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1. Estimating dose-response relationships for vitamin D with coronary heart disease, stroke, and all-cause mortality: observational and Mendelian randomisation analyses

Author

Sofianopoulou, Eleni, Kaptoge, Stephen K, Afzal, Shoaib, Jiang, Tao, Gill, Dipender, Gundersen, Thomas E, Bolton, Thomas R, Allara, Elias, Arnold, Matthew G, Mason, Amy M, Chung, Ryan, Pennells, Lisa A M, Shi, Fanchao, Sun, Luanluan, Willeit, Peter, Forouhi, Nita G, Langenberg, Claudia, Sharp, Stephen J, Panico, Salvatore, Engström, Gunnar, Melander, Olle, Tong, Tammy Y N, Perez-Cornago, Aurora, Norberg, Margareta, Johansson, Ingegerd, Katzke, Verena, Srour, Bernard, Sánchez, María José, Redondo-Sánchez, Daniel, Olsen, Anja, Dahm, Christina C, Overvad, Kim, Brustad, Magritt, Skeie, Guri, Moreno-Iribas, Conchi, Onland-Moret, N Charlotte, van der Schouw, Yvonne T, Tsilidis, Konstantinos K, Heath, Alicia K, Agnoli, Claudia, Krogh, Vittorio, de Boer, Ian H, Kobylecki, Camilla Jannie, Çolak, Yunus, Zittermann, Armin, Sundström, Johan, Welsh, Paul, Weiderpass, Elisabete, Aglago, Elom K, Ferrari, Pietro, Clarke, Robert, Boutron, Marie-Christine, Severi, Gianluca, MacDonald, Conor, Providencia, Rui, Masala, Giovanna, Zamora Ros, Raul, Boer, Jolanda, Verschuren, Wm Monique, Cawthon, Peggy, Schierbeck, Louise L, Cooper, Cyrus, Schulze, Matthias B, Bergmann, Manuela M, Hannemann, Anke, Kiechl, Stefan, Brenner, Hermann, van Schoor, Natasja M, Albertorio, Juan R, Sacerdote, Carlotta, Linneberg, Allan, Kårhus, LineL, Huerta, José María, Imaz, Liher, Joergensen, Christel, Ben-Shlomo, Yoav, Lundqvist, Annamari, Gallacher, John, Sattar, Naveed, Wood, Angela M, Wareham, Nicholas J, Nordestgaard, Børge G, Di Angelantonio, Emanuele, Danesh, John, Butterworth, Adam S, and Burgess, Stephen

Published
2024
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3. Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses

