5409-6605], Schulze, Matthias B [0000-0002-0830-5277], Sieri, Sabina [0000-0001-5201-172X], Sundström, Johan [0000-0003-2247-8454], Tikhonoff, Valérie [0000-0001-7846-0101], Tong, Tammy [0000-0002-0284-8959], Tzoulaki, Ioanna [0000-0002-4275-9328], van der Schouw, Yvonne T [0000-0002-4605-435X], Wannamethee, S Goya [0000-0001-9484-9977], Weiderpass, Elisabete [0000-0003-2237-0128], Willeit, Peter [0000-0002-1866-7159], Woodward, Mark [0000-0001-9800-5296], Yamagishi, Kazumasa [0000-0003-3301-5519], Zamora-Ros, Raul [0000-0002-6236-6804], Gagnon, David R [0000-0002-6367-3179], Tsao, Philip S [0000-0001-7274-9318], Edwards, Todd L [0000-0003-4318-6119], Damrauer, Scott M [0000-0001-8009-1632], Joseph, Jacob [0000-0002-7279-4896], Pennells, Lisa [0000-0002-8594-3061], Gaziano, Thomas A [0000-0002-5985-345X], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nick [0000-0003-1422-2993], Hung, Adriana M [0000-0002-3203-1608], Butterworth, Adam S [0000-0002-6915-9015], Di Angelantonio, Emanuele [0000-0001-8776-6719], Apollo - University of Cambridge Repository, Gaziano, Liam, Sun, Luanluan, Arnold, Matthew, Bell, Steven, Cho, Kelly, Kaptoge, Stephen K, Song, Rebecca J, Burgess, Stephen, Posner, Daniel C, Mosconi, Katja, Robinson-Cohen, Cassianne, Mason, Amy M, Bolton, Thomas R, Tao, Ran, Allara, Elia, Schubert, Petra, Chen, Lingyan, Staley, James R, Staplin, Natalie, Altay, Servet, Amiano, Pilar, Arndt, Volker, Ärnlöv, Johan, Barr, Elizabeth L M, Björkelund, Cecilia, Boer, Jolanda M A, Brenner, Hermann, Casiglia, Edoardo, Chiodini, Paolo, Cooper, Jackie A, Coresh, Josef, Cushman, Mary, Dankner, Rachel, Davidson, Karina W, de Jongh, Renate T, Donfrancesco, Chiara, Engström, Gunnar, Freisling, Heinz, de la Cámara, Agustín Gómez, Gudnason, Vilmundur, Hankey, Graeme J, Hansson, Per-Olof, Heath, Alicia K, Hoorn, Ewout J, Imano, Hironori, Jassal, Simerjot K, Kaaks, Rudolf, Katzke, Verena, Kauhanen, Jussi, Kiechl, Stefan, Koenig, Wolfgang, Kronmal, Richard A, Kyrø, Cecilie, Lawlor, Deborah A, Ljungberg, Börje, Macdonald, Conor, Masala, Giovanna, Meisinger, Christa, Melander, Olle, Moreno Iribas, Conchi, Ninomiya, Toshiharu, Nitsch, Dorothea, Nordestgaard, Børge G, Onland-Moret, Charlotte, Palmieri, Luigi, Petrova, Dafina, Garcia, Jose Ramón Quiró, Rosengren, Annika, Sacerdote, Carlotta, Sakurai, Masaru, Santiuste, Carmen, Schulze, Matthias B, Sieri, Sabina, Sundström, Johan, Tikhonoff, Valérie, Tjønneland, Anne, Tong, Tammy, Tumino, Rosario, Tzoulaki, Ioanna, van der Schouw, Yvonne T, Monique Verschuren, W M, Völzke, Henry, Wallace, Robert B, Wannamethee, S Goya, Weiderpass, Elisabete, Willeit, Peter, Woodward, Mark, Yamagishi, Kazumasa, Zamora-Ros, Raul, Akwo, Elvis A, Pyarajan, Saiju, Gagnon, David R, Tsao, Philip S, Muralidhar, Sumitra, Edwards, Todd L, Damrauer, Scott M, Joseph, Jacob, Pennells, Lisa, Wilson, Peter W F, Harrison, Seamu, Gaziano, Thomas A, Inouye, Michael, Baigent, Colin, Casas, Juan P, Langenberg, Claudia, Wareham, Nick, Riboli, Elio, Gaziano, J Michael, Danesh, John, Hung, Adriana M, Butterworth, Adam S, Wood, Angela M, Di Angelantonio, Emanuele, Internal medicine, AMS - Ageing & Vitality, AMS - Musculoskeletal Health, Amsterdam Gastroenterology Endocrinology Metabolism, Epidemiology and Data Science, APH - Aging & Later Life, and APH - Personalized Medicine

Subjects
kidney disease, General Practice, Emerging Risk Factors Collaboration/EPIC-CVD/Million Veteran Program, Coronary Disease, coronary disease, Kidney, Malalties coronàries, 1117 Public Health and Health Services, Coronary diseases, SDG 3 - Good Health and Well-being, cardiovascular disease, Risk Factors, Physiology (medical), Diabetes Mellitus, Humans, Cardiac and Cardiovascular Systems, Prospective Studies, 1102 Cardiorespiratory Medicine and Haematology, Kardiologi, Kidney diseases, Malalties cardiovasculars, Cardiovascular Diseases, Kidney Diseases, Stroke, 1103 Clinical Sciences, Mendelian Randomization Analysis, kidney diseases, stroke, Allmänmedicin, Cardiovascular diseases, Cardiovascular System & Hematology, Malalties del ronyó, Cardiology and Cardiovascular Medicine, cardiovascular diseases
Abstract

Background: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. Methods: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. Results: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values 105 mL·min –1 ·1.73 m –2 , compared with those with eGFR between 60 and 105 mL·min –1 ·1.73 m –2 . Mendelian randomization analyses for CHD showed an association among participants with eGFR –1 ·1.73 m –2 , with a 14% (95% CI, 3%–27%) higher CHD risk per 5 mL·min –1 ·1.73 m –2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min –1 ·1.73 m –2 . Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. Conclusions: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

Published
2022

8. 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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