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37 results on '"Ago, Tetsuro"'

1. Decreased Estimated Glomerular Filtration Rate and Proteinuria and Long-Term Outcomes After Ischemic Stroke: A Longitudinal Observational Cohort Study

Author

Ueki, Kana, Matsuo, Ryu, Kuwashiro, Takahiro, Irie, Fumi, Wakisaka, Yoshinobu, Ago, Tetsuro, Kamouchi, Masahiro, Kitazono, Takanari, Ishitsuka, Takao, Ibayashi, Setsuro, Kusuda, Kenji, Fujii, Kenichiro, Nagao, Tetsuhiko, Okada, Yasushi, Yasaka, Masahiro, Ooboshi, Hiroaki, Irie, Katsumi, Omae, Tsuyoshi, Toyoda, Kazunori, Nakane, Hiroshi, Sugimori, Hiroshi, Arakawa, Shuji, Fukuda, Kenji, Kitayama, Jiro, Fujimoto, Shigeru, Arihiro, Shoji, Kuroda, Junya, Fukushima, Yoshihisa, Nakamura, Kuniyuki, Kiyohara, Takuya, Hata, Jun, and Kumai, Yasuhiro

Published
2023
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2. Stroke genetics informs drug discovery and risk prediction across ancestries

Author

Mishra, Aniket, Malik, Rainer, Hachiya, Tsuyoshi, Jürgenson, Tuuli, Namba, Shinichi, Posner, Daniel C., Kamanu, Frederick K., Koido, Masaru, Le Grand, Quentin, Shi, Mingyang, He, Yunye, Georgakis, Marios K., Caro, Ilana, Krebs, Kristi, Liaw, Yi-Ching, Vaura, Felix C., Lin, Kuang, Winsvold, Bendik Slagsvold, Srinivasasainagendra, Vinodh, Parodi, Livia, Bae, Hee-Joon, Chauhan, Ganesh, Chong, Michael R., Tomppo, Liisa, Akinyemi, Rufus, Roshchupkin, Gennady V., Habib, Naomi, Jee, Yon Ho, Thomassen, Jesper Qvist, Abedi, Vida, Cárcel-Márquez, Jara, Nygaard, Marianne, Leonard, Hampton L., Yang, Chaojie, Yonova-Doing, Ekaterina, Knol, Maria J., Lewis, Adam J., Judy, Renae L., Ago, Tetsuro, Amouyel, Philippe, Armstrong, Nicole D., Bakker, Mark K., Bartz, Traci M., Bennett, David A., Bis, Joshua C., Bordes, Constance, Børte, Sigrid, Cain, Anael, Ridker, Paul M., Cho, Kelly, Chen, Zhengming, Cruchaga, Carlos, Cole, John W., de Jager, Phil L., de Cid, Rafael, Endres, Matthias, Ferreira, Leslie E., Geerlings, Mirjam I., Gasca, Natalie C., Gudnason, Vilmundur, Hata, Jun, He, Jing, Heath, Alicia K., Ho, Yuk-Lam, Havulinna, Aki S., Hopewell, Jemma C., Hyacinth, Hyacinth I., Inouye, Michael, Jacob, Mina A., Jeon, Christina