Author

Gaziano, Liam, primary, Sun, Luanluan, additional, Arnold, Matthew, additional, Bell, Steven, additional, Cho, Kelly, additional, Kaptoge, Stephen K., additional, Song, Rebecca J., additional, Burgess, Stephen, additional, Posner, Daniel C., additional, Mosconi, Katja, additional, Robinson-Cohen, Cassianne, additional, Mason, Amy M., additional, Bolton, Thomas R., additional, Tao, Ran, additional, Allara, Elias, additional, Schubert, Petra, additional, Chen, Lingyan, additional, Staley, James R., additional, Staplin, Natalie, additional, Altay, Servet, additional, Amiano, Pilar, additional, Arndt, Volker, additional, Ärnlöv, Johan, additional, Barr, Elizabeth L.M., additional, Björkelund, Cecilia, additional, Boer, Jolanda M.A., additional, Brenner, Hermann, additional, Casiglia, Edoardo, additional, Chiodini, Paolo, additional, Cooper, Jackie A., additional, Coresh, Josef, additional, Cushman, Mary, additional, Dankner, Rachel, additional, Davidson, Karina W., additional, de Jongh, Renate T., additional, Donfrancesco, Chiara, additional, Engström, Gunnar, additional, Freisling, Heinz, additional, de la Cámara, Agustín Gómez, additional, Gudnason, Vilmundur, additional, Hankey, Graeme J., additional, Hansson, Per-Olof, additional, Heath, Alicia K., additional, Hoorn, Ewout J., additional, Imano, Hironori, additional, Jassal, Simerjot K., additional, Kaaks, Rudolf, additional, Katzke, Verena, additional, Kauhanen, Jussi, additional, Kiechl, Stefan, additional, Koenig, Wolfgang, additional, Kronmal, Richard A., additional, Kyrø, Cecilie, additional, Lawlor, Deborah A., additional, Ljungberg, Börje, additional, MacDonald, Conor, additional, Masala, Giovanna, additional, Meisinger, Christa, additional, Melander, Olle, additional, Moreno Iribas, Conchi, additional, Ninomiya, Toshiharu, additional, Nitsch, Dorothea, additional, Nordestgaard, Børge G., additional, Onland-Moret, Charlotte, additional, Palmieri, Luigi, additional, Petrova, Dafina, additional, Garcia, Jose Ramón Quirós, additional, Rosengren, Annika, additional, Sacerdote, Carlotta, additional, Sakurai, Masaru, additional, Santiuste, Carmen, additional, Schulze, Matthias B., additional, Sieri, Sabina, additional, Sundström, Johan, additional, Tikhonoff, Valérie, additional, Tjønneland, Anne, additional, Tong, Tammy, additional, Tumino, Rosario, additional, Tzoulaki, Ioanna, additional, van der Schouw, Yvonne T., additional, Monique Verschuren, W.M., additional, Völzke, Henry, additional, Wallace, Robert B., additional, Wannamethee, S. Goya, additional, Weiderpass, Elisabete, additional, Willeit, Peter, additional, Woodward, Mark, additional, Yamagishi, Kazumasa, additional, Zamora-Ros, Raul, additional, Akwo, Elvis A., additional, Pyarajan, Saiju, additional, Gagnon, David R., additional, Tsao, Philip S., additional, Muralidhar, Sumitra, additional, Edwards, Todd L., additional, Damrauer, Scott M., additional, Joseph, Jacob, additional, Pennells, Lisa, additional, Wilson, Peter W.F., additional, Harrison, Seamus, additional, Gaziano, Thomas A., additional, Inouye, Michael, additional, Baigent, Colin, additional, Casas, Juan P., additional, Langenberg, Claudia, additional, Wareham, Nick, additional, Riboli, Elio, additional, Gaziano, J.Michael, additional, Danesh, John, additional, Hung, Adriana M., additional, Butterworth, Adam S., additional, Wood, Angela M., additional, Di Angelantonio, Emanuele, additional, Koettgen, Anna, additional, Shaw, Jonathan, additional, Atkins, Robert, additional, Zimmet, Paul, additional, Whincup, Peter, additional, Willeit, Johann, additional, Leitner, Christoph, additional, Tybjaerg-Hansen, Anne, additional, Schnohr, Peter, additional, Afzal, Shoaib, additional, Pablos, David Lora, additional, Arriscado, Cristina Martin, additional, Ferreiro, Carmen Romero, additional, Stocker, Hannah, additional, Schöttker, Ben, additional, Holleczek, Bernd, additional, Chetrit, Angela, additional, Welin, Lennart, additional, Svärdsudd, Kurt, additional, Lissner, Lauren, additional, Hange, Dominique, additional, Mehlig, Kirsten, additional, Nagel, Dorothea, additional, Norman, Paul E., additional, Almeida, Osvaldo, additional, Flicker, Leon, additional, Hata, Jun, additional, Honda, Takanori, additional, Furuta, Yoshihiko, additional, Iso, Hiroyasu, additional, Kitamura, Akihiko, additional, Muraki, Isao, additional, Salonen, Jukka T., additional, Tuomainen, Tomi-Pekka, additional, van Zutphen, E. M., additional, van Schoor, N. M., additional, Lo Noce, Cinzia, additional, Kronmal, Richard, additional, Lappas, Georg, additional, Nilsson, Peter M., additional, Hedblad, Bo, additional, Shaffer, Jonathan, additional, Schwartz, Joseph, additional, Shimbo, Daichi, additional, Sato, Shinichi, additional, Hayama-Terada, Mina, additional, Jassal, Simerjot, additional, Aspelund, Thor, additional, Thorsson, Bolli, additional, Sigurdsson, Gunnar, additional, Chaker, Layal, additional, Ikram, Kamran M., additional, Kavousi, Maryam, additional, Tunstall-Pedoe, Hugh, additional, Can, Günay, additional, Yüksel, Hüsniye, additional, Özkan, Uğur, additional, Nakagawa, Hideaki, additional, Morikawa, Yuko, additional, Ishizaki, Masao, additional, Feskens, Edith, additional, Geleijnse, Johanna M, additional, and Kromhout, Daan, additional

