378 results on '"Emdin, Connor A."'
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52. rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis
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Teo, Kevin, Abeysekera, Kushala WM, Adams, Leon, Aigner, Elmar, Anstee, Quentin M, Banales, Jesus M, Banerjee, Rajarshi, Basu, Priyadarshi, Berg, Thomas, Bhatnagar, Pallav, Buch, Stephan, Canbay, Ali, Caprio, Sonia, Chatterjee, Ankita, Ida Chen, Yii-Der, Chowdhury, Abhijit, Daly, Ann K, Datz, Christian, de Gracia Hahn, Dana, DiStefano, Johanna K, Dong, Jiawen, Duret, Amedine, EU-PNAFLD Investigators, Emdin, Connor, Fairey, Madison, Gerhard, Glenn S, GOLD Consortium, Guo, Xiuqing, Hampe, Jochen, Hickman, Matthew, Heintz, Lena, Hudert, Christian, Hunter, Harriet, Kelly, Matt, Kozlitina, Julia, Krawczyk, Marcin, Lammert, Frank, Langenberg, Claudia, Lavine, Joel, Li, Lin, Lim, Hong Kai, Loomba, Rohit, Luukkonen, Panu K, Melton, Phillip E, Mori, Trevor A, Palmer, Nicholette D, Parisinos, Constantinos A, Pillai, Sreekumar G, Qayyum, Faiza, Reichert, Matthias C, Romeo, Stefano, Rotter, Jerome I, Im, Yu Ri, Santoro, Nicola, Schafmayer, Clemens, Speliotes, Elizabeth K, Stender, Stefan, Stickel, Felix, Still, Christopher D, Strnad, Pavel, Taylor, Kent D, Tybjærg-Hansen, Anne, Umano, Giuseppina Rosaria, Utukuri, Mrudula, Valenti, Luca, Wagenknecht, Lynne E, Wareham, Nicholas J, Watanabe, Richard M, Wattacheril, Julia, Yaghootkar, Hanieh, Yki-Järvinen, Hannele, Young, Kendra A, Mann, Jake P, Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Mann, Jake [0000-0002-4711-9215], and Apollo - University of Cambridge Repository
- Subjects
Liver Cirrhosis ,Diabetes ,Membrane Proteins ,Alanine Transaminase ,ALSPAC ,Fibrosis ,Triglyceride ,Polymorphism, Single Nucleotide ,MBOAT7 ,Liver ,Non-alcoholic Fatty Liver Disease ,NAFLD ,Drug Discovery ,Humans ,Genetic Predisposition to Disease ,Acyltransferases - Abstract
BACKGROUND & AIMS: A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in NAFLD; however, these findings have not been consistently replicated in the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of NAFLD and to characterise its role in the regulation of related metabolic phenotypes through a meta-analysis. METHODS: We performed a meta-analysis of studies with data on the association between rs641738C>T genotype and liver fat, NAFLD histology, and serum alanine aminotransferase (ALT), lipids or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed a random effects meta-analysis using recessive, additive and dominant genetic models. RESULTS: Data from 1,066,175 participants (9,688 with liver biopsies) across 42 studies were included in the meta-analysis. rs641738C>T was associated with higher liver fat on CT/MRI (+0.03 standard deviations [95% CI 0.02-0.05], pz = 4.8×10-5) and diagnosis of NAFLD (odds ratio [OR] 1.17 [95% CI 1.05-1.3], pz = 0.003) in Caucasian adults. The variant was also positively associated with presence of advanced fibrosis (OR 1.22 [95% CI 1.03-1.45], pz = 0.021) in Caucasian adults using a recessive model of inheritance (CC + CT vs. TT). Meta-analysis of data from previous GWAS found the variant to be associated with higher ALT (pz = 0.002) and lower serum triglycerides (pz = 1.5×10-4). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD. CONCLUSIONS: Our study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent. LAY SUMMARY: Fatty liver disease is a common condition where fat builds up in the liver, which can cause liver inflammation and scarring (including 'cirrhosis'). It is closely linked to obesity and diabetes, but some genes are also thought to be important. We did this study to see whether one specific change ('variant') in one gene ('MBOAT7') was linked to fatty liver disease. We took data from over 40 published studies and found that this variant near MBOAT7 is linked to more severe fatty liver disease. This means that drugs designed to work on MBOAT7 could be useful for treating fatty liver disease.
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- 2021
53. Abstract 056: Alcohol Increases Risk Of Cardiovascular Disease At All Levels Of Intake
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Biddinger, Kiran J, primary, Emdin, Connor, additional, Haas, Mary E, additional, Wang, Minxian, additional, Hindy, George, additional, Ellinor, Patrick T, additional, Kathiresan, Sekar, additional, Khera, Amit V, additional, and Aragam, Krishna, additional
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- 2021
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54. rs641738C>T nearMBOAT7is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis
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Medicina, Medikuntza, Teo, Kevin, Abeysekera, Kushala W.M., Adams, Leon, Aigner, Elmar, Anstee, Quentin M., Bañales Asurmendi, Jesús María, Banerjee, Rajarshi, Basu, Priyadarshi, Berg, Thomas, Bhatnagar, Pallav, Buch, Stephan, Canbay, Ali, Caprio, Sonia, Chatterjee, Ankita, Chen, Yii-Der Ida, Chowdhury, Abhijit, Daly, Ann K., Datz, Christian, De Gracia Hahn, Dana, DiStefano, Johanna K., Dong, Jiawen, Duret, Amedine, EU-PNAFLD Investigators, Emdin, Connor, Fairey, Madison, Gerhard, Glenn S., GOLD Consortium, Guo, Xiuqing, Hampe, Jochen, Hickman, Matthew, Heintz, Lena, Hudert, Christian, Hunter, Harriet, Kelly, Matt, Kozlitina, Julia, Krawczyk, Marcin, Lammert, Frank, Langenberg, Claudia, Lavine, Joel, Li, Lin, Lim, Hong Kai, Loomba, Rohit, Luukkonen, Panu K., Melton, Phillip E., Mori, Trevor A., Palmer, Nicholette D., Parisinos, Constantinos A., Pillai, Sreekumar G., Qayyum, Faiza, Reichert, Matthias C., Romeo, Stefano, Rotter, Jerome I., Im, Yu Ri, Santoro, Nicola, Schafmayer, Clemens, Speliotes, Elizabeth K., Stender, Stefan, Stickel, Felix, Still, Christopher D., Strnad, Pavel, Taylor, Kent D., Tybjærg-Hansen, Anne, Umano, Giuseppina Rosaria, Utukuri, Mrudula, Valenti, Luca, Wagenknecht, Lynne E., Wareham, Nicholas J., Watanabe, Richard M., Wattacheril, Julia, Yaghootkar, Hanieh, Yki-Järvinen, Hannele, Young, Kendra A., Mann, Jake P., Medicina, Medikuntza, Teo, Kevin, Abeysekera, Kushala W.M., Adams, Leon, Aigner, Elmar, Anstee, Quentin M., Bañales Asurmendi, Jesús María, Banerjee, Rajarshi, Basu, Priyadarshi, Berg, Thomas, Bhatnagar, Pallav, Buch, Stephan, Canbay, Ali, Caprio, Sonia, Chatterjee, Ankita, Chen, Yii-Der Ida, Chowdhury, Abhijit, Daly, Ann K., Datz, Christian, De Gracia Hahn, Dana, DiStefano, Johanna K., Dong, Jiawen, Duret, Amedine, EU-PNAFLD Investigators, Emdin, Connor, Fairey, Madison, Gerhard, Glenn S., GOLD Consortium, Guo, Xiuqing, Hampe, Jochen, Hickman, Matthew, Heintz, Lena, Hudert, Christian, Hunter, Harriet, Kelly, Matt, Kozlitina, Julia, Krawczyk, Marcin, Lammert, Frank, Langenberg, Claudia, Lavine, Joel, Li, Lin, Lim, Hong Kai, Loomba, Rohit, Luukkonen, Panu K., Melton, Phillip E., Mori, Trevor A., Palmer, Nicholette D., Parisinos, Constantinos A., Pillai, Sreekumar G., Qayyum, Faiza, Reichert, Matthias C., Romeo, Stefano, Rotter, Jerome I., Im, Yu Ri, Santoro, Nicola, Schafmayer, Clemens, Speliotes, Elizabeth K., Stender, Stefan, Stickel, Felix, Still, Christopher D., Strnad, Pavel, Taylor, Kent D., Tybjærg-Hansen, Anne, Umano, Giuseppina Rosaria, Utukuri, Mrudula, Valenti, Luca, Wagenknecht, Lynne E., Wareham, Nicholas J., Watanabe, Richard M., Wattacheril, Julia, Yaghootkar, Hanieh, Yki-Järvinen, Hannele, Young, Kendra A., and Mann, Jake P.
- Abstract
Background & Aims: A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in NAFLD; however, these findings have not been consistently replicated in the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of NAFLD and to characterise its role in the regulation of related metabolic phenotypes through a meta-analysis. Methods: We performed a meta-analysis of studies with data on the association between rs641738C>T genotype and liver fat, NAFLD histology, and serum alanine aminotransferase (ALT), lipids or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed a random effects meta-analysis using recessive, additive and dominant genetic models. Results: Data from 1,066,175 participants (9,688 with liver biopsies) across 42 studies were included in the meta-analysis. rs641738C>T was associated with higher liver fat on CT/MRI (+0.03 standard deviations [95% CI 0.02-0.05], p(z) = 4.8x10(-5)) and diagnosis of NAFLD (odds ratio [OR] 1.17 [95% CI 1.05-1.3], p(z) = 0.003) in Caucasian adults. The variant was also positively associated with presence of advanced fibrosis (OR 1.22 [95% CI 1.03-1.45], p(z) = 0.021) in Caucasian adults using a recessive model of inheritance (CC + CT vs. TT). Meta-analysis of data from previous GWAS found the variant to be associated with higher ALT (p(z) = 0.002) and lower serum triglycerides (p(z) = 1.5x10(-4)). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD. Conclusions: Our study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent. Lay summary: Fatty liver disease is a common condition where fat builds up in the liver, which can cause liver inflammation and scarring (including 'cirrhosis'). It is closely linked to obesity and diabetes
- Published
- 2021
55. Correction: A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease
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Emdin, Connor A., primary, Haas, Mary E., additional, Khera, Amit V., additional, Aragam, Krishna, additional, Chaffin, Mark, additional, Klarin, Derek, additional, Hindy, George, additional, Jiang, Lan, additional, Wei, Wei-Qi, additional, Feng, Qiping, additional, Karjalainen, Juha, additional, Havulinna, Aki, additional, Kiiskinen, Tuomo, additional, Bick, Alexander, additional, Ardissino, Diego, additional, Wilson, James G., additional, Schunkert, Heribert, additional, McPherson, Ruth, additional, Watkins, Hugh, additional, Elosua, Roberto, additional, Bown, Matthew J., additional, Samani, Nilesh J., additional, Baber, Usman, additional, Erdmann, Jeanette, additional, Gupta, Namrata, additional, Danesh, John, additional, Saleheen, Danish, additional, Chang, Kyong-Mi, additional, Vujkovic, Marijana, additional, Voight, Ben, additional, Damrauer, Scott, additional, Lynch, Julie, additional, Kaplan, David, additional, Serper, Marina, additional, Tsao, Philip, additional, Program, Million Veteran, additional, Mercader, Josep, additional, Hanis, Craig, additional, Daly, Mark, additional, Denny, Joshua, additional, Gabriel, Stacey, additional, and Kathiresan, Sekar, additional
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- 2021
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56. Electronic Health Record-Based Genome-Wide Meta-Analysis and Mendelian Randomization Identify Metabolic and Phenotypic Consequences of Non-Alcoholic Fatty Liver Disease
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Ghodsian, Nooshin, primary, Abner, Erik, additional, Emdin, Connor A., additional, Gobeil, Émilie, additional, Taba, Nele, additional, Haas, Mary J., additional, Perrot, Nicolas, additional, Manikpurage, Hasanga D., additional, Gagnon, Éloi, additional, Bourgault, Jérôme, additional, St-Amand, Alexis, additional, Couture, Christian, additional, Mitchell, Patricia, additional, Bossé, Yohan, additional, Mathieu, Patrick, additional, Vohl, Marie-Claude, additional, Tchernof, André, additional, Thériault, Sébastien, additional, Khera, Amit V., additional, Esko, Tõnu, additional, and Arsenault, Benoit, additional
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- 2021
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57. Epicardial and subcutaneous adipose tissue in Indigenous and non-Indigenous individuals: Implications for cardiometabolic diseases
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Sun, David F., Kangaharan, Nadarajah, Costello, Benedict, Nicholls, Stephen J., Emdin, Connor A., Tse, Rexson, Gallagher, Celine, Kaur, Amrina, Roberts-Thomson, Kurt C., Mahajan, Rajiv, Lau, Dennis H., Sanders, Prashanthan, and Wong, Christopher X.