E., Jern, Christina, Kamouchi, Masahiro, Keene, Keith L., Kitazono, Takanari, Kittner, Steven J., Konuma, Takahiro, Kumar, Amit, Lacaze, Paul, Launer, Lenore J., Lee, Keon-Joo, Lepik, Kaido, Li, Jiang, Li, Liming, Manichaikul, Ani, Markus, Hugh S., Marston, Nicholas A., Meitinger, Thomas, Mitchell, Braxton D., Montellano, Felipe A., Morisaki, Takayuki, Mosley, Thomas H., Nalls, Mike A., Nordestgaard, Børge G., O’Donnell, Martin J., Okada, Yukinori, Onland-Moret, N. Charlotte, Ovbiagele, Bruce, Peters, Annette, Psaty, Bruce M., Rich, Stephen S., Rosand, Jonathan, Sabatine, Marc S., Sacco, Ralph L., Saleheen, Danish, Sandset, Else Charlotte, Salomaa, Veikko, Sargurupremraj, Muralidharan, Sasaki, Makoto, Satizabal, Claudia L., Schmidt, Carsten O., Shimizu, Atsushi, Smith, Nicholas L., Sloane, Kelly L., Sutoh, Yoichi, Sun, Yan V., Tanno, Kozo, Tiedt, Steffen, Tatlisumak, Turgut, Torres-Aguila, Nuria P., Tiwari, Hemant K., Trégouët, David-Alexandre, Trompet, Stella, Tuladhar, Anil Man, Tybjærg-Hansen, Anne, van Vugt, Marion, Vibo, Riina, Verma, Shefali S., Wiggins, Kerri L., Wennberg, Patrik, Woo, Daniel, Wilson, Peter W. F., Xu, Huichun, Yang, Qiong, Yoon, Kyungheon, Millwood, Iona Y., Gieger, Christian, Ninomiya, Toshiharu, Grabe, Hans J., Jukema, J. Wouter, Rissanen, Ina L., Strbian, Daniel, Kim, Young Jin, Chen, Pei-Hsin, Mayerhofer, Ernst, Howson, Joanna M. M., Irvin, Marguerite R., Adams, Hieab, Wassertheil-Smoller, Sylvia, Christensen, Kaare, Ikram, Mohammad A., Rundek, Tatjana, Worrall, Bradford B., Lathrop, G. Mark, Riaz, Moeen, Simonsick, Eleanor M., Kõrv, Janika, França, Paulo H. C., Zand, Ramin, Prasad, Kameshwar, Frikke-Schmidt, Ruth, de Leeuw, Frank-Erik, Liman, Thomas, Haeusler, Karl Georg, Ruigrok, Ynte M., Heuschmann, Peter Ulrich, Longstreth, W. T., Jung, Keum Ji, Bastarache, Lisa, Paré, Guillaume, Damrauer, Scott M., Chasman, Daniel I., Rotter, Jerome I., Anderson, Christopher D., Zwart, John-Anker, Niiranen, Teemu J., Fornage, Myriam, Liaw, Yung-Po, Seshadri, Sudha, Fernández-Cadenas, Israel, Walters, Robin G., Ruff, Christian T., Owolabi, Mayowa O., Huffman, Jennifer E., Milani, Lili, Kamatani, Yoichiro, Dichgans, Martin, and Debette, Stephanie