Published
2022
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4. Estimating dose-response relationships for vitamin D with coronary heart disease, stroke, and all-cause mortality: observational and Mendelian randomisation analyses

Author

Sofianopoulou, Eleni, primary, Kaptoge, Stephen K, additional, Afzal, Shoaib, additional, Jiang, Tao, additional, Gill, Dipender, additional, Gundersen, Thomas E, additional, Bolton, Thomas R, additional, Allara, Elias, additional, Arnold, Matthew G, additional, Mason, Amy M, additional, Chung, Ryan, additional, Pennells, Lisa A M, additional, Shi, Fanchao, additional, Sun, Luanluan, additional, Willeit, Peter, additional, Forouhi, Nita G, additional, Langenberg, Claudia, additional, Sharp, Stephen J, additional, Panico, Salvatore, additional, Engström, Gunnar, additional, Melander, Olle, additional, Tong, Tammy Y N, additional, Perez-Cornago, Aurora, additional, Norberg, Margareta, additional, Johansson, Ingegerd, additional, Katzke, Verena, additional, Srour, Bernard, additional, José Sánchez, María, additional, Redondo-Sánchez, Daniel, additional, Olsen, Anja, additional, Dahm, Christina C, additional, Overvad, Kim, additional, Brustad, Magritt, additional, Skeie, Guri, additional, Moreno-Iribas, Conchi, additional, Onland-Moret, N Charlotte, additional, van der Schouw, Yvonne T, additional, Tsilidis, Konstantinos K, additional, Heath, Alicia K, additional, Agnoli, Claudia, additional, Krogh, Vittorio, additional, de Boer, Ian H, additional, Kobylecki, Camilla Jannie, additional, Çolak, Yunus, additional, Zittermann, Armin, additional, Sundström, Johan, additional, Welsh, Paul, additional, Weiderpass, Elisabete, additional, Aglago, Elom K, additional, Ferrari, Pietro, additional, Clarke, Robert, additional, Boutron, Marie-Christine, additional, Severi, Gianluca, additional, MacDonald, Conor, additional, Providencia, Rui, additional, Masala, Giovanna, additional, Zamora Ros, Raul, additional, Boer, Jolanda, additional, Verschuren, WM Monique, additional, Cawthon, Peggy, additional, Schierbeck, Louise L, additional, Cooper, Cyrus, additional, Schulze, Matthias B, additional, Bergmann, Manuela M, additional, Hannemann, Anke, additional, Kiechl, Stefan, additional, Brenner, Hermann, additional, van Schoor, Natasja M, additional, Albertorio, Juan R, additional, Sacerdote, Carlotta, additional, Linneberg, Allan, additional, Kårhus, Line L, additional, Huerta, José María, additional, Imaz, Liher, additional, Joergensen, Christel, additional, Ben-Shlomo, Yoav, additional, Lundqvist, Annamari, additional, Gallacher, John, additional, Sattar, Naveed, additional, Wood, Angela M, additional, Wareham, Nicholas J, additional, Nordestgaard, Børge G, additional, Di Angelantonio, Emanuele, additional, Danesh, John, additional, Butterworth, Adam S, additional, and Burgess, Stephen, additional

Published
2021
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5. RETRACTED: Estimating dose-response relationships for vitamin D with coronary heart disease, stroke, and all-cause mortality: observational and Mendelian randomisation analyses