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- 2020
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58. Electronic Health Record-Based Genome-Wide Meta-Analysis Provides New Insights on the Genetic Architecture of Non-Alcoholic Fatty Liver Disease
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Ghodsian, Nooshin, primary, Abner, Erik, additional, Emdin, Connor A., additional, Gobeil, Émilie, additional, Taba, Nele, additional, Haas, Mary E., additional, Perrot, Nicolas, additional, Manikpurage, Hasanga D., additional, Gagnon, Éloi, additional, Bourgault, Jérôme, additional, St-Amand, Alexis, additional, Couture, Christian, additional, Mitchell, Patricia L., additional, Bossé, Yohan, additional, Mathieu, Patrick, additional, Vohl, Marie-Claude, additional, Tchernof, André, additional, Thériault, Sébastien, additional, Khera, Amit V., additional, Esko, Tõnu, additional, and Arsenault, Benoit, additional
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- 2021
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59. rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis
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Teo, Kevin, primary, Abeysekera, Kushala W.M., additional, Adams, Leon, additional, Aigner, Elmar, additional, Anstee, Quentin M., additional, Banales, Jesus M., additional, Banerjee, Rajarshi, additional, Basu, Priyadarshi, additional, Berg, Thomas, additional, Bhatnagar, Pallav, additional, Buch, Stephan, additional, Canbay, Ali, additional, Caprio, Sonia, additional, Chatterjee, Ankita, additional, Ida Chen, Yii-Der, additional, Chowdhury, Abhijit, additional, Daly, Ann K., additional, Datz, Christian, additional, de Gracia Hahn, Dana, additional, DiStefano, Johanna K., additional, Dong, Jiawen, additional, Duret, Amedine, additional, Emdin, Connor, additional, Fairey, Madison, additional, Gerhard, Glenn S., additional, Guo, Xiuqing, additional, Hampe, Jochen, additional, Hickman, Matthew, additional, Heintz, Lena, additional, Hudert, Christian, additional, Hunter, Harriet, additional, Kelly, Matt, additional, Kozlitina, Julia, additional, Krawczyk, Marcin, additional, Lammert, Frank, additional, Langenberg, Claudia, additional, Lavine, Joel, additional, Li, Lin, additional, Lim, Hong Kai, additional, Loomba, Rohit, additional, Luukkonen, Panu K., additional, Melton, Phillip E., additional, Mori, Trevor A., additional, Palmer, Nicholette D., additional, Parisinos, Constantinos A., additional, Pillai, Sreekumar G., additional, Qayyum, Faiza, additional, Reichert, Matthias C., additional, Romeo, Stefano, additional, Rotter, Jerome I., additional, Im, Yu Ri, additional, Santoro, Nicola, additional, Schafmayer, Clemens, additional, Speliotes, Elizabeth K., additional, Stender, Stefan, additional, Stickel, Felix, additional, Still, Christopher D., additional, Strnad, Pavel, additional, Taylor, Kent D., additional, Tybjærg-Hansen, Anne, additional, Umano, Giuseppina Rosaria, additional, Utukuri, Mrudula, additional, Valenti, Luca, additional, Wagenknecht, Lynne E., additional, Wareham, Nicholas J., additional, Watanabe, Richard M., additional, Wattacheril, Julia, additional, Yaghootkar, Hanieh, additional, Yki-Järvinen, Hannele, additional, Young, Kendra A., additional, Mann, Jake P., additional, Vreugdenhil, Anita, additional, Alisi, Anna, additional, Socha, Piotr, additional, Jańczyk, Wojciech, additional, Baumann, Ulrich, additional, Rajwal, Sanjay, additional, van Mourik, Indra, additional, Lacaille, Florence, additional, Dabbas, Myriam, additional, Kelly, Deirdre A., additional, Nobili, Valerio, additional, Eiriksdottir, Gudny, additional, Garcia, Melissa E., additional, Gudnason, Vilmundur, additional, Harris, Tamara B., additional, Kim, Lauren J., additional, Launer, Lenore J., additional, Nalls, Michael A., additional, Smith, Albert V., additional, Clark, Jeanne M., additional, Hernaez, Ruben, additional, Kao, W.H. Linda, additional, Mitchell, Braxton D., additional, Shuldiner, Alan R., additional, Yerges-Armstrong, Laura M., additional, Borecki, Ingrid B., additional, Carr, J. Jeffrey, additional, Feitosa, Mary F., additional, Wu, Jun, additional, Butler, Johannah L., additional, Fox, Caroline S., additional, Hirschhorn, Joel N., additional, Hoffmann, Udo, additional, Hwang, Shih-Jen, additional, Massaro, Joseph M., additional, O'Donnell, Christopher J., additional, Palmer, Cameron D., additional, and Sahani, Dushyant V., additional
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- 2021
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60. HeterozygousABCG5Gene Deficiency and Risk of Coronary Artery Disease
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Nomura, Akihiro, primary, Emdin, Connor A., additional, Won, Hong Hee, additional, Peloso, Gina M., additional, Natarajan, Pradeep, additional, Ardissino, Diego, additional, Danesh, John, additional, Schunkert, Heribert, additional, Correa, Adolfo, additional, Bown, Matthew J., additional, Samani, Nilesh J., additional, Erdmann, Jeanette, additional, McPherson, Ruth, additional, Watkins, Hugh, additional, Saleheen, Danish, additional, Elosua, Roberto, additional, Kawashiri, Masa-aki, additional, Tada, Hayato, additional, Gupta, Namrata, additional, Shah, Svati H., additional, Rader, Daniel J., additional, Gabriel, Stacey, additional, Khera, Amit V., additional, and Kathiresan, Sekar, additional
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- 2020
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61. Machine learning enables new insights into clinical significance of and genetic contributions to liver fat accumulation
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Haas, Mary E., primary, Pirruccello, James P., additional, Friedman, Samuel N., additional, Emdin, Connor A., additional, Ajmera, Veeral H., additional, Simon, Tracey G., additional, Homburger, Julian R., additional, Guo, Xiuqing, additional, Budoff, Matthew, additional, Corey, Kathleen E., additional, Zhou, Alicia Y., additional, Philippakis, Anthony, additional, Ellinor, Patrick T., additional, Loomba, Rohit, additional, Batra, Puneet, additional, and Khera, Amit V., additional
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- 2020
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62. 1937-P: ALK-7: A Validated Target for the Treatment of Obesity
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BU, YUN, primary, ZHAO, MIN, additional, FREDERICKS, MAUREEN, additional, CANNELL, MARISHKA, additional, DAGON, YOSSI, additional, EMDIN, CONNOR A., additional, OKUNISHI, KATSUHIDE, additional, WANG, HAO, additional, SAKO, DIANNE, additional, CASTONGUAY, ROSELYNE, additional, SURAGANI, RAJASEKHAR N.V., additional, KATHIRESAN, SEKAR, additional, GRINBERG, ASYA, additional, KNOPF, JOHN, additional, PEARSALL, ROBERT S., additional, KUMAR, RAVINDRA, additional, and IZUMI, TETSURO, additional
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- 2020
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63. Physiology as a Lingua Franca for Clinical Machine Learning
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Sarma, Gopal P., primary, Reinertsen, Erik, additional, Aguirre, Aaron, additional, Anderson, Chris, additional, Batra, Puneet, additional, Choi, Seung-Hoan, additional, Di Achille, Paolo, additional, Diamant, Nathaniel, additional, Ellinor, Patrick, additional, Emdin, Connor, additional, Fahed, Akl C., additional, Friedman, Samuel, additional, Harrington, Lia, additional, Ho, Jennifer E., additional, Khera, Amit V., additional, Khurshid, Shaan, additional, Klarqvist, Marcus, additional, Lubitz, Steve, additional, Philippakis, Anthony, additional, Pirruccello, James, additional, Reeder, Christopher, additional, Stultz, Collin, additional, and Westover, Brandon, additional
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- 2020
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64. Genome-Wide Polygenic Score and Cardiovascular Outcomes With Evacetrapib in Patients With High-Risk Vascular Disease
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Emdin, Connor A., primary, Bhatnagar, Pallav, additional, Wang, Minxian, additional, Pillai, Sreekumar G., additional, Li, Lin, additional, Qian, Hui-Rong, additional, Riesmeyer, Jeffrey S., additional, Lincoff, A. Michael, additional, Nicholls, Stephen J., additional, Nissen, Steven E., additional, Ruotolo, Giacomo, additional, Kathiresan, Sekar, additional, and Khera, Amit V., additional
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- 2020
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65. Genetics of blood lipids among ~300,000 multi-ethnic participants of the Million Veteran Program
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Klarin, Derek, Damrauer, Scott M, Cho, Kelly, Sun, Yan V, Teslovich, Tanya M, Honerlaw, Jacqueline, Gagnon, David R, DuVall, Scott L, Li, Jin, Peloso, Gina M, Chaffin, Mark, Small, Aeron M, Huang, Jie, Tang, Hua, Lynch, Julie A, Ho, Yuk-Lam, Liu, Dajiang J, Emdin, Connor A, Li, Alexander H, Huffman, Jennifer E, Lee, Jennifer S, Natarajan, Pradeep, Chowdhury, Rajiv, Saleheen, Danish, Vujkovic, Marijana, Baras, Aris, Pyarajan, Saiju, Di Angelantonio, Emanuele, Neale, Benjamin M, Naheed, Aliya, Khera, Amit V, Danesh, John, Chang, Kyong-Mi, Abecasis, Gonçalo, Willer, Cristen, Dewey, Frederick E, Carey, David J, Global Lipids Genetics Consortium, Myocardial Infarction Genetics (MIGen) Consortium, Geisinger-Regeneron DiscovEHR Collaboration, VA Million Veteran Program, Concato, John, Gaziano, J Michael, O'Donnell, Christopher J, Tsao, Philip S, Kathiresan, Sekar, Rader, Daniel J, Wilson, Peter WF, Assimes, Themistocles L, Gagnon, David R [0000-0002-6367-3179], Chaffin, Mark [0000-0002-1234-5562], Emdin, Connor A [0000-0002-2385-8259], Huffman, Jennifer E [0000-0002-9672-2491], Vujkovic, Marijana [0000-0003-4924-5714], Neale, Benjamin M [0000-0003-1513-6077], Willer, Cristen [0000-0001-5645-4966], Kathiresan, Sekar [0000-0002-6724-032X], Assimes, Themistocles L [0000-0003-2349-0009], and Apollo - University of Cambridge Repository
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Male ,Genotype ,Black People ,Hispanic or Latino ,Middle Aged ,Lipid Metabolism ,Lipids ,Polymorphism, Single Nucleotide ,White People ,Diabetes Mellitus, Type 2 ,Cardiovascular Diseases ,Ethnicity ,Humans ,Female ,Aged ,Genome-Wide Association Study ,Veterans - Abstract
The Million Veteran Program (MVP) was established in 2011 as a national research initiative to determine how genetic variation influences the health of US military veterans. Here we genotyped 312,571 MVP participants using a custom biobank array and linked the genetic data to laboratory and clinical phenotypes extracted from electronic health records covering a median of 10.0 years of follow-up. Among 297,626 veterans with at least one blood lipid measurement, including 57,332 black and 24,743 Hispanic participants, we tested up to around 32 million variants for association with lipid levels and identified 118 novel genome-wide significant loci after meta-analysis with data from the Global Lipids Genetics Consortium (total n > 600,000). Through a focus on mutations predicted to result in a loss of gene function and a phenome-wide association study, we propose novel indications for pharmaceutical inhibitors targeting PCSK9 (abdominal aortic aneurysm), ANGPTL4 (type 2 diabetes) and PDE3B (triglycerides and coronary disease).