Abstract

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P< 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2Aand FURIN) and variants (such as at GRK5and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

Published
2022
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3. Multi‐phenotype analyses of hemostatic traits with cardiovascular events reveal novel genetic associations

Author

Temprano‐Sagrera, Gerard, Sitlani, Colleen M., Bone, William P., Martin‐Bornez, Miguel, Voight, Benjamin F., Morrison, Alanna C., Damrauer, Scott M., de Vries, Paul S., Smith, Nicholas L., Sabater‐Lleal, Maria, Dehghan, Abbas, Heath, Adam S, Morrison, Alanna C, Reiner, Alex P, Johnson, Andrew, Richmond, Anne, Peters, Annette, van Hylckama Vlieg, Astrid, McKnight, Barbara, Psaty, Bruce M, Hayward, Caroline, Ward‐Caviness, Cavin, O’Donnell, Christopher, Chasman, Daniel, Strachan, David P, Tregouet, David A, Mook‐Kanamori, Dennis, Gill, Dipender, Thibord, Florian, Asselbergs, Folkert W, Leebeek, Frank W.G., Rosendaal, Frits R, Davies, Gail, Homuth, Georg, Temprano, Gerard, Campbell, Harry, Taylor, Herman A, Bressler, Jan, Huffman, Jennifer E, Rotter, Jerome I, Yao, Jie, Wilson, James F, Bis, Joshua C, Hahn, Julie M, Desch, Karl C, Wiggins, Kerri L, Raffield, Laura M, Bielak, Lawrence F, Yanek, Lisa R, Kleber, Marcus E, Sabater‐Lleal, Maria, Mueller, Martina, Kavousi, Maryam, Mangino, Massimo, Liu, Melissa, Brown, Michael R, Conomos, Matthew P, Jhun, Min‐A, Chen, Ming‐Huei, de Maat, Moniek P.M., Pankratz, Nathan, Smith, Nicholas L, Peyser, Patricia A, Elliot, Paul, de Vries, Paul S, Wei, Peng, Wild, Philipp S, Morange, Pierre E, van der Harst, Pim, Yang, Qiong, Le, Ngoc‐Quynh, Marioni, Riccardo, Li, Ruifang, Damrauer, Scott M, Cox, Simon R, Trompet, Stella, Felix, Stephan B, Völker, Uwe, Tang, Weihong, Koenig, Wolfgang, Jukema, J. Wouter, Guo, Xiuqing, Lindstrom, Sara, Wang, Lu, Smith, Erin N, Gordon, William, van Hylckama Vlieg, Astrid, de Andrade, Mariza, Brody, Jennifer A, Pattee, Jack W, Haessler, Jeffrey, Brumpton, Ben M, Chasman, Daniel I, Suchon, Pierre, Chen, Ming‐Huei, Turman, Constance, Germain, Marine, Wiggins, Kerri L, MacDonald, James, Braekkan, Sigrid K, Armasu, Sebastian M, Pankratz, Nathan, Jackson, Rabecca D, Nielsen, Jonas B, Giulianini, Franco, Puurunen, Marja K, Ibrahim, Manal, Heckbert, Susan R, Bammler, Theo K, Frazer, Kelly A, McCauley, Bryan M, Taylor, Kent, Pankow, James S, Reiner, Alexander P, Gabrielsen, Maiken E, Deleuze, Jean‐François, O’Donnell, Chris J, Kim, Jihye, McKnight, Barbara, Kraft, Peter, Hansen, John‐Bjarne, Rosendaal, Frits R, Heit, John A, Psaty, Bruce M, Tang, Weihong, Kooperberg, Charles, Hveem, Kristian, Ridker, Paul M, Morange, Pierre‐Emmanuel, Johnson, Andrew D, Kabrhel, Christopher, Trégouët, David‐Alexandre, Smith, Nicholas L, Malik, Rainer, Chauhan, Ganesh, Traylor, Matthew, Sargurupremraj, Muralidharan, Okada, Yukinori, Mishra, Aniket, Rutten‐Jacobs, Loes, Giese, Anne‐Katrin, van der Laan, Sander W, Gretarsdottir, Solveig, Anderson, Christopher D, Chong, Michael, Adams, Hieab HH, Ago, Tetsuro, Almgren, Peter, Amouyel, Philippe, Ay, Hakan, Bartz, Traci M, Benavente, Oscar R, Bevan, Steve, Boncoraglio, Giorgio B, Brown, Robert D, Butterworth, Adam S, Carrera, Caty, Carty, Cara L, Chasman, Daniel I, Chen, Wei‐Min, Cole, John W, Correa, Adolfo, Cotlarciuc, Ioana, Cruchaga, Carlos, Danesh, John, de Bakker, Paul IW, DeStefano, Anita L, den Hoed, Marcel, Duan, Qing, Engelter, Stefan T, Falcone, Guido J, Gottesman, Rebecca F, Grewal, Raji P, Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeffrey, Harris, Tamara B, Hassan, Ahamad, Havulinna, Aki S, Heckbert, Susan R, Holliday, Elizabeth