Author

Sofianopoulou, Eleni, Kaptoge, Stephen K, Afzal, Shoaib, Jiang, Tao, Gill, Dipender, Gundersen, Thomas E, Bolton, Thomas R, Allara, Elias, Arnold, Matthew G, Mason, Amy M, Chung, Ryan, Pennells, Lisa A M, Shi, Fanchao, Sun, Luanluan, Willeit, Peter, Forouhi, Nita G, Langenberg, Claudia, Sharp, Stephen J, Panico, Salvatore, Engström, Gunnar, Melander, Olle, Tong, Tammy Y N, Perez-Cornago, Aurora, Norberg, Margareta, Johansson, Ingegerd, Katzke, Verena, Srour, Bernard, José Sánchez, María, Redondo-Sánchez, Daniel, Olsen, Anja, Dahm, Christina C, Overvad, Kim, Brustad, Magritt, Skeie, Guri, Moreno-Iribas, Conchi, Onland-Moret, N Charlotte, van der Schouw, Yvonne T, Tsilidis, Konstantinos K, Heath, Alicia K, Agnoli, Claudia, Krogh, Vittorio, de Boer, Ian H, Kobylecki, Camilla Jannie, Çolak, Yunus, Zittermann, Armin, Sundström, Johan, Welsh, Paul, Weiderpass, Elisabete, Aglago, Elom K, Ferrari, Pietro, Clarke, Robert, Boutron, Marie-Christine, Severi, Gianluca, MacDonald, Conor, Providencia, Rui, Masala, Giovanna, Zamora Ros, Raul, Boer, Jolanda, Verschuren, WM Monique, Cawthon, Peggy, Schierbeck, Louise L, Cooper, Cyrus, Schulze, Matthias B, Bergmann, Manuela M, Hannemann, Anke, Kiechl, Stefan, Brenner, Hermann, van Schoor, Natasja M, Albertorio, Juan R, Sacerdote, Carlotta, Linneberg, Allan, Kårhus, Line L, Huerta, José María, Imaz, Liher, Joergensen, Christel, Ben-Shlomo, Yoav, Lundqvist, Annamari, Gallacher, John, Sattar, Naveed, Wood, Angela M, Wareham, Nicholas J, Nordestgaard, Børge G, Di Angelantonio, Emanuele, Danesh, John, Butterworth, Adam S, and Burgess, Stephen

Published
2021
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6. Body mass index and all cause mortality in HUNT and UK Biobank studies: linear and non-linear mendelian randomisation analyses

Author

Sun, Yi-Qian, Burgess, Stephen, Staley, James R, Wood, Angela M, Bell, Steven, Kaptoge, Stephen K, Guo, Qi, Bolton, Thomas R, Mason, Amy M, Butterworth, Adam S, Di Angelantonio, Emanuele, Vie, Gunnhild Å, Bjørngaard, Johan H, Kinge, Jonas Minet, Chen, Yue, and Mai, Xiao-Mei

Subjects
Adult, Male, Norway, Research, nutritional and metabolic diseases, Mendelian Randomization Analysis, Middle Aged, United Kingdom, Body Mass Index, Thinness, Cardiovascular Diseases, Risk Factors, Cause of Death, Neoplasms, Humans, Female, Obesity, Sex Distribution, Aged
Abstract

Objective To investigate the shape of the causal relation between body mass index (BMI) and mortality. Design Linear and non-linear mendelian randomisation analyses. Setting Nord-Trøndelag Health (HUNT) Study (Norway) and UK Biobank (United Kingdom). Participants Middle to early late aged participants of European descent: 56 150 from the HUNT Study and 366 385 from UK Biobank. Main outcome measures All cause and cause specific (cardiovascular, cancer, and non-cardiovascular non-cancer) mortality. Results 12 015 and 10 344 participants died during a median of 18.5 and 7.0 years of follow-up in the HUNT Study and UK Biobank, respectively. Linear mendelian randomisation analyses indicated an overall positive association between genetically predicted BMI and the risk of all cause mortality. An increase of 1 unit in genetically predicted BMI led to a 5% (95% confidence interval 1% to 8%) higher risk of mortality in overweight participants (BMI 25.0-29.9) and a 9% (4% to 14%) higher risk of mortality in obese participants (BMI ≥30.0) but a 34% (16% to 48%) lower risk in underweight (BMI

Published
2019

7. Association of LPA Variants 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 R., 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, Medical Research Council Biostatistics Unit, University of Cambridge, Cambridge, United Kingdom, MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom, Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark, The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark, Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark, Institute of Health and Wellbeing, University of Glasgow, Glasgow, United Kingdom, Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom, Department of Cardiology, Leiden University Medical Centre, Leiden, the Netherlands, and Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia

Published
2018

8. Genetic predictors of testosterone and their associations with cardiovascular disease and risk factors: A Mendelian randomization investigation

Author

Schooling, C Mary, Luo, Shan, Au Yeung, Shiu Lun, Thompson, Deborah J, Karthikeyan, Savita, Bolton, Thomas R, Mason, Amy M, Ingelsson, Erik, Burgess, Stephen, Thompson, Deborah [0000-0003-1465-5799], Karthikeyan, Savita [0000-0002-4798-5746], Mason, Amy [0000-0002-8019-0777], Burgess, Stephen [0000-0001-5365-8760], and Apollo - University of Cambridge Repository