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- 2018
66. rs641738C>T near MBOAT7 promotes steatosis, NASH, fibrosis and hepatocellular carcinoma in non-alcoholic fatty liver disease: a meta-analysis
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Teo, Kevin, Abeysekera, Kushala WM, Adams, Leon, Aigner, Elmar, Banerjee, Rajarshi, Basu, Priyadarshi, Berg, Thomas, Bhatnagar, Pallav, Buch, Stephan, Canbay, Ali, Caprio, Sonia, Chatterjee, Ankita, Chen, Yii-Der Ida, Datz, Christian, de Gracia Hahn, Dana, DiStefano, Johanna K, Dong, Jiawen, Duret, Amedine, Emdin, Connor, Fairey, Madison, Gerhard, Glenn S, Guo, Xiuqing, Hampe, Jochen, Hickman, Matthew, Heintz, Lena, Hudert, Christian, Hunter, Harriet, Kelly, Matt, Kozlitina, Julia, Krawczyk, Marcin, Lammert, Frank, Langenberg, Claudia, Lavine, Joel, Lim, Hong Kai, Luukkonen, Panu, Melton, Philip E, Mori, Trevor A, Parisinos, Constantinos A, Pillai, Sreekumar G, Qayyum, Faiza, Reichert, Matthias C, Romeo, Stefano, Rotter, Jerome, Im, Yu Ri, Santoro, Nicola, Schafmayer, Clemens, Speliotes, Elizabeth K, Stender, Stefan, Stickel, Felix, Still, Christopher D, Strnad, Pavel, Taylor, Kent D, Tybjaerg-Hansen, Anne, Umano, Giuseppina Rosaria, Utukuri, Mrudula, Valenti, Luca, Wareham, Nicholas J, Wattacheril, Julia, Yki-Jarvinen, Hannele, and Mann, Jake P
- Abstract
A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in non-alcoholic fatty liver disease (NAFLD), however, these findings have not been consistently replicated in the literature. Therefore, we aimed to establish whether rs641738 is a risk factor for NAFLD through meta-analysis. Data from 134,015 participants (7,692 with liver biopsies and 50,680 with imaging) was included in the meta-analysis. The minor T-allele of rs641738C>T was associated with higher liver fat on CT/MRI using an additive genetic model (+0.05 standard deviations [95% CI: 0.01 - 0.09], p=0.025), and with an increased risk of NAFLD (per-allele OR: 1.08 [95% CI: 1.01 - 1.15]), nonalcoholic steatohepatitis (OR: 1.11 [95% CI: 1.02 - 1.21]), advanced fibrosis (OR: 1.14 [95% CI: 1.05 - 1.23]), and hepatocellular carcinoma (OR: 1.43 [95% CI: 1.22 - 1.67]) in adults with NAFLD. Sub-group analysis did not demonstrate a difference in Caucasians and non-Caucasians. Rs641738C>T was not associated with markers of insulin resistance but was associated with higher risk of stroke in the UK Biobank. These data validate rs641738C>T near MBOAT7 as a risk factor for the development, activity, and stage of NAFLD including hepatocellular carcinoma.
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- 2019
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67. Machine learning enables new insights into clinical significance of and genetic contributions to liver fat accumulation
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Haas, Mary, Haas, Mary, Pirruccello, James, Friedman, Samuel, Emdin, Connor, Ajmera, Veeral, Simon, Tracey, Homburger, Julian, Guo, Xiuqing, Budoff, Matthew, Corey, Kathleen, Zhou, Alicia, Philippakis, Anthony, Ellinor, Patrick, Loomba, Rohit, Batra, Puneet, Khera, Amit, Haas, Mary, Haas, Mary, Pirruccello, James, Friedman, Samuel, Emdin, Connor, Ajmera, Veeral, Simon, Tracey, Homburger, Julian, Guo, Xiuqing, Budoff, Matthew, Corey, Kathleen, Zhou, Alicia, Philippakis, Anthony, Ellinor, Patrick, Loomba, Rohit, Batra, Puneet, and Khera, Amit
- Abstract
Excess accumulation of liver fat – termed hepatic steatosis when fat accounts for > 5.5% of liver content – is a leading risk factor for end-stage liver disease and is strongly associated with important cardiometabolic disorders. Using a truth dataset of 4,511 UK Biobank participants with liver fat previously quantified via abdominal MRI imaging, we developed a machine learning algorithm to quantify liver fat with correlation coefficients of 0.97 and 0.99 in hold-out testing datasets and applied this algorithm to raw imaging data from an additional 32,192 participants. Among all 36,703 individuals with abdominal MRI imaging, median liver fat was 2.2%, with 6,250 (17%) meeting criteria for hepatic steatosis. Although individuals afflicted with hepatic steatosis were more likely to have been diagnosed with conditions such as obesity or diabetes, a prediction model based on clinical data alone without imaging could not reliably estimate liver fat content. To identify genetic drivers of variation in liver fat, we first conducted a common variant association study of 9.8 million variants, confirming three known associations for variants in the TM6SF2, APOE , and PNPLA3 genes and identifying five new variants associated with increased hepatic fat in or near the MARC1, ADH1B, TRIB1, GPAM and MAST3 genes. A polygenic score that integrated information from each of these eight variants was strongly associated with future clinical diagnosis of liver diseases. Next, we performed a rare variant association study in a subset of 11,021 participants with gene sequencing data available, identifying an association between inactivating variants in the APOB gene and substantially lower LDL cholesterol, but more than 10-fold increased risk of steatosis. Taken together, these results provide proof of principle for the use of machine learning algorithms on raw imaging data to enable epidemiologic studies and genetic discovery.
- Published
- 2020
68. Quantifying the Impact of Rare and Ultra-rare Coding Variation across the Phenotypic Spectrum
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Ganna, Andrea, Satterstrom, F. Kyle, Zekavat, Seyedeh M., Das, Indraniel, Kurki, Mitja I., Churchhouse, Claire, Alfoldi, Jessica, Martin, Alicia R., Havulinna, Aki S., Byrnes, Andrea, Thompson, Wesley K., Nielsen, Philip R., Karczewski, Konrad J., Saarentaus, Elmo, Rivas, Manuel A., Gupta, Namrata, Pietiläinen, Olli, Emdin, Connor A., Lescai, Francesco, Bybjerg-Grauholm, Jonas, Flannick, Jason, Mercader, Josep M., Udler, Miriam, Laakso, Markku, Salomaa, Veikko, Hultman, Christina, Ripatti, Samuli, Hämäläinen, Eija, Moilanen, Jukka S., Körkkö, Jarmo, Kuismin, Outi, Nordentoft, Merete, Hougaard, David M., Mors, Ole, Werge, Thomas, Mortensen, Preben Bo, MacArthur, Daniel, Daly, Mark J., Sullivan, Patrick F., Locke, Adam E., Palotie, Aarno, Børglum, Anders D., Kathiresan, Sekar, and Neale, Benjamin M.
- Published
- 2018
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69. 17 - Global Risk Assessment
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Jensen, Jesper K., Khera, Amit V., and Emdin, Connor A.
- Published
- 2018
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70. Association of Rare and Common Variation in the Lipoprotein Lipase Gene With Coronary Artery Disease
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Khera, Amit V, Won, Hong-Hee, Peloso, Gina M, O'Dushlaine, Colm, Liu, Dajiang, Stitziel, Nathan O, Natarajan, Pradeep, Nomura, Akihiro, Emdin, Connor A, Gupta, Namrata, Borecki, Ingrid B, Asselta, Rosanna, Duga, Stefano, Merlini, Piera Angelica, Correa, Adolfo, Kessler, Thorsten, Wilson, James G, Bown, Matthew J, Hall, Alistair S, Braund, Peter S, Carey, David J, Murray, Michael F, Kirchner, H Lester, Leader, Joseph B, Lavage, Daniel R, Manus, J Neil, Hartzel, Dustin N, Samani, Nilesh J, Schunkert, Heribert, Marrugat, Jaume, Elosua, Roberto, McPherson, Ruth, Farrall, Martin, Watkins, Hugh, Lander, Eric S, Rader, Daniel J, Danesh, John, Ardissino, Diego, Gabriel, Stacey, Willer, Cristen, Abecasis, Gonçalo R, Saleheen, Danish, Dewey, Frederick E, Kathiresan, Sekar, Myocardial Infarction Genetics Consortium, DiscovEHR Study Group, Danesh, John [0000-0003-1158-6791], and Apollo - University of Cambridge Repository
- Subjects
Adult ,Male ,Heterozygote ,Genotype ,Lipoproteins ,Coronary Artery Disease ,Middle Aged ,Lipoprotein Lipase ,Cross-Sectional Studies ,Case-Control Studies ,Mutation ,Odds Ratio ,Humans ,Female ,Age of Onset ,Triglycerides - Abstract
IMPORTANCE: The activity of lipoprotein lipase (LPL) is the rate-determining step in clearing triglyceride-rich lipoproteins from the circulation. Mutations that damage the LPL gene (LPL) lead to lifelong deficiency in enzymatic activity and can provide insight into the relationship of LPL to human disease. OBJECTIVE: To determine whether rare and/or common variants in LPL are associated with early-onset coronary artery disease (CAD). DESIGN, SETTING, AND PARTICIPANTS: In a cross-sectional study, LPL was sequenced in 10 CAD case-control cohorts of the multinational Myocardial Infarction Genetics Consortium and a nested CAD case-control cohort of the Geisinger Health System DiscovEHR cohort between 2010 and 2015. Common variants were genotyped in up to 305 699 individuals of the Global Lipids Genetics Consortium and up to 120 600 individuals of the CARDIoGRAM Exome Consortium between 2012 and 2014. Study-specific estimates were pooled via meta-analysis. EXPOSURES: Rare damaging mutations in LPL included loss-of-function variants and missense variants annotated as pathogenic in a human genetics database or predicted to be damaging by computer prediction algorithms trained to identify mutations that impair protein function. Common variants in the LPL gene region included those independently associated with circulating triglyceride levels. MAIN OUTCOMES AND MEASURES: Circulating lipid levels and CAD. RESULTS: Among 46 891 individuals with LPL gene sequencing data available, the mean (SD) age was 50 (12.6) years and 51% were female. A total of 188 participants (0.40%; 95% CI, 0.35%-0.46%) carried a damaging mutation in LPL, including 105 of 32 646 control participants (0.32%) and 83 of 14 245 participants with early-onset CAD (0.58%). Compared with 46 703 noncarriers, the 188 heterozygous carriers of an LPL damaging mutation displayed higher plasma triglyceride levels (19.6 mg/dL; 95% CI, 4.6-34.6 mg/dL) and higher odds of CAD (odds ratio = 1.84; 95% CI, 1.35-2.51; P < .001). An analysis of 6 common LPL variants resulted in an odds ratio for CAD of 1.51 (95% CI, 1.39-1.64; P = 1.1 × 10-22) per 1-SD increase in triglycerides. CONCLUSIONS AND RELEVANCE: The presence of rare damaging mutations in LPL was significantly associated with higher triglyceride levels and presence of coronary artery disease. However, further research is needed to assess whether there are causal mechanisms by which heterozygous lipoprotein lipase deficiency could lead to coronary artery disease.