G, Howard, George, Hsu, Fang‐Chi, Hyacinth, Hyacinth I, Arfan Ikram, M, Ingelsson, Erik, Irvin, Marguerite R, Jian, Xueqiu, Jiménez‐Conde, Jordi, Johnson, Julie A, Jukema, J Wouter, Kanai, Masahiro, Keene, Keith L, Kissela, Brett M, Kleindorfer, Dawn O, Kooperberg, Charles, Kubo, Michiaki, Lange, Leslie A, Langefeld, Carl D, Langenberg, Claudia, Launer, Lenore J, Lee, Jin‐Moo, Lemmens, Robin, Leys, Didier, Lewis, Cathryn M, Lin, Wei‐Yu, Lindgren, Arne G, Lorentzen, Erik, Magnusson, Patrik K, Maguire, Jane, Manichaikul, Ani, McArdle, Patrick F, Meschia, James F, Mitchell, Braxton D, Mosley, Thomas H, Nalls, Michael A, Ninomiya, Toshiharu, O’Donnell, Martin J, Psaty, Bruce M, Pulit, Sara L, Rannikmäe, Kristiina, Reiner, Alexander P, Rexrode, Kathryn M, Rice, Kenneth, Rich, Stephen S, Ridker, Paul M, Rost, Natalia S, Rothwell, Peter M, Rotter, Jerome I, Rundek, Tatjana, Sacco, Ralph L, Sakaue, Saori, Sale, Michele M, Salomaa, Veikko, Sapkota, Bishwa R, Schmidt, Reinhold, Schmidt, Carsten O, Schminke, Ulf, Sharma, Pankaj, Slowik, Agnieszka, Sudlow, Cathie LM, Tanislav, Christian, Tatlisumak, Turgut, Taylor, Kent D, Thijs, Vincent NS, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tiedt, Steffen, Trompet, Stella, Tzourio, Christophe, van Duijn, Cornelia M, Walters, Matthew, Wareham, Nicholas J, Wassertheil‐Smoller, Sylvia, Wilson, James G, Wiggins, Kerri L, Yang, Qiong, Yusuf, Salim, Amin, Najaf, Aparicio, Hugo S, Arnett, Donna K, Attia, John, Beiser, Alexa S, Berr, Claudine, Buring, Julie E, Bustamante, Mariana, Caso, Valeria, Cheng, Yu‐Ching, Hoan Choi, Seung, Chowhan, Ayesha, Cullell, Natalia, Dartigues, Jean‐François, Delavaran, Hossein, Delgado, Pilar, Dörr, Marcus, Engström, Gunnar, Ford, Ian, Gurpreet, Wander S, Hamsten, Anders, Heitsch, Laura, Hozawa, Atsushi, Ibanez, Laura, Ilinca, Andreea, Ingelsson, Martin, Iwasaki, Motoki, Jackson, Rebecca D, Jood, Katarina, Jousilahti, Pekka, Kaffashian, Sara, Kalra, Lalit, Kamouchi, Masahiro, Kitazono, Takanari, Kjartansson, Olafur, Kloss, Manja, Koudstaal, Peter J, Krupinski, Jerzy, Labovitz, Daniel L, Laurie, Cathy C, Levi, Christopher R, Li, Linxin, Lind, Lars, Lindgren, Cecilia M, Lioutas, Vasileios, Mei Liu, Yong, Lopez, Oscar L, Makoto, Hirata, Martinez‐Majander, Nicolas, Matsuda, Koichi, Minegishi, Naoko, Montaner, Joan, Morris, Andrew P, Muiño, Elena, Müller‐Nurasyid, Martina, Norrving, Bo, Ogishima, Soichi, Parati, Eugenio A, Reddy Peddareddygari, Leema, Pedersen, Nancy L, Pera, Joanna, Perola, Markus, Pezzini, Alessandro, Pileggi, Silvana, Rabionet, Raquel, Riba‐Llena, Iolanda, Ribasés, Marta, Romero, Jose R, Roquer, Jaume, Rudd, Anthony G, Sarin, Antti‐Pekka, Sarju, Ralhan, Sarnowski, Chloe, Sasaki, Makoto, Satizabal, Claudia L, Satoh, Mamoru, Sattar, Naveed, Sawada, Norie, Sibolt, Gerli, Sigurdsson, Ásgeir, Smith, Albert, Sobue, Kenji, Soriano‐Tárraga, Carolina, Stanne, Tara, Colin Stine, O, Stott, David J, Strauch, Konstantin, Takai, Takako, Tanaka, Hideo, Tanno, Kozo, Teumer, Alexander, Tomppo, Liisa, Torres‐Aguila, Nuria P, Touze, Emmanuel, Tsugane, Shoichiro, Uitterlinden, Andre G, Valdimarsson, Einar M, van der Lee, Sven J, Völzke, Henry, Wakai, Kenji, Weir, David, Williams, Stephen R, Wolfe, Charles DA, Wong, Quenna, Xu, Huichun, Yamaji, Taiki, Sanghera, Dharambir K, Melander, Olle, Jern, Christina, Strbian, Daniel, Fernandez‐Cadenas, Israel, Longstreth, W T, Rolfs, Arndt, Hata, Jun, Woo, Daniel, Rosand, Jonathan, Pare, Guillaume, Hopewell, Jemma C, Saleheen, Danish, Stefansson, Kari, Worrall, Bradford B, Kittner, Steven J, Seshadri, Sudha, Fornage, Myriam, Markus, Hugh S, Howson, Joanna MM, Kamatani, Yoichiro, Debette, Stephanie, and Dichgans, Martin