Subjects
Male, Jumonji Domain-Containing Histone Demethylases, BMI, body mass index, CAD, coronary artery disease, HDL, high-density lipoprotein, Blood Pressure, Receptors, Cell Surface, Coronary Artery Disease, Article, Risk Factors, LDL, low-density lipoprotein, Mendelian randomization, Humans, Genetic epidemiology, Sex hormones, Testosterone, Genetic Predisposition to Disease, RCT, randomized controlled trial, Disease aetiology, Aged, Anthropometry, SHBG, sex hormone-binding globulin, Genetic Variation, Oxidoreductases, N-Demethylating, Mendelian Randomization Analysis, Middle Aged, Lipids, United Kingdom, United States, Stroke, Adiponectin, Causal inference, Genome-Wide Association Study
Abstract

Background Testosterone supplementation has been linked to increased cardiovascular disease risk in some observational studies. The causal role of testosterone can be investigated using a Mendelian randomization approach. Methods and results We assessed genetic associations of variants in two gene regions (SHBG and JMJD1C) with several cardiovascular risk factors (lipids, adiponectin, blood pressure, anthropometric traits) plus male pattern baldness, including control outcomes and potential mediators. We assessed genetic associations with coronary artery disease (CAD) risk in the CARDIoGRAMplusC4D consortium (171,191 individuals including 60,801 cases), and associations with CAD and ischaemic stroke risk in the UK Biobank (367,643 individuals including 25,352 CAD cases and 3650 ischaemic stroke cases). Genetic predictors of increased serum testosterone were associated with lipids, blood pressure, and height. There was some evidence of an association with risk of CAD (SHBG gene region: odds ratio (OR) 0.95 per 1 unit increase in log-transformed testosterone [95% confidence interval: 0.81–1.12, p = 0.55]; JMJD1C gene region: OR 1.24 [1.01–1.51, p = 0.04]) and ischaemic stroke both overall (SHBG: OR 1.05 [0.64, 1.73, p = 0.83]; JMJD1C: OR 2.52 [1.33, 4.77, p = 0.005]) and in men. However, associations with some control outcomes were in the opposite direction to that expected. Conclusions Sex hormone-related mechanisms appear to be relevant to cardiovascular risk factors and for stroke (particularly for men). However, the extent that these findings are specifically informative about endogenous testosterone or testosterone supplementation is unclear. These findings underline a fundamental limitation for the use of Mendelian randomization where biological knowledge about the function of genetic variants is uncertain., Highlights • Genetic predictors of testosterone were associated with cardiovascular risk factors, such as lipids and blood pressure. • However, associations were not consistent between the two gene regions considered in this analysis. • Some genetic predictors of increased testosterone associated with higher coronary artery disease and ischaemic stroke risk. • This suggests that some sex hormone-related mechanisms are implicated in cardiovascular disease. • However, the extent to which these analyses are predictive of the effects of testosterone supplementation is unclear.

Published
2018

9. Body mass index and all cause mortality in HUNT and UK Biobank studies: linear and non-linear mendelian randomisation analyses

Author

Sun, Yi-Qian, primary, Burgess, Stephen, additional, Staley, James R, additional, Wood, Angela M, additional, Bell, Steven, additional, Kaptoge, Stephen K, additional, Guo, Qi, additional, Bolton, Thomas R, additional, Mason, Amy M, additional, Butterworth, Adam S, additional, Di Angelantonio, Emanuele, additional, Vie, Gunnhild Å, additional, Bjørngaard, Johan H, additional, Kinge, Jonas Minet, additional, Chen, Yue, additional, and Mai, Xiao-Mei, additional

Published
2019
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10. 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

12. Association of LPA Variants With Risk of Coronary Disease and the Implications for Lipoprotein(a)-Lowering Therapies: A Mendelian Randomization Analysis.

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 R., Tybjærg-Hansen, Anne, Benn, Marianne, Langsted, Anne, Schnohr, Peter, Vedel-Krogh, Signe, Kobylecki, Camilla J., and Ford, Ian

Published
2018
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14. 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

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