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- 2018
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71. Heterozygous ATP-binding Cassette Transporter G5 Gene Deficiency and Risk of Coronary Artery Disease
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Nomura, Akihiro, primary, Emdin, Connor A., additional, Won, Hong Hee, additional, Peloso, Gina M., additional, Natarajan, Pradeep, additional, Ardissino, Diego, additional, Danesh, John, additional, Schunkert, Heribert, additional, Correa, Adolfo, additional, Bown, Matthew J., additional, Samani, Nilesh J., additional, Erdmann, Jeanette, additional, McPherson, Ruth, additional, Watkins, Hugh, additional, Saleheen, Danish, additional, Elosua, Roberto, additional, Kawashiri, Masa-aki, additional, Tada, Hayato, additional, Gupta, Namrata, additional, Shah, Svati H., additional, Rader, Daniel J., additional, Gabriel, Stacey, additional, Khera, Amit V., additional, and Kathiresan, Sekar, additional
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- 2019
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72. A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease
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Emdin, Connor A., primary, Haas, Mary, additional, Khera, Amit V., additional, Aragam, Krishna, additional, Chaffin, Mark, additional, Jiang, Lan, additional, Wei, Wei-Qi, additional, Feng, Qiping, additional, Karjalainen, Juha, additional, Havulinna, Aki, additional, Kiiskinen, Tuomo, additional, Bick, Alexander, additional, Ardissino, Diego, additional, Wilson, James G., additional, Schunkert, Heribert, additional, McPherson, Ruth, additional, Watkins, Hugh, additional, Elosua, Roberto, additional, Bown, Matthew J, additional, Samani, Nilesh J, additional, Baber, Usman, additional, Erdmann, Jeanette, additional, Gupta, Namrata, additional, Danesh, John, additional, Saleheen, Danish, additional, Daly, Mark, additional, Denny, Joshua, additional, Gabriel, Stacey, additional, and Kathiresan, Sekar, additional
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- 2019
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73. Protein-Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart DiseaseNovelty and Significance
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Nomura, Akihiro, Won, Hong-Hee, Khera, Amit V., Takeuchi, Fumihiko, Ito, Kaoru, McCarthy, Shane, Emdin, Connor A., Klarin, Derek, Natarajan, Pradeep, Gupta, Namrata, Peloso, Gina M., Borecki, Ingrid B., Teslovich, Tanya M., Asselta, Rosanna, Duga, Stefano, Merlini, Piera A., Correa, Adolfo, Kessler, Thorsten, Wilson, James G., Bown, Matthew J., Hall, Alistair S., Braund, Peter S., Carey, David J., Kirchner, H. Lester, Leader, Joseph B., Lavage, Daniel R., Manus, J. Neil, Hartze, Dustin N., Samani, Nilesh J., Schunkert, Heribert, Marrugat, Jaume, Elosua, Roberto, McPherson, Ruth, Farrall, Martin, Watkins, Hugh, Juang, Jyh-Ming J., Hsiung, Chao A., Lin, Shih-Yi, Wang, Jun-Sing, Tada, Hayato, Kawashiri, Masa-aki, Inazu, Akihiro, Yamagishi, Masakazu, Katsuya, Tomohiro, Nakashima, Eitaro, Nakatochi, Masahiro, Yamamoto, Ken, Yokota, Mitsuhiro, Momozawa, Yukihide, Rotter, Jerome I., Rader, Daniel J., Danesh, John, Ardissino, Diego, Gabriel, Stacey, Willer, Cristen J., Abecasis, Goncalo R., Saleheen, Danish, Kubo, Michiaki, Kato, Norihiro, Ida Chen, Yii-Der, Dewey, Frederick E., Kathiresan, Sekar, Zekavat, Seyedeh M., Murray, Michael F, Lander, Eric Steven, Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Zekavat, Seyedeh M., Murray, Michael F, and Lander, Eric Steven
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lipids (amino acids, peptides, and proteins) - Abstract
Rationale: Therapies that inhibit CETP (cholesteryl ester transfer protein) have failed to demonstrate a reduction in risk for coronary heart disease (CHD). Human DNA sequence variants that truncate the CETP gene may provide insight into the efficacy of CETP inhibition. Objective: To test whether protein-truncating variants (PTVs) at the CETP gene were associated with plasma lipid levels and CHD. Methods and Results: We sequenced the exons of the CETP gene in 58 469 participants from 12 case-control studies (18 817 CHD cases, 39 652 CHD-free controls). We defined PTV as those that lead to a premature stop, disrupt canonical splice sites, or lead to insertions/deletions that shift frame. We also genotyped 1 Japanese-specific PTV in 27561 participants from 3 case-control studies (14 286 CHD cases, 13 275 CHD-free controls). We tested association of CETP PTV carrier status with both plasma lipids and CHD. Among 58 469 participants with CETP gene-sequencing data available, average age was 51.5 years and 43% were women; 1 in 975 participants carried a PTV at the CETP gene. Compared with noncarriers, carriers of PTV at CETP had higher high-density lipoprotein cholesterol (effect size, 22.6 mg/dL; 95% confidence interval, 18-27; P
- Published
- 2017
74. Inherited myeloproliferative neoplasm risk affects haematopoietic stem cells.
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Bao, Erik L., Nandakumar, Satish K., Liao, Xiaotian, Bick, Alexander G., Karjalainen, Juha, Tabaka, Marcin, Gan, Olga I., Havulinna, Aki S., Kiiskinen, Tuomo T. J., Lareau, Caleb A., de Lapuente Portilla, Aitzkoa L., Li, Bo, Emdin, Connor, Codd, Veryan, Nelson, Christopher P., Walker, Christopher J., Churchhouse, Claire, de la Chapelle, Albert, Klein, Daryl E., and Nilsson, Björn
- Abstract
Myeloproliferative neoplasms (MPNs) are blood cancers that are characterized by the excessive production of mature myeloid cells and arise from the acquisition of somatic driver mutations in haematopoietic stem cells (HSCs). Epidemiological studies indicate a substantial heritable component of MPNs that is among the highest known for cancers1. However, only a limited number of genetic risk loci have been identified, and the underlying biological mechanisms that lead to the acquisition of MPNs remain unclear. Here, by conducting a large-scale genome-wide association study (3,797 cases and 1,152,977 controls), we identify 17 MPN risk loci (P < 5.0 × 10
−8 ), 7 of which have not been previously reported. We find that there is a shared genetic architecture between MPN risk and several haematopoietic traits from distinct lineages; that there is an enrichment for MPN risk variants within accessible chromatin of HSCs; and that increased MPN risk is associated with longer telomere length in leukocytes and other clonal haematopoietic states—collectively suggesting that MPN risk is associated with the function and self-renewal of HSCs. We use gene mapping to identify modulators of HSC biology linked to MPN risk, and show through targeted variant-to-function assays that CHEK2 and GFI1B have roles in altering the function of HSCs to confer disease risk. Overall, our results reveal a previously unappreciated mechanism for inherited MPN risk through the modulation of HSC function. A genome-wide association study identifies 17 genetic loci that are associated with the risk of myeloproliferative neoplasms (MPNs), and shows that the modulation of haematopoietic stem cell function drives MPN risk. [ABSTRACT FROM AUTHOR]- Published
- 2020
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75. A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease.
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Emdin, Connor A., Haas, Mary E., Khera, Amit V., Aragam, Krishna, Chaffin, Mark, Klarin, Derek, Hindy, George, Jiang, Lan, Wei, Wei-Qi, Feng, Qiping, Karjalainen, Juha, Havulinna, Aki, Kiiskinen, Tuomo, Bick, Alexander, Ardissino, Diego, Wilson, James G., Schunkert, Heribert, McPherson, Ruth, Watkins, Hugh, and Elosua, Roberto
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- *
LIVER diseases , *BLOOD cholesterol , *FATTY liver , *ALANINE aminotransferase , *LIVER enzymes , *ALPHA 1-antitrypsin - Abstract
Analyzing 12,361 all-cause cirrhosis cases and 790,095 controls from eight cohorts, we identify a common missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.91, p = 2.3*10−11). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (-0.025 SD, 3.7*10−43), alkaline phosphatase (-0.025 SD, 1.2*10−37), total cholesterol (-0.030 SD, p = 1.9*10−36) and LDL cholesterol (-0.027 SD, p = 5.1*10−30) levels. We identified a series of additional MARC1 alleles (low-frequency missense p.M187K and rare protein-truncating p.R200Ter) that also associated with lower cholesterol levels, liver enzyme levels and reduced risk of cirrhosis (0 cirrhosis cases for 238 R200Ter carriers versus 17,046 cases of cirrhosis among 759,027 non-carriers, p = 0.04) suggesting that deficiency of the MARC1 enzyme may lower blood cholesterol levels and protect against cirrhosis. Author summary: Cirrhosis is a leading cause of death worldwide. However, the genetic underpinnings of cirrhosis remain poorly understood. In this study, we analyze twelve thousand individuals with cirrhosis and identify a common missense variant in a gene called MARC1 that protects against cirrhosis. Carriers of this missense variant also have lower blood cholesterol levels, lower liver enzyme levels and reduced liver fat. We identify an additional two low-frequency coding variants in MARC1 that are also associated with lower cholesterol levels, lower liver enzyme levels and protection from cirrhosis. Finally, we identify an individual homozygous for a predicted loss-of-function variant in MARC1 who exhibits very low blood LDL cholesterol levels. These genetic findings suggest that MARC1 deficiency may lower blood cholesterol levels and protect against cirrhosis, pointing to MARC1 as a potential therapeutic target for liver disease. [ABSTRACT FROM AUTHOR]
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- 2020
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76. DNA Sequence Variation in ACVR1C Encoding the Activin Receptor-Like Kinase 7 Influences Body Fat Distribution and Protects Against Type 2 Diabetes
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Emdin, Connor A., primary, Khera, Amit V., additional, Aragam, Krishna, additional, Haas, Mary, additional, Chaffin, Mark, additional, Klarin, Derek, additional, Natarajan, Pradeep, additional, Bick, Alexander, additional, Zekavat, Seyedeh M., additional, Nomura, Akihiro, additional, Ardissino, Diego, additional, Wilson, James G., additional, Schunkert, Heribert, additional, McPherson, Ruth, additional, Watkins, Hugh, additional, Elosua, Roberto, additional, Bown, Matthew J., additional, Samani, Nilesh J., additional, Baber, Usman, additional, Erdmann, Jeanette, additional, Gupta, Namrata, additional, Danesh, John, additional, Saleheen, Danish, additional, Gabriel, Stacey, additional, and Kathiresan, Sekar, additional
- Published
- 2018
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77. Genetic Association of Arterial Stiffness Index with Blood Pressure and Coronary Artery Disease
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Zekavat, Seyedeh M., primary, Haas, Mary, additional, Aragam, Krishna, additional, Emdin, Connor, additional, Khera, Amit V., additional, Klarin, Derek, additional, Zhao, Hongyu, additional, and Natarajan, Pradeep, additional
- Published
- 2018
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78. Non‐physician clinician provided HIV treatment results in equivalent outcomes as physician‐provided care: a meta‐analysis
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Emdin, Connor A., Chong, Nicholas J., and Millson, Peggy E.
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Antiviral agents -- Dosage and administration ,Physicians -- Practice -- Comparative analysis ,AIDS treatment -- Methods ,Nurses -- Practice -- Comparative analysis ,HIV infection -- Care and treatment ,Health - Abstract
Introduction: A severe healthcare worker shortage in sub‐Saharan Africa is inhibiting the expansion of HIV treatment. Task shifting, the transfer of antiretroviral therapy (ART) management and initiation from doctors to nurses and other non‐physician clinicians, has been proposed to address this problem. However, many health officials remain wary about implementing task shifting policies due to concerns that non‐physicians will provide care inferior to physicians. To determine if non‐physician‐provided HIV care does result in equivalent outcomes to physician‐provided care, a meta‐analysis was performed. Methods: Online databases were searched using a predefined strategy. The results for four primary outcomes were combined using a random effects model with sub‐groups of non‐physician‐managed ART and ‐initiated ART. TB diagnosis rates, adherence, weight gain and patient satisfaction were summarized qualitatively. Results: Mortality (N=59,666) had similar outcomes for non‐physicians and physicians, with a hazard ratio of 1.05 (CI: 0.88–1.26). The increase in CD4 levels at one year, as a difference in means of 2.3 (N=17,142, CI: −12.7–17.3), and viral failure at one year, as a risk ratio of 0.89 (N=10,344, CI: 0.65–1.23), were similar for physicians and non‐physicians. Interestingly, loss to follow‐up (LTFU) (N=53,435) was reduced for non‐physicians with a hazard ratio of 0.72 (CI: 0.56–0.94). TB diagnosis rates, adherence and weight gain were similar for non‐physicians and physicians. Patient satisfaction appeared higher for non‐physicians in qualitative components of studies and was attributed to non‐physicians spending more time with patients as well as providing more holistic care. Conclusions: Non‐physician‐provided HIV care results in equivalent outcomes to care provided by physicians and may result in decreased LTFU rates., Introduction In response to the HIV epidemic, countries in sub‐Saharan Africa and other low‐income regions are attempting to increase access to antiretroviral therapy (ART). The HPTN052 treatment as prevention trial, [...]