Abstract

Multi‐phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes.

Published
2022
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4. Multi‐phenotype analyses of hemostatic traits with cardiovascular events reveal novel genetic associations

Author

Temprano‐Sagrera, Gerard, Sitlani, Colleen M., Bone, William P., Martin‐Bornez, Miguel, Voight, Benjamin F., Morrison, Alanna C., Damrauer, Scott M., de Vries, Paul S., Smith, Nicholas L., Sabater‐Lleal, Maria, Dehghan, Abbas, Heath, Adam S, Morrison, Alanna C, Reiner, Alex P, Johnson, Andrew, Richmond, Anne, Peters, Annette, van Hylckama Vlieg, Astrid, McKnight, Barbara, Psaty, Bruce M, Hayward, Caroline, Ward‐Caviness, Cavin, O’Donnell, Christopher, Chasman, Daniel, Strachan, David P, Tregouet, David A, Mook‐Kanamori, Dennis, Gill, Dipender, Thibord, Florian, Asselbergs, Folkert W, Leebeek, Frank W.G., Rosendaal, Frits R, Davies, Gail, Homuth, Georg, Temprano, Gerard, Campbell, Harry, Taylor, Herman A, Bressler, Jan, Huffman, Jennifer E, Rotter, Jerome I, Yao, Jie, Wilson, James F, Bis, Joshua C, Hahn, Julie M, Desch, Karl C, Wiggins, Kerri L, Raffield, Laura M, Bielak, Lawrence F, Yanek, Lisa R, Kleber, Marcus E, Sabater‐Lleal, Maria, Mueller, Martina, Kavousi, Maryam, Mangino, Massimo, Liu, Melissa, Brown, Michael R, Conomos, Matthew P, Jhun, Min‐A, Chen, Ming‐Huei, de Maat, Moniek P.M., Pankratz, Nathan, Smith, Nicholas L, Peyser, Patricia A, Elliot, Paul, de Vries, Paul S, Wei, Peng, Wild, Philipp S, Morange, Pierre E, van der Harst, Pim, Yang, Qiong, Le, Ngoc‐Quynh, Marioni, Riccardo, Li, Ruifang, Damrauer, Scott M, Cox, Simon R, Trompet, Stella, Felix, Stephan B, Völker, Uwe, Tang, Weihong, Koenig, Wolfgang, Jukema, J. Wouter, Guo, Xiuqing, Lindstrom, Sara, Wang, Lu, Smith, Erin N, Gordon, William, van Hylckama Vlieg, Astrid, de Andrade, Mariza, Brody, Jennifer A, Pattee, Jack W, Haessler, Jeffrey, Brumpton, Ben M, Chasman, Daniel I, Suchon, Pierre, Chen, Ming‐Huei, Turman, Constance, Germain, Marine, Wiggins, Kerri L, MacDonald, James, Braekkan, Sigrid K, Armasu, Sebastian M, Pankratz, Nathan, Jackson, Rabecca D, Nielsen, Jonas B, Giulianini, Franco, Puurunen, Marja K, Ibrahim, Manal, Heckbert, Susan R, Bammler, Theo K, Frazer, Kelly A, McCauley, Bryan M, Taylor, Kent, Pankow, James S, Reiner, Alexander P, Gabrielsen, Maiken E, Deleuze, Jean‐François, O’Donnell, Chris J, Kim, Jihye, McKnight, Barbara, Kraft, Peter, Hansen, John‐Bjarne, Rosendaal, Frits R, Heit, John A, Psaty, Bruce M, Tang, Weihong, Kooperberg, Charles, Hveem, Kristian, Ridker, Paul M, Morange, Pierre‐Emmanuel, Johnson, Andrew D, Kabrhel, Christopher, Trégouët, David‐Alexandre, Smith, Nicholas L, Malik, Rainer, Chauhan, Ganesh, Traylor, Matthew, Sargurupremraj, Muralidharan, Okada, Yukinori, Mishra, Aniket, Rutten‐Jacobs, Loes, Giese, Anne‐Katrin, van der Laan, Sander W, Gretarsdottir, Solveig, Anderson, Christopher D, Chong, Michael, Adams, Hieab HH, Ago, Tetsuro, Almgren, Peter, Amouyel, Philippe, Ay, Hakan, Bartz, Traci M, Benavente, Oscar R, Bevan, Steve, Boncoraglio, Giorgio B, Brown, Robert D, Butterworth, Adam S, Carrera, Caty, Carty, Cara L, Chasman, Daniel I, Chen, Wei‐Min, Cole, John W, Correa, Adolfo, Cotlarciuc, Ioana, Cruchaga, Carlos, Danesh, John, de Bakker, Paul IW, DeStefano, Anita L, den Hoed, Marcel, Duan, Qing, Engelter, Stefan T, Falcone, Guido J, Gottesman, Rebecca F, Grewal, Raji P, Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeffrey, Harris, Tamara B, Hassan, Ahamad, Havulinna, Aki S, Heckbert, Susan R, Holliday, Elizabeth G, Howard, George, Hsu, Fang‐Chi, Hyacinth, Hyacinth I, Arfan