- Published
- 2013
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79. Protein-Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart DiseaseNovelty and Significance
- Author
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Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Zekavat, Seyedeh M., Murray, Michael F, Lander, Eric Steven, Nomura, Akihiro, Won, Hong-Hee, Khera, Amit V., Takeuchi, Fumihiko, Ito, Kaoru, McCarthy, Shane, Emdin, Connor A., Klarin, Derek, Natarajan, Pradeep, Gupta, Namrata, Peloso, Gina M., Borecki, Ingrid B., Teslovich, Tanya M., Asselta, Rosanna, Duga, Stefano, Merlini, Piera A., Correa, Adolfo, Kessler, Thorsten, Wilson, James G., Bown, Matthew J., Hall, Alistair S., Braund, Peter S., Carey, David J., Kirchner, H. Lester, Leader, Joseph B., Lavage, Daniel R., Manus, J. Neil, Hartze, Dustin N., Samani, Nilesh J., Schunkert, Heribert, Marrugat, Jaume, Elosua, Roberto, McPherson, Ruth, Farrall, Martin, Watkins, Hugh, Juang, Jyh-Ming J., Hsiung, Chao A., Lin, Shih-Yi, Wang, Jun-Sing, Tada, Hayato, Kawashiri, Masa-aki, Inazu, Akihiro, Yamagishi, Masakazu, Katsuya, Tomohiro, Nakashima, Eitaro, Nakatochi, Masahiro, Yamamoto, Ken, Yokota, Mitsuhiro, Momozawa, Yukihide, Rotter, Jerome I., Rader, Daniel J., Danesh, John, Ardissino, Diego, Gabriel, Stacey, Willer, Cristen J., Abecasis, Goncalo R., Saleheen, Danish, Kubo, Michiaki, Kato, Norihiro, Ida Chen, Yii-Der, Dewey, Frederick E., Kathiresan, Sekar, Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Zekavat, Seyedeh M., Murray, Michael F, Lander, Eric Steven, Nomura, Akihiro, Won, Hong-Hee, Khera, Amit V., Takeuchi, Fumihiko, Ito, Kaoru, McCarthy, Shane, Emdin, Connor A., Klarin, Derek, Natarajan, Pradeep, Gupta, Namrata, Peloso, Gina M., Borecki, Ingrid B., Teslovich, Tanya M., Asselta, Rosanna, Duga, Stefano, Merlini, Piera A., Correa, Adolfo, Kessler, Thorsten, Wilson, James G., Bown, Matthew J., Hall, Alistair S., Braund, Peter S., Carey, David J., Kirchner, H. Lester, Leader, Joseph B., Lavage, Daniel R., Manus, J. Neil, Hartze, Dustin N., Samani, Nilesh J., Schunkert, Heribert, Marrugat, Jaume, Elosua, Roberto, McPherson, Ruth, Farrall, Martin, Watkins, Hugh, Juang, Jyh-Ming J., Hsiung, Chao A., Lin, Shih-Yi, Wang, Jun-Sing, Tada, Hayato, Kawashiri, Masa-aki, Inazu, Akihiro, Yamagishi, Masakazu, Katsuya, Tomohiro, Nakashima, Eitaro, Nakatochi, Masahiro, Yamamoto, Ken, Yokota, Mitsuhiro, Momozawa, Yukihide, Rotter, Jerome I., Rader, Daniel J., Danesh, John, Ardissino, Diego, Gabriel, Stacey, Willer, Cristen J., Abecasis, Goncalo R., Saleheen, Danish, Kubo, Michiaki, Kato, Norihiro, Ida Chen, Yii-Der, Dewey, Frederick E., and Kathiresan, Sekar
- Abstract
Rationale: Therapies that inhibit CETP (cholesteryl ester transfer protein) have failed to demonstrate a reduction in risk for coronary heart disease (CHD). Human DNA sequence variants that truncate the CETP gene may provide insight into the efficacy of CETP inhibition. Objective: To test whether protein-truncating variants (PTVs) at the CETP gene were associated with plasma lipid levels and CHD. Methods and Results: We sequenced the exons of the CETP gene in 58 469 participants from 12 case-control studies (18 817 CHD cases, 39 652 CHD-free controls). We defined PTV as those that lead to a premature stop, disrupt canonical splice sites, or lead to insertions/deletions that shift frame. We also genotyped 1 Japanese-specific PTV in 27561 participants from 3 case-control studies (14 286 CHD cases, 13 275 CHD-free controls). We tested association of CETP PTV carrier status with both plasma lipids and CHD. Among 58 469 participants with CETP gene-sequencing data available, average age was 51.5 years and 43% were women; 1 in 975 participants carried a PTV at the CETP gene. Compared with noncarriers, carriers of PTV at CETP had higher high-density lipoprotein cholesterol (effect size, 22.6 mg/dL; 95% confidence interval, 18-27; P<1.0×10-4), lower low-density lipoprotein cholesterol (-12.2 mg/dL; 95% confidence interval, -23 to -0.98; P=0.033), and lower triglycerides (-6.3%; 95% confidence interval, -12 to -0.22; P=0.043). CETP PTV carrier status was associated with reduced risk for CHD (summary odds ratio, 0.70; 95% confidence interval, 0.54-0.90; P=5.1×10-3). Conclusions: Compared with noncarriers, carriers of PTV at CETP displayed higher high-density lipoprotein cholesterol, lower low-density lipoprotein cholesterol, lower triglycerides, and lower risk for CHD.
- Published
- 2018
80. Physiology as a Lingua Franca for Clinical Machine Learning
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Aguirre, Aaron, Anderson, Chris, Batra, Puneet, Choi, Seung-Hoan, Di Achille, Paolo, Diamant, Nathaniel, Ellinor, Patrick, Emdin, Connor, Fahed, Akl C., Friedman, Samuel, Harrington, Lia, Ho, Jennifer E., Khera, Amit V., Khurshid, Shaan, Klarqvist, Marcus, Lubitz, Steve, Philippakis, Anthony, Pirruccello, James, Reeder, Christopher, Stultz, Collin, Westover, Brandon, Sarma, Gopal P., and Reinertsen, Erik
- Published
- 2020
- Full Text
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81. Phenotypic Characterization of Genetically Lowered Human Lipoprotein(a) Levels
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Emdin, Connor A, Khera, Amit V, Natarajan, Pradeep, Klarin, Derek, Won, Hong-Hee, Peloso, Gina M, Stitziel, Nathan O, Nomura, Akihiro, Zekavat, Seyedeh M, Bick, Alexander G, Gupta, Namrata, Asselta, Rosanna, Duga, Stefano, Merlini, Piera Angelica, Correa, Adolfo, Kessler, Thorsten, Wilson, James G, Bown, Matthew J, Hall, Alistair S, Braund, Peter S, Samani, Nilesh J, Schunkert, Heribert, Marrugat, Jaume, Elosua, Roberto, McPherson, Ruth, Farrall, Martin, Watkins, Hugh, Willer, Cristen, Abecasis, Gonçalo R, Felix, Janine F, Vasan, Ramachandran S, Lander, Eric, Rader, Daniel J, Danesh, John, Ardissino, Diego, Gabriel, Stacey, Saleheen, Danish, Kathiresan, Sekar, CHARGE–Heart Failure Consortium, CARDIoGRAM Exome Consortium, Danesh, John [0000-0003-1158-6791], and Apollo - University of Cambridge Repository
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Male ,Coronary Disease ,DNA ,Genetic Therapy ,phenome-wide association study ,Prognosis ,Polymorphism, Single Nucleotide ,Phenotype ,single nucleotide polymorphism ,Risk Factors ,Humans ,genetics ,Female ,coronary heart disease ,Biomarkers ,Genome-Wide Association Study ,Lipoprotein(a) - Abstract
Background Genomic analyses have suggested that the LPA gene and its associated plasma biomarker, lipoprotein(a) (Lp[a]), represent a causal risk factor for coronary heart disease (CHD). As such, lowering Lp(a) levels has emerged as a therapeutic strategy. Beyond target identification, human genetics may contribute to the development of new therapies by defining the full spectrum of beneficial and adverse consequences and by developing a dose–response curve of target perturbation. Objectives The goal of this study was to establish the full phenotypic impact of LPA gene variation and to estimate a dose–response curve between genetically altered plasma Lp(a) and risk for CHD. Methods We leveraged genetic variants at the LPA gene from 3 data sources: individual-level data from 112,338 participants in the U.K. Biobank; summary association results from large-scale genome-wide association studies; and LPA gene sequencing results from case subjects with CHD and control subjects free of CHD. Results One SD genetically lowered Lp(a) level was associated with a 29% lower risk of CHD (odds ratio [OR]: 0.71; 95% confidence interval [CI]: 0.69 to 0.73), a 31% lower risk of peripheral vascular disease (OR: 0.69; 95% CI: 0.59 to 0.80), a 13% lower risk of stroke (OR: 0.87; 95% CI: 0.79 to 0.96), a 17% lower risk of heart failure (OR: 0.83; 95% CI: 0.73 to 0.94), and a 37% lower risk of aortic stenosis (OR: 0.63; 95% CI: 0.47 to 0.83). We observed no association with 31 other disorders, including type 2 diabetes and cancer. Variants that led to gain of LPA gene function increased the risk for CHD, whereas those that led to loss of gene function reduced the CHD risk. Conclusions Beyond CHD, genetically lowered Lp(a) levels are associated with a lower risk of peripheral vascular disease, stroke, heart failure, and aortic stenosis. As such, pharmacological lowering of plasma Lp(a) may influence a range of atherosclerosis-related diseases.
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- 2016
82. Impact of missed treatment opportunities on outcomes in hospitalised patients with heart failure
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Walker, Simon, primary, Spackman, Eldon, additional, Conrad, Nathalie, additional, Emdin, Connor A, additional, Griffin, Ed, additional, Rahimi, Kazem, additional, and Sculpher, Mark, additional
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- 2017
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83. Genome-wide polygenic score to identify a monogenic risk-equivalent for coronary disease
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Khera, Amit V., primary, Chaffin, Mark, additional, Aragam, Krishna G., additional, Emdin, Connor A., additional, Klarin, Derek, additional, Haas, Mary E., additional, Roselli, Carolina, additional, Natarajan, Pradeep, additional, and Kathiresan, Sekar, additional
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- 2017
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84. Income Disparities in Absolute Cardiovascular Risk and Cardiovascular Risk Factors in the United States, 1999-2014
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Odutayo, Ayodele, primary, Gill, Peter, additional, Shepherd, Shaun, additional, Akingbade, Aquila, additional, Hopewell, Sally, additional, Tennankore, Karthik, additional, Hunn, Benjamin H., additional, and Emdin, Connor A., additional
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- 2017
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85. Genetic Predisposition to Abdominal Obesity and Cardiometabolic Risk—Reply
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Emdin, Connor A., primary, Khera, Amit V., additional, and Kathiresan, Sekar, additional
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- 2017
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86. ANGPTL3 Deficiency and Protection Against Coronary Artery Disease
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Stitziel, Nathan O., primary, Khera, Amit V., additional, Wang, Xiao, additional, Bierhals, Andrew J., additional, Vourakis, A. Christina, additional, Sperry, Alexandra E., additional, Natarajan, Pradeep, additional, Klarin, Derek, additional, Emdin, Connor A., additional, Zekavat, Seyedeh M., additional, Nomura, Akihiro, additional, Erdmann, Jeanette, additional, Schunkert, Heribert, additional, Samani, Nilesh J., additional, Kraus, William E., additional, Shah, Svati H., additional, Yu, Bing, additional, Boerwinkle, Eric, additional, Rader, Daniel J., additional, Gupta, Namrata, additional, Frossard, Philippe M., additional, Rasheed, Asif, additional, Danesh, John, additional, Lander, Eric S., additional, Gabriel, Stacey, additional, Saleheen, Danish, additional, Musunuru, Kiran, additional, and Kathiresan, Sekar, additional
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- 2017
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87. Genetic Analysis of Venous Thromboembolism in UK Biobank Identifies the ZFPM2 Locus and Implicates Obesity as a Causal Risk Factor
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Klarin, Derek, primary, Emdin, Connor A., additional, Natarajan, Pradeep, additional, Conrad, Mark F., additional, and Kathiresan, Sekar, additional
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- 2017
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88. GENETIC RISK, ADHERENCE TO A HEALTHY LIFESTYLE, AND RISK OF CORONARY ARTERY DISEASE
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Khera, Amit V., primary, Emdin, Connor A., additional, Drake, Isabel, additional, Natarajan, Pradeep, additional, Bick, Alexander, additional, Cook, Nancy, additional, Chasman, Daniel, additional, Baber, Usman, additional, Mehran, Roxana, additional, Rader, Daniel, additional, Fuster, Valentin, additional, Boerwinkle, Eric, additional, Olle, Melander, additional, Orho-Melander, Marju, additional, Ridker, Paul, additional, and Kathiresan, Sekar, additional
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- 2017
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89. Heterozygous ABCG5Gene Deficiency and Risk of Coronary Artery Disease
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Nomura, Akihiro, Emdin, Connor A., Won, Hong Hee, Peloso, Gina M., Natarajan, Pradeep, Ardissino, Diego, Danesh, John, Schunkert, Heribert, Correa, Adolfo, Bown, Matthew J., Samani, Nilesh J., Erdmann, Jeanette, McPherson, Ruth, Watkins, Hugh, Saleheen, Danish, Elosua, Roberto, Kawashiri, Masa-aki, Tada, Hayato, Gupta, Namrata, Shah, Svati H., Rader, Daniel J., Gabriel, Stacey, Khera, Amit V., and Kathiresan, Sekar
- Abstract
Supplemental Digital Content is available in the text.