Ikram, M, Ingelsson, Erik, Irvin, Marguerite R, Jian, Xueqiu, Jiménez‐Conde, Jordi, Johnson, Julie A, Jukema, J Wouter, Kanai, Masahiro, Keene, Keith L, Kissela, Brett M, Kleindorfer, Dawn O, Kooperberg, Charles, Kubo, Michiaki, Lange, Leslie A, Langefeld, Carl D, Langenberg, Claudia, Launer, Lenore J, Lee, Jin‐Moo, Lemmens, Robin, Leys, Didier, Lewis, Cathryn M, Lin, Wei‐Yu, Lindgren, Arne G, Lorentzen, Erik, Magnusson, Patrik K, Maguire, Jane, Manichaikul, Ani, McArdle, Patrick F, Meschia, James F, Mitchell, Braxton D, Mosley, Thomas H, Nalls, Michael A, Ninomiya, Toshiharu, O’Donnell, Martin J, Psaty, Bruce M, Pulit, Sara L, Rannikmäe, Kristiina, Reiner, Alexander P, Rexrode, Kathryn M, Rice, Kenneth, Rich, Stephen S, Ridker, Paul M, Rost, Natalia S, Rothwell, Peter M, Rotter, Jerome I, Rundek, Tatjana, Sacco, Ralph L, Sakaue, Saori, Sale, Michele M, Salomaa, Veikko, Sapkota, Bishwa R, Schmidt, Reinhold, Schmidt, Carsten O, Schminke, Ulf, Sharma, Pankaj, Slowik, Agnieszka, Sudlow, Cathie LM, Tanislav, Christian, Tatlisumak, Turgut, Taylor, Kent D, Thijs, Vincent NS, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tiedt, Steffen, Trompet, Stella, Tzourio, Christophe, van Duijn, Cornelia M, Walters, Matthew, Wareham, Nicholas J, Wassertheil‐Smoller, Sylvia, Wilson, James G, Wiggins, Kerri L, Yang, Qiong, Yusuf, Salim, Amin, Najaf, Aparicio, Hugo S, Arnett, Donna K, Attia, John, Beiser, Alexa S, Berr, Claudine, Buring, Julie E, Bustamante, Mariana, Caso, Valeria, Cheng, Yu‐Ching, Hoan Choi, Seung, Chowhan, Ayesha, Cullell, Natalia, Dartigues, Jean‐François, Delavaran, Hossein, Delgado, Pilar, Dörr, Marcus, Engström, Gunnar, Ford, Ian, Gurpreet, Wander S, Hamsten, Anders, Heitsch, Laura, Hozawa, Atsushi, Ibanez, Laura, Ilinca, Andreea, Ingelsson, Martin, Iwasaki, Motoki, Jackson, Rebecca D, Jood, Katarina, Jousilahti, Pekka, Kaffashian, Sara, Kalra, Lalit, Kamouchi, Masahiro, Kitazono, Takanari, Kjartansson, Olafur, Kloss, Manja, Koudstaal, Peter J, Krupinski, Jerzy, Labovitz, Daniel L, Laurie, Cathy C, Levi, Christopher R, Li, Linxin, Lind, Lars, Lindgren, Cecilia M, Lioutas, Vasileios, Mei Liu, Yong, Lopez, Oscar L, Makoto, Hirata, Martinez‐Majander, Nicolas, Matsuda, Koichi, Minegishi, Naoko, Montaner, Joan, Morris, Andrew P, Muiño, Elena, Müller‐Nurasyid, Martina, Norrving, Bo, Ogishima, Soichi, Parati, Eugenio A, Reddy Peddareddygari, Leema, Pedersen, Nancy L, Pera, Joanna, Perola, Markus, Pezzini, Alessandro, Pileggi, Silvana, Rabionet, Raquel, Riba‐Llena, Iolanda, Ribasés, Marta, Romero, Jose R, Roquer, Jaume, Rudd, Anthony G, Sarin, Antti‐Pekka, Sarju, Ralhan, Sarnowski, Chloe, Sasaki, Makoto, Satizabal, Claudia L, Satoh, Mamoru, Sattar, Naveed, Sawada, Norie, Sibolt, Gerli, Sigurdsson, Ásgeir, Smith, Albert, Sobue, Kenji, Soriano‐Tárraga, Carolina, Stanne, Tara, Colin Stine, O, Stott, David J, Strauch, Konstantin, Takai, Takako, Tanaka, Hideo, Tanno, Kozo, Teumer, Alexander, Tomppo, Liisa, Torres‐Aguila, Nuria P, Touze, Emmanuel, Tsugane, Shoichiro, Uitterlinden, Andre G, Valdimarsson, Einar M, van der Lee, Sven J, Völzke, Henry, Wakai, Kenji, Weir, David, Williams, Stephen R, Wolfe, Charles DA, Wong, Quenna, Xu, Huichun, Yamaji, Taiki, Sanghera, Dharambir K, Melander, Olle, Jern, Christina, Strbian, Daniel, Fernandez‐Cadenas, Israel, Longstreth, W T, Rolfs, Arndt, Hata, Jun, Woo, Daniel, Rosand, Jonathan, Pare, Guillaume, Hopewell, Jemma C, Saleheen, Danish, Stefansson, Kari, Worrall, Bradford B, Kittner, Steven J, Seshadri, Sudha, Fornage, Myriam, Markus, Hugh S, Howson, Joanna MM, Kamatani, Yoichiro, Debette, Stephanie, and Dichgans, Martin