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- 2020
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90. Exome-wide association study of plasma lipids in > 300,000 individuals
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Liu, Dajiang J., Peloso, Gina M., Yu, Haojie, Butterworth, Adam S., Wang, Xiao, Mahajan, Anubha, Saleheen, Danish, Emdin, Connor, Alam, Dewan, Alves, Alexessander Couto, Amouyel, Philippe, Di Angelantonio, Emanuele, Arveiler, Dominique, Assimes, Themistocles L., Auer, Paul L., Baber, Usman, Ballantyne, Christie M., Bang, Lia E., Benn, Marianne, Bis, Joshua C., Boehnke, Michael, Boerwinkle, Eric, Bork-Jensen, Jette, Bottinger, Erwin P., Brandslund, Ivan, Brown, Morris, Busonero, Fabio, Caulfield, Mark J., Chambers, John C., Chasman, Daniel I., Chen, Y. Eugene, Chen, Yii-Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y., Connell, John M., Cucca, Francesco, Cupples, L. Adrienne, Damrauer, Scott M., Davies, Gail, Deary, Ian J., Dedoussis, George, Denny, Joshua C., Dominiczak, Anna, Dube, Marie-Pierre, Ebeling, Tapani, Eiriksdottir, Gudny, Esko, Tonu, Farmaki, Aliki-Eleni, Feitosa, Mary F., Ferrario, Marco, Ferrieres, Jean, Ford, Ian, Fornage, Myriam, Franks, Paul W., Frayling, Timothy M., Frikke-Schmidt, Ruth, Fritsche, Lars G., Frossard, Philippe, Fuster, Valentin, Ganesh, Santhi K., Gao, Wei, Garcia, Melissa E., Gieger, Christian, Giulianini, Franco, Goodarzi, Mark O., Grallert, Harald, Grarup, Niels, Groop, Leif, Grove, Megan L., Gudnason, Vilmundur, Hansen, Torben, Harris, Tamara B., Hayward, Caroline, Hirschhorn, Joel N., Holmen, Oddgeir L., Huffman, Jennifer, Huo, Yong, Hveem, Kristian, Jabeen, Sehrish, Jackson, Anne U., Jakobsdottir, Johanna, Jarvelin, Marjo-Riitta, Jensen, Gorm B., Jorgensen, Marit E., Jukema, J. Wouter, Justesen, Johanne M., Kamstrup, Pia R., Kanoni, Stavroula, Karpe, Fredrik, Kee, Frank, Khera, Amit V., Klarin, Derek, Koistinen, Heikki A., Kooner, Jaspal S., Kooperberg, Charles, Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo, Langenberg, Claudia, Langsted, Anne, Launer, Lenore J., Lauritzen, Torsten, Liewald, David C. M., Lin, Li An, Linneberg, Allan, Loos, Ruth J. F., Lu, Yingchang, Lu, Xiangfeng, Magi, Reedik, Malarstig, Anders, Manichaikul, Ani, Manning, Alisa K., Mantyselka, Pekka, Marouli, Eirini, Masca, Nicholas G. D., Maschio, Andrea, Meigs, James B., Melander, Olle, Metspalu, Andres, Morris, Andrew P., Morrison, Alanna C., Mulas, Antonella, Mueller-Nurasyid, Martina, Munroe, Patricia B., Neville, Matt J., Nielsen, Jonas B., Nielsen, Sune F., Nordestgaard, Borge G., Ordovas, Jose M., Mehran, Roxana, O'Donnell, Christoper J., Orho-Melander, Marju, Molony, Cliona M., Muntendam, Pieter, Padmanabhan, Sandosh, Palmer, Colin N. A., Pasko, Dorota, Patel, Aniruddh P., Pedersen, Oluf, Perola, Markus, Peters, Annette, Pisinger, Charlotta, Pistis, Giorgio, Polasek, Ozren, Poulter, Neil, Psaty, Bruce M., Rader, Daniel J., Rasheed, Asif, Rauramaa, Rainer, Reilly, Dermot F., Reiner, Alex P., Renström, Frida, Rich, Stephen S., Ridker, Paul M., Rioux, John D., Robertson, Neil R., Roden, Dan M., Rotter, Jerome I., Rudan, Igor, Salomaa, Veikko, Samani, Nilesh J., Sanna, Serena, Sattar, Naveed, Schmidt, Ellen M., Scott, Robert A., Sever, Peter, Sevilla, Raquel S., Shaffer, Christian M., Sim, Xueling, Sivapalaratnam, Suthesh, Small, Kerrin S., Smith, Albert V., Smith, Blair H., Somayajula, Sangeetha, Southam, Lorraine, Spector, Timothy D., Speliotes, Elizabeth K., Starr, John M., Stirrups, Kathleen E., Stitziel, Nathan, Strauch, Konstantin, Stringham, Heather M., Surendran, Praveen, Tada, Hayato, Tall, Alan R., Tang, Hua, Tardif, Jean-Claude, Taylor, Kent D., Trompet, Stella, Tsao, Philip S., Tuomilehto, Jaakko, Tybjaerg-Hansen, Anne, van Zuydam, Natalie R., Varbo, Anette, Varga, Tibor V., Virtamo, Jarmo, Waldenberger, Melanie, Wang, Nan, Wareham, Nick J., Warren, Helen R., Weeke, Peter E., Weinstock, Joshua, Wessel, Jennifer, Wilson, James G., Wilson, Peter W. F., Xu, Ming, Yaghootkar, Hanieh, Young, Robin, Zeggini, Eleftheria, Zhang, He, Zheng, Neil S., Zhang, Weihua, Zhang, Yan, Zhou, Wei, Zhou, Yanhua, Zoledziewska, Magdalena, Howson, Joanna M. M., Danesh, John, McCarthy, Mark I., Cowan, Chad A., Abecasis, Goncalo, Deloukas, Panos, Musunuru, Kiran, Willer, Cristen J., Kathiresan, Sekar, Liu, Dajiang J., Peloso, Gina M., Yu, Haojie, Butterworth, Adam S., Wang, Xiao, Mahajan, Anubha, Saleheen, Danish, Emdin, Connor, Alam, Dewan, Alves, Alexessander Couto, Amouyel, Philippe, Di Angelantonio, Emanuele, Arveiler, Dominique, Assimes, Themistocles L., Auer, Paul L., Baber, Usman, Ballantyne, Christie M., Bang, Lia E., Benn, Marianne, Bis, Joshua C., Boehnke, Michael, Boerwinkle, Eric, Bork-Jensen, Jette, Bottinger, Erwin P., Brandslund, Ivan, Brown, Morris, Busonero, Fabio, Caulfield, Mark J., Chambers, John C., Chasman, Daniel I., Chen, Y. Eugene, Chen, Yii-Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y., Connell, John M., Cucca, Francesco, Cupples, L. Adrienne, Damrauer, Scott M., Davies, Gail, Deary, Ian J., Dedoussis, George, Denny, Joshua C., Dominiczak, Anna, Dube, Marie-Pierre, Ebeling, Tapani, Eiriksdottir, Gudny, Esko, Tonu, Farmaki, Aliki-Eleni, Feitosa, Mary F., Ferrario, Marco, Ferrieres, Jean, Ford, Ian, Fornage, Myriam, Franks, Paul W., Frayling, Timothy M., Frikke-Schmidt, Ruth, Fritsche, Lars G., Frossard, Philippe, Fuster, Valentin, Ganesh, Santhi K., Gao, Wei, Garcia, Melissa E., Gieger, Christian, Giulianini, Franco, Goodarzi, Mark O., Grallert, Harald, Grarup, Niels, Groop, Leif, Grove, Megan L., Gudnason, Vilmundur, Hansen, Torben, Harris, Tamara B., Hayward, Caroline, Hirschhorn, Joel N., Holmen, Oddgeir L., Huffman, Jennifer, Huo, Yong, Hveem, Kristian, Jabeen, Sehrish, Jackson, Anne U., Jakobsdottir, Johanna, Jarvelin, Marjo-Riitta, Jensen, Gorm B., Jorgensen, Marit E., Jukema, J. Wouter, Justesen, Johanne M., Kamstrup, Pia R., Kanoni, Stavroula, Karpe, Fredrik, Kee, Frank, Khera, Amit V., Klarin, Derek, Koistinen, Heikki A., Kooner, Jaspal S., Kooperberg, Charles, Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo, Langenberg, Claudia, Langsted, Anne, Launer, Lenore J., Lauritzen, Torsten, Liewald, David C. M., Lin, Li An, Linneberg, Allan, Loos, Ruth J. F., Lu, Yingchang, Lu, Xiangfeng, Magi, Reedik, Malarstig, Anders, Manichaikul, Ani, Manning, Alisa K., Mantyselka, Pekka, Marouli, Eirini, Masca, Nicholas G. D., Maschio, Andrea, Meigs, James B., Melander, Olle, Metspalu, Andres, Morris, Andrew P., Morrison, Alanna C., Mulas, Antonella, Mueller-Nurasyid, Martina, Munroe, Patricia B., Neville, Matt J., Nielsen, Jonas B., Nielsen, Sune F., Nordestgaard, Borge G., Ordovas, Jose M., Mehran, Roxana, O'Donnell, Christoper J., Orho-Melander, Marju, Molony, Cliona M., Muntendam, Pieter, Padmanabhan, Sandosh, Palmer, Colin N. A., Pasko, Dorota, Patel, Aniruddh P., Pedersen, Oluf, Perola, Markus, Peters, Annette, Pisinger, Charlotta, Pistis, Giorgio, Polasek, Ozren, Poulter, Neil, Psaty, Bruce M., Rader, Daniel J., Rasheed, Asif, Rauramaa, Rainer, Reilly, Dermot F., Reiner, Alex P., Renström, Frida, Rich, Stephen S., Ridker, Paul M., Rioux, John D., Robertson, Neil R., Roden, Dan M., Rotter, Jerome I., Rudan, Igor, Salomaa, Veikko, Samani, Nilesh J., Sanna, Serena, Sattar, Naveed, Schmidt, Ellen M., Scott, Robert A., Sever, Peter, Sevilla, Raquel S., Shaffer, Christian M., Sim, Xueling, Sivapalaratnam, Suthesh, Small, Kerrin S., Smith, Albert V., Smith, Blair H., Somayajula, Sangeetha, Southam, Lorraine, Spector, Timothy D., Speliotes, Elizabeth K., Starr, John M., Stirrups, Kathleen E., Stitziel, Nathan, Strauch, Konstantin, Stringham, Heather M., Surendran, Praveen, Tada, Hayato, Tall, Alan R., Tang, Hua, Tardif, Jean-Claude, Taylor, Kent D., Trompet, Stella, Tsao, Philip S., Tuomilehto, Jaakko, Tybjaerg-Hansen, Anne, van Zuydam, Natalie R., Varbo, Anette, Varga, Tibor V., Virtamo, Jarmo, Waldenberger, Melanie, Wang, Nan, Wareham, Nick J., Warren, Helen R., Weeke, Peter E., Weinstock, Joshua, Wessel, Jennifer, Wilson, James G., Wilson, Peter W. F., Xu, Ming, Yaghootkar, Hanieh, Young, Robin, Zeggini, Eleftheria, Zhang, He, Zheng, Neil S., Zhang, Weihua, Zhang, Yan, Zhou, Wei, Zhou, Yanhua, Zoledziewska, Magdalena, Howson, Joanna M. M., Danesh, John, McCarthy, Mark I., Cowan, Chad A., Abecasis, Goncalo, Deloukas, Panos, Musunuru, Kiran, Willer, Cristen J., and Kathiresan, Sekar
- Abstract
We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-densitylipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.
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- 2017
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91. A Genetic Variant Associated with Five Vascular Diseases Is a Distal Regulator of Endothelin-1 Gene Expression
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Gupta, Rajat M, Hadaya, Joseph, Trehan, Aditi, Zekavat, Seyedeh M, Roselli, Carolina, Klarin, Derek, Emdin, Connor A, Hilvering, Catharina R E, Bianchi, Valerio, Mueller, Christian, Khera, Amit V, Ryan, Russell J H, Engreitz, Jesse M, Issner, Robbyn, Shoresh, Noam, Epstein, Charles B, de Laat, Wouter, Brown, Jonathan D, Schnabel, Renate B, Bernstein, Bradley E, Kathiresan, Sekar, Gupta, Rajat M, Hadaya, Joseph, Trehan, Aditi, Zekavat, Seyedeh M, Roselli, Carolina, Klarin, Derek, Emdin, Connor A, Hilvering, Catharina R E, Bianchi, Valerio, Mueller, Christian, Khera, Amit V, Ryan, Russell J H, Engreitz, Jesse M, Issner, Robbyn, Shoresh, Noam, Epstein, Charles B, de Laat, Wouter, Brown, Jonathan D, Schnabel, Renate B, Bernstein, Bradley E, and Kathiresan, Sekar
- Abstract
Genome-wide association studies (GWASs) implicate the PHACTR1 locus (6p24) in risk for five vascular diseases, including coronary artery disease, migraine headache, cervical artery dissection, fibromuscular dysplasia, and hypertension. Through genetic fine mapping, we prioritized rs9349379, a common SNP in the third intron of the PHACTR1 gene, as the putative causal variant. Epigenomic data from human tissue revealed an enhancer signature at rs9349379 exclusively in aorta, suggesting a regulatory function for this SNP in the vasculature. CRISPR-edited stem cell-derived endothelial cells demonstrate rs9349379 regulates expression of endothelin 1 (EDN1), a gene located 600 kb upstream of PHACTR1. The known physiologic effects of EDN1 on the vasculature may explain the pattern of risk for the five associated diseases. Overall, these data illustrate the integration of genetic, phenotypic, and epigenetic analysis to identify the biologic mechanism by which a common, non-coding variant can distally regulate a gene and contribute to the pathogenesis of multiple vascular diseases.
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- 2017
92. A Genetic Variant Associated with Five Vascular Diseases Is a Distal Regulator of Endothelin-1 Gene Expression
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Divisie Biomedische Genetica, Hubrecht Institute with UMC, Cancer, Gupta, Rajat M., Hadaya, Joseph, Trehan, Aditi, Zekavat, Seyedeh M., Roselli, Carolina, Klarin, Derek, Emdin, Connor A., Hilvering, Catharina R.E., Bianchi, Valerio, Mueller, Christian, Khera, Amit V., Ryan, Russell J.H., Engreitz, Jesse M., Issner, Robbyn, Shoresh, Noam, Epstein, Charles B., de Laat, Wouter, Brown, Jonathan D., Schnabel, Renate B., Bernstein, Bradley E., Kathiresan, Sekar, Divisie Biomedische Genetica, Hubrecht Institute with UMC, Cancer, Gupta, Rajat M., Hadaya, Joseph, Trehan, Aditi, Zekavat, Seyedeh M., Roselli, Carolina, Klarin, Derek, Emdin, Connor A., Hilvering, Catharina R.E., Bianchi, Valerio, Mueller, Christian, Khera, Amit V., Ryan, Russell J.H., Engreitz, Jesse M., Issner, Robbyn, Shoresh, Noam, Epstein, Charles B., de Laat, Wouter, Brown, Jonathan D., Schnabel, Renate B., Bernstein, Bradley E., and Kathiresan, Sekar
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- 2017
93. Exome-wide association study of plasma lipids in >300,000 individuals
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Liu, Dajiang J., Peloso, Gina M., Yu, Haojie, Butterworth, Adam S., Wang, Xiao, Mahajan, Anubha, Saleheen, Danish, Emdin, Connor, Alam, Dewan, Alves, Alexessander Couto, Amouyel, Philippe, Angelantonio, Emanuele DI, Arveiler, Dominique, Assimes, Themistocles L., Auer, Paul L., Baber, Usman, Ballantyne, Christie M., Bang, Lia E., Benn, Marianne, Bis, Joshua C., Boehnke, Michael, Boerwinkle, Eric, Bork-Jensen, Jette, Bottinger, Erwin P., Brandslund, Ivan, Brown, Morris, Busonero, Fabio, Caulfield, Mark J., Chambers, John C., Chasman, Daniel I., Chen, Y. Eugene, Chen, Yii Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y., Connell, John M., Cucca, Francesco, Cupples, L. Adrienne, Damrauer, Scott M., Davies, Gail, Deary, Ian J., Dedoussis, George, Denny, Joshua C., Dominiczak, Anna, Dubé, Marie Pierre, Ebeling, Tapani, Eiriksdottir, Gudny, Esko, Toñu, Farmaki, Aliki Eleni, Feitosa, Mary F., Ferrario, Marco, Ferrieres, Jean, Ford, Ian, Fornage, Myriam, Franks, Paul W., Frayling, Timothy M., Frikke-Schmidt, Ruth, Fritsche, Lars G., Frossard, Philippe, Fuster, Valentin, Ganesh, Santhi K., Gao, Wei, Garcia, Melissa E., Gieger, Christian, Giulianini, Franco, Goodarzi, Mark O., Grallert, Harald, Grarup, Niels, Groop, Leif, Grove, Megan L., Gudnason, Vilmundur, Hansen, Torben, Harris, Tamara B., Hayward, Caroline, Hirschhorn, Joel N., Holmen, Oddgeir L., Huffman, Jennifer, Huo, Yong, Hveem, Kristian, Jabeen, Sehrish, Jackson, Anne U., Jakobsdottir, Johanna, Jarvelin, Marjo Riitta, Jensen, Gorm B., Jørgensen, Marit E., Jukema, J. Wouter, Justesen, Johanne M., Kamstrup, Pia R., Kanoni, Stavroula, Karpe, Fredrik, Kee, Frank, Khera, Amit V., Klarin, Derek, Koistinen, Heikki A., Kooner, Jaspal S., Kooperberg, Charles, Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo, Langenberg, Claudia, Langsted, Anne, Launer, Lenore J., Lauritzen, Torsten, MLiewald, David C., Lin, Li An, Linneberg, Allan, Loos, Ruth J.F., Lu, Yingchang, Lu, Xiangfeng, Mägi, Reedik, Malarstig, Anders, Manichaikul, Ani, Manning, Alisa K., Mäntyselkä, Pekka, Marouli, Eirini, Masca, Nicholas G.D., Maschio, Andrea, Meigs, James B., Melander, Olle, Metspalu, Andres, Morris, Andrew P., Morrison, Alanna C., Mulas, Antonella, Müller-Nurasyid, Martina, Munroe, Patricia B., Neville, Matt J., Nielsen, Sune F., Nielsen, Jonas B., Nordestgaard, Børge G., Ordovas, Jose M., Mehran, Roxana, O'Donnell, Christoper J., Orho-Melander, Marju, Molony, Cliona M., Muntendam, Pieter, Padmanabhan, Sandosh, Palmer, Colin N.A., Pasko, Dorota, Patel, Aniruddh P., Pedersen, Oluf, Perola, Markus, Peters, Annette, Pisinger, Charlotta, Pistis, Giorgio, Polasek, Ozren, Poulter, Neil, Psaty, Bruce M., Rader, Daniel J., Rasheed, Asif, Rauramaa, Rainer, Reilly, Dermot F., Reiner, Alex P., Renström, Frida, Rich, Stephen S., Ridker, Paul M., Rioux, John D., Robertson, Neil R., Roden, Dan M., Rotter, Jerome I., Rudan, Igor, Salomaa, Veikko, Samani, Nilesh J., Sanna, Serena, Sattar, Naveed, Schmidt, Ellen M., Scott, Robert A., Sever, Peter, Sevilla, Raquel S., Shaffer, Christian M., Sim, Xueling, Sivapalaratnam, Suthesh, Small, Kerrin S., Smith, Albert V., Smith, Blair H., Somayajula, Sangeetha, Southam, Lorraine, Spector, Timothy D., Speliotes, Elizabeth K., Starr, John M., Stirrups, Kathleen E., Stitziel, Nathan, Strauch, Konstantin, Stringham, Heather M., Surendran, Praveen, Tada, Hayato, Tall, Alan R., Tang, Hua, Tardif, Jean Claude, Taylor, Kent D., Trompet, Stella, Tsao, Philip S., Tuomilehto, Jaakko, Tybjaerg-Hansen, Anne, Zuydam, Natalie R.Van, Varbo, Anette, Varga, Tibor V., Virtamo, Jarmo, Waldenberger, Melanie, Wang, Nan, Wareham, Nick J., Warren, Helen R., Weeke, Peter E., Weinstock, Joshua, Wessel, Jennifer, Wilson, James G., Wilson, Peter W.F., Xu, Ming, Yaghootkar, Hanieh, Young, Robin, Zeggini, Eleftheria, Zhang, He, Zheng, Neil S., Zhang, Weihua, Zhang, Yan, Zhou, Wei, Zhou, Yanhua, Zoledziewska, Magdalena, Howson, Joanna M.M., Danesh, John, McCarthy, Mark I., Cowan, Chad A., Abecasis, Goncalo, Deloukas, Panos, Musunuru, Kiran, Willer, Cristen J., Kathiresan, Sekar, V Varga, Tibor, Liu, Dajiang J., Peloso, Gina M., Yu, Haojie, Butterworth, Adam S., Wang, Xiao, Mahajan, Anubha, Saleheen, Danish, Emdin, Connor, Alam, Dewan, Alves, Alexessander Couto, Amouyel, Philippe, Angelantonio, Emanuele DI, Arveiler, Dominique, Assimes, Themistocles L., Auer, Paul L., Baber, Usman, Ballantyne, Christie M., Bang, Lia E., Benn, Marianne, Bis, Joshua C., Boehnke, Michael, Boerwinkle, Eric, Bork-Jensen, Jette, Bottinger, Erwin P., Brandslund, Ivan, Brown, Morris, Busonero, Fabio, Caulfield, Mark J., Chambers, John C., Chasman, Daniel I., Chen, Y. Eugene, Chen, Yii Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y., Connell, John M., Cucca, Francesco, Cupples, L. Adrienne, Damrauer, Scott M., Davies, Gail, Deary, Ian J., Dedoussis, George, Denny, Joshua C., Dominiczak, Anna, Dubé, Marie Pierre, Ebeling, Tapani, Eiriksdottir, Gudny, Esko, Toñu, Farmaki, Aliki Eleni, Feitosa, Mary F., Ferrario, Marco, Ferrieres, Jean, Ford, Ian, Fornage, Myriam, Franks, Paul W., Frayling, Timothy M., Frikke-Schmidt, Ruth, Fritsche, Lars G., Frossard, Philippe, Fuster, Valentin, Ganesh, Santhi K., Gao, Wei, Garcia, Melissa E., Gieger, Christian, Giulianini, Franco, Goodarzi, Mark O., Grallert, Harald, Grarup, Niels, Groop, Leif, Grove, Megan L., Gudnason, Vilmundur, Hansen, Torben, Harris, Tamara B., Hayward, Caroline, Hirschhorn, Joel N., Holmen, Oddgeir L., Huffman, Jennifer, Huo, Yong, Hveem, Kristian, Jabeen, Sehrish, Jackson, Anne U., Jakobsdottir, Johanna, Jarvelin, Marjo Riitta, Jensen, Gorm B., Jørgensen, Marit E., Jukema, J. Wouter, Justesen, Johanne M., Kamstrup, Pia R., Kanoni, Stavroula, Karpe, Fredrik, Kee, Frank, Khera, Amit V., Klarin, Derek, Koistinen, Heikki A., Kooner, Jaspal S., Kooperberg, Charles, Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo, Langenberg, Claudia, Langsted, Anne, Launer, Lenore J., Lauritzen, Torsten, MLiewald, David C., Lin, Li An, Linneberg, Allan, Loos, Ruth J.F., Lu, Yingchang, Lu, Xiangfeng, Mägi, Reedik, Malarstig, Anders, Manichaikul, Ani, Manning, Alisa K., Mäntyselkä, Pekka, Marouli, Eirini, Masca, Nicholas G.D., Maschio, Andrea, Meigs, James B., Melander, Olle, Metspalu, Andres, Morris, Andrew P., Morrison, Alanna C., Mulas, Antonella, Müller-Nurasyid, Martina, Munroe, Patricia B., Neville, Matt J., Nielsen, Sune F., Nielsen, Jonas B., Nordestgaard, Børge G., Ordovas, Jose M., Mehran, Roxana, O'Donnell, Christoper J., Orho-Melander, Marju, Molony, Cliona M., Muntendam, Pieter, Padmanabhan, Sandosh, Palmer, Colin N.A., Pasko, Dorota, Patel, Aniruddh P., Pedersen, Oluf, Perola, Markus, Peters, Annette, Pisinger, Charlotta, Pistis, Giorgio, Polasek, Ozren, Poulter, Neil, Psaty, Bruce M., Rader, Daniel J., Rasheed, Asif, Rauramaa, Rainer, Reilly, Dermot F., Reiner, Alex P., Renström, Frida, Rich, Stephen S., Ridker, Paul M., Rioux, John D., Robertson, Neil R., Roden, Dan M., Rotter, Jerome I., Rudan, Igor, Salomaa, Veikko, Samani, Nilesh J., Sanna, Serena, Sattar, Naveed, Schmidt, Ellen M., Scott, Robert A., Sever, Peter, Sevilla, Raquel S., Shaffer, Christian M., Sim, Xueling, Sivapalaratnam, Suthesh, Small, Kerrin S., Smith, Albert V., Smith, Blair H., Somayajula, Sangeetha, Southam, Lorraine, Spector, Timothy D., Speliotes, Elizabeth K., Starr, John M., Stirrups, Kathleen E., Stitziel, Nathan, Strauch, Konstantin, Stringham, Heather M., Surendran, Praveen, Tada, Hayato, Tall, Alan R., Tang, Hua, Tardif, Jean Claude, Taylor, Kent D., Trompet, Stella, Tsao, Philip S., Tuomilehto, Jaakko, Tybjaerg-Hansen, Anne, Zuydam, Natalie R.Van, Varbo, Anette, Varga, Tibor V., Virtamo, Jarmo, Waldenberger, Melanie, Wang, Nan, Wareham, Nick J., Warren, Helen R., Weeke, Peter E., Weinstock, Joshua, Wessel, Jennifer, Wilson, James G., Wilson, Peter W.F., Xu, Ming, Yaghootkar, Hanieh, Young, Robin, Zeggini, Eleftheria, Zhang, He, Zheng, Neil S., Zhang, Weihua, Zhang, Yan, Zhou, Wei, Zhou, Yanhua, Zoledziewska, Magdalena, Howson, Joanna M.M., Danesh, John, McCarthy, Mark I., Cowan, Chad A., Abecasis, Goncalo, Deloukas, Panos, Musunuru, Kiran, Willer, Cristen J., Kathiresan, Sekar, and V Varga, Tibor
- Abstract
We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-densitylipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TGrich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.