Abstract

Multi‐phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes. To discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events. Summary statistics from genome wide‐association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI‐1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi‐trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85 × 10−9obtained after applying Bonferroni correction for the number of multi‐trait combinations performed (n= 27). Across the 27 multi‐trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes. The discovery of four novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits.

Published
2022
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9. Upregulation of Annexin A1 in Reactive Astrocytes and Its Subtle Induction in Microglia at the Boundaries of Human Brain Infarcts.

Author

Shijo, Masahiro, Hamasaki, Hideomi, Honda, Hiroyuki, Suzuki, Satoshi O, Tachibana, Masaki, Ago, Tetsuro, Kitazono, Takanari, Iihara, Koji, and Iwaki, Toru

Abstract

Annexin A1 (ANXA1) has multiple functions, including anti-inflammatory effects, and is thought to be neuroprotective in various pathophysiologies of the central nervous system. The importance of ANXA1 in microglia and endothelial cells in ischemic environments in the brain has been recognized, but its detailed behavior in astrocytes in the ischemic brain remains unknown. Using immunohistochemistry, we therefore assessed the altered distribution of ANXA1 in human brain infarcts using 14 autopsied samples and 18 surgical samples. Elevated expression of ANXA1 was observed in reactive astrocytes in peri-infarct regions. ANXA1 accumulated at the cell periphery and in swollen cytoplasmic processes of reactive astrocytes, as well as at the rim of vacuoles at the boundary of necrosis, and colocalized with aberrantly distributed aquaporin 4 and excitatory amino acid transporter 1. Foamy macrophages in the necrotic core also expressed abundant ANXA1, whereas resident microglia at the boundary of necrosis rarely showed intrinsic expression of ANXA1. This characteristic distribution of ANXA1 in human brain infarcts may represent the good adaptability of reactive astrocytes to ischemic damage.

Published
2019
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10. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