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- 2017
94. Atrial fibrillation and risks of cardiovascular disease, renal disease, and death: systematic review and meta-analysis
- Author
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Massachusetts Institute of Technology. Department of Economics, Hsiao, Allan, Odutayo, Ayodele, Wong, Christopher X, Hopewell, Sally, Altman, Douglas G, Emdin, Connor A, Massachusetts Institute of Technology. Department of Economics, Hsiao, Allan, Odutayo, Ayodele, Wong, Christopher X, Hopewell, Sally, Altman, Douglas G, and Emdin, Connor A
- Abstract
Objective: To quantify the association between atrial fibrillation and cardiovascular disease, renal disease, and death. Design: Systematic review and meta-analysis. Data sources: Medline and Embase. Eligibility criteria: Cohort studies examining the association between atrial fibrillation and cardiovascular disease, renal disease, and death. Two reviewers independently extracted study characteristics and the relative risk of outcomes associated with atrial fibrillation: specifically, all cause mortality, cardiovascular mortality, major cardiovascular events, any stroke, ischaemic stroke, haemorrhagic stroke, ischaemic heart disease, sudden cardiac death, congestive heart failure, chronic kidney disease, and peripheral arterial disease. Estimates were pooled with inverse variance weighted random effects meta-analysis. Results: 104 eligible cohort studies involving 9 686 513 participants (587 867 with atrial fibrillation) were identified. Atrial fibrillation was associated with an increased risk of all cause mortality (relative risk 1.46, 95% confidence interval 1.39 to 1.54), cardiovascular mortality (2.03, 1.79 to 2.30), major cardiovascular events (1.96, 1.53 to 2.51), stroke (2.42, 2.17 to 2.71), ischaemic stroke (2.33, 1.84 to 2.94), ischaemic heart disease (1.61, 1.38 to 1.87), sudden cardiac death (1.88, 1.36 to 2.60), heart failure (4.99, 3.04 to 8.22), chronic kidney disease (1.64, 1.41 to 1.91), and peripheral arterial disease (1.31, 1.19 to 1.45) but not haemorrhagic stroke (2.00, 0.67 to 5.96). Among the outcomes examined, the highest absolute risk increase was for heart failure. Associations between atrial fibrillation and included outcomes were broadly consistent across subgroups and in sensitivity analyses. Conclusions: Atrial fibrillation is associated with an increased risk of death and an increased risk of cardiovascular and renal disease. Interventions aimed at reducing outcomes beyond stroke are warranted in patients with atrial fibrillation.
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- 2017
95. Association between trial registration and positive study findings: cross sectional study (Epidemiological Study of Randomized Trials—ESORT)
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Massachusetts Institute of Technology. Department of Economics, Hsiao, Allan, Odutayo, Ayodele, Emdin, Connor A, Shakir, Mubeen, Copsey, Bethan, Dutton, Susan, Chiocchia, Virginia, Schlussel, Michael, Dutton, Peter, Roberts, Corran, Altman, Douglas G, Hopewell, Sally, Massachusetts Institute of Technology. Department of Economics, Hsiao, Allan, Odutayo, Ayodele, Emdin, Connor A, Shakir, Mubeen, Copsey, Bethan, Dutton, Susan, Chiocchia, Virginia, Schlussel, Michael, Dutton, Peter, Roberts, Corran, Altman, Douglas G, and Hopewell, Sally
- Abstract
Objective To assess whether randomised controlled trials (RCTs) that were registered were less likely to report positive study findings compared with RCTs that were not registered and whether the association varied by funding source. Design Cross sectional study. Study sample All primary RCTs published in December 2012 and indexed in PubMed by November 2013. Trial registration was determined based on the report of a trial registration number in published RCTs or the identification of the trial in a search of trial registries. Trials were separated into prospectively and retrospectively registered studies. Main outcome measure Association between trial registration and positive study findings. Results 1122 eligible RCTs were identified, of which 593 (52.9%) were registered and 529 (47.1%) were not registered. Overall, registration was marginally associated with positive study findings (adjusted risk ratio 0.87, 95% confidence interval 0.78 to 0.98), even with stratification as prospectively and retrospectively registered trials (0.87, 0.74 to 1.03 and 0.88, 0.78 to 1.00, respectively). The interaction term between overall registration and funding source was marginally statistically significant and relative risk estimates were imprecise (0.75, 0.63 to 0.89 for non-industry funded and 1.03, 0.79 to 1.36 for industry funded, P interaction=0.046). Furthermore, a statistically significant interaction was not maintained in sensitivity analyses. Within each stratum of funding source, relative risk estimates were also imprecise for the association between positive study findings and prospective and retrospective registration. Conclusion Among published RCTs, there was little evidence of a difference in positive study findings between registered and non-registered clinical trials, even with stratification by timing of registration. Relative risk estimates were imprecise in subgroups of non-industry and industry funded trials.
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- 2017
96. Atrial fibrillation as risk factor for cardiovascular disease and death in women compared with men: systematic review and meta-analysis of cohort studies
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Massachusetts Institute of Technology. Department of Economics, Hsiao, Allan, Emdin, Connor A, Wong, Christopher X, Altman, Douglas G, Peters, Sanne AE, Woodward, Mark, Odutayo, Ayodele A, Massachusetts Institute of Technology. Department of Economics, Hsiao, Allan, Emdin, Connor A, Wong, Christopher X, Altman, Douglas G, Peters, Sanne AE, Woodward, Mark, and Odutayo, Ayodele A
- Abstract
Objective: To determine whether atrial fibrillation is a stronger risk factor for cardiovascular disease and death in women compared with men. Design: Meta-analysis of cohort studies. Data: sources Studies published between January 1966 and March 2015, identified through a systematic search of Medline and Embase and review of references. Eligibility for selecting studies: Cohort studies with a minimum of 50 participants with and 50 without atrial fibrillation that reported sex specific associations between atrial fibrillation and all cause mortality, cardiovascular mortality, stroke, cardiac events (cardiac death and non-fatal myocardial infarction), and heart failure. Data extraction: Two independent reviewers extracted study characteristics and maximally adjusted sex specific relative risks. Inverse variance weighted random effects meta-analysis was used to pool sex specific relative risks and their ratio. Results: 30 studies with 4 371 714 participants were identified. Atrial fibrillation was associated with a higher risk of all cause mortality in women (ratio of relative risks for women compared with men 1.12, 95% confidence interval 1.07 to 1.17) and a significantly stronger risk of stroke (1.99, 1.46 to 2.71), cardiovascular mortality (1.93, 1.44 to 2.60), cardiac events (1.55, 1.15 to 2.08), and heart failure (1.16, 1.07 to 1.27). Results were broadly consistent in sensitivity analyses. Conclusion: Atrial fibrillation is a stronger risk factor for cardiovascular disease and death in women compared with men, though further research would be needed to determine any causality., Rhodes Scholarship
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- 2017
97. Genetic Risk, Adherence to a Healthy Lifestyle, and Coronary Disease
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Khera, Amit V., primary, Emdin, Connor A., additional, Drake, Isabel, additional, Natarajan, Pradeep, additional, Bick, Alexander G., additional, Cook, Nancy R., additional, Chasman, Daniel I., additional, Baber, Usman, additional, Mehran, Roxana, additional, Rader, Daniel J., additional, Fuster, Valentin, additional, Boerwinkle, Eric, additional, Melander, Olle, additional, Orho-Melander, Marju, additional, Ridker, Paul M, additional, and Kathiresan, Sekar, additional
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- 2016
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98. Associations of Epicardial, Abdominal, and Overall Adiposity With Atrial Fibrillation
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Wong, Christopher X., primary, Sun, Michelle T., additional, Odutayo, Ayodele, additional, Emdin, Connor A., additional, Mahajan, Rajiv, additional, Lau, Dennis H., additional, Pathak, Rajeev K., additional, Wong, Dennis T., additional, Selvanayagam, Joseph B., additional, Sanders, Prashanthan, additional, and Clarke, Robert, additional
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- 2016
- Full Text
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99. Phenotypic Characterization of Genetically Lowered Human Lipoprotein(a) Levels
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Emdin, Connor A., primary, Khera, Amit V., additional, Natarajan, Pradeep, additional, Klarin, Derek, additional, Won, Hong-Hee, additional, Peloso, Gina M., additional, Stitziel, Nathan O., additional, Nomura, Akihiro, additional, Zekavat, Seyedeh M., additional, Bick, Alexander G., additional, Gupta, Namrata, additional, Asselta, Rosanna, additional, Duga, Stefano, additional, Merlini, Piera Angelica, additional, Correa, Adolfo, additional, Kessler, Thorsten, additional, Wilson, James G., additional, Bown, Matthew J., additional, Hall, Alistair S., additional, Braund, Peter S., additional, Samani, Nilesh J., additional, Schunkert, Heribert, additional, Marrugat, Jaume, additional, Elosua, Roberto, additional, McPherson, Ruth, additional, Farrall, Martin, additional, Watkins, Hugh, additional, Willer, Cristen, additional, Abecasis, Gonçalo R., additional, Felix, Janine F., additional, Vasan, Ramachandran S., additional, Lander, Eric, additional, Rader, Daniel J., additional, Danesh, John, additional, Ardissino, Diego, additional, Gabriel, Stacey, additional, Saleheen, Danish, additional, and Kathiresan, Sekar, additional
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- 2016
- Full Text
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100. Proportion and Characteristics of US Adults Who May Be Eligible From Additional Blood Pressure Lowering Based on Absolute Risk: Table 1.
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Odutayo, Ayodele A., primary, Tennankore, Karthik K., additional, and Emdin, Connor A., additional
- Published
- 2016
- Full Text
- View/download PDF
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