Author

Malik, Rainer, Chauhan, Ganesh, Traylor, Matthew, Sargurupremraj, Muralidharan, Okada, Yukinori, Mishra, Aniket, Rutten-Jacobs, Loes, Giese, Anne-Katrin, van der Laan, Sander W., Gretarsdottir, Solveig, Anderson, Christopher D., Chong, Michael, Adams, Hieab H. H., Ago, Tetsuro, Almgren, Peter, Amouyel, Philippe, Ay, Hakan, Bartz, Traci M., Benavente, Oscar R., Bevan, Steve, Boncoraglio, Giorgio B., Brown, Robert D., Butterworth, Adam S., Carrera, Caty, Carty, Cara L., Chasman, Daniel I., Chen, Wei-Min, Cole, John W., Correa, Adolfo, Cotlarciuc, Ioana, Cruchaga, Carlos, Danesh, John, de Bakker, Paul I. W., DeStefano, Anita L., den Hoed, Marcel, Duan, Qing, Engelter, Stefan T., Falcone, Guido J., Gottesman, Rebecca F., Grewal, Raji P., Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeffrey, Harris, Tamara B., Hassan, Ahamad, Havulinna, Aki S., Heckbert, Susan R., Holliday, Elizabeth G., Howard, George, Hsu, Fang-Chi, Hyacinth, Hyacinth I., Ikram, M. Arfan, Ingelsson, Erik, Irvin, Marguerite R., Jian, Xueqiu, Jiménez-Conde, Jordi, Johnson, Julie A., Jukema, J. Wouter, Kanai, Masahiro, Keene, Keith L., Kissela, Brett M., Kleindorfer, Dawn O., Kooperberg, Charles, Kubo, Michiaki, Lange, Leslie A., Langefeld, Carl D., Langenberg, Claudia, Launer, Lenore J., Lee, Jin-Moo, Lemmens, Robin, Leys, Didier, Lewis, Cathryn M., Lin, Wei-Yu, Lindgren, Arne G., Lorentzen, Erik, Magnusson, Patrik K., Maguire, Jane, Manichaikul, Ani, McArdle, Patrick F., Meschia, James F., Mitchell, Braxton D., Mosley, Thomas H., Nalls, Michael A., Ninomiya, Toshiharu, O’Donnell, Martin J., Psaty, Bruce M., Pulit, Sara L., Rannikmäe, Kristiina, Reiner, Alexander P., Rexrode, Kathryn M., Rice, Kenneth, Rich, Stephen S., Ridker, Paul M., Rost, Natalia S., Rothwell, Peter M., Rotter, Jerome I., Rundek, Tatjana, Sacco, Ralph L., Sakaue, Saori, Sale, Michele M., Salomaa, Veikko, Sapkota, Bishwa R., Schmidt, Reinhold, Schmidt, Carsten O., Schminke, Ulf, Sharma, Pankaj, Slowik, Agnieszka, Sudlow, Cathie L. M., Tanislav, Christian, Tatlisumak, Turgut, Taylor, Kent D., Thijs, Vincent N. S., Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tiedt, Steffen, Trompet, Stella, Tzourio, Christophe, van Duijn, Cornelia M., Walters, Matthew, Wareham, Nicholas J., Wassertheil-Smoller, Sylvia, Wilson, James G., Wiggins, Kerri L., Yang, Qiong, Yusuf, Salim, Bis, Joshua C., Pastinen, Tomi, Ruusalepp, Arno, Schadt, Eric E., Koplev, Simon, Björkegren, Johan L. M., Codoni, Veronica, Civelek, Mete, Smith, Nicholas L., Trégouët, David A., Christophersen, Ingrid E., Roselli, Carolina, Lubitz, Steven A., Ellinor, Patrick T., Tai, E. Shyong, Kooner, Jaspal S., Kato, Norihiro, He, Jiang, van der Harst, Pim, Elliott, Paul, Chambers, John C., Takeuchi, Fumihiko, Johnson, Andrew D., Sanghera, Dharambir K., Melander, Olle, Jern, Christina, Strbian, Daniel, Fernandez-Cadenas, Israel, Longstreth, W. T., Rolfs, Arndt, Hata, Jun, Woo, Daniel, Rosand, Jonathan, Pare, Guillaume, Hopewell, Jemma C., Saleheen, Danish, Stefansson, Kari, Worrall, Bradford B., Kittner, Steven J., Seshadri, Sudha, Fornage, Myriam, Markus, Hugh S., Howson, Joanna M. M., Kamatani, Yoichiro, Debette, Stephanie, and Dichgans, Martin

Abstract

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n= 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

Published
2018
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11. Association Between Onset-to-Door Time and Clinical Outcomes After Ischemic Stroke

Author

Matsuo, Ryu, Yamaguchi, Yuko, Matsushita, Tomonaga, Hata, Jun, Kiyuna, Fumi, Fukuda, Kenji, Wakisaka, Yoshinobu, Kuroda, Junya, Ago, Tetsuro, Kitazono, Takanari, Kamouchi, Masahiro, Ishitsuka, Takao, Ibayashi, Setsuro, Kusuda, Kenji, Fujii, Kenichiro, Nagao, Tetsuhiko, Okada, Yasushi, Yasaka, Masahiro, Ooboshi, Hiroaki, Irie, Katsumi, Omae, Tsuyoshi, Toyoda, Kazunori, Nakane, Hiroshi, Sugimori, Hiroshi, Arakawa, Shuji, Tetsuro, Ago, Kitayama, Jiro, Fujimoto, Shigeru, Arihiro, Shoji, and Fukushima, Yoshihisa

Abstract

Supplemental Digital Content is available in the text.

Published
2017
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13. Genetic Predisposition to Ischemic Stroke

Author

Hachiya, Tsuyoshi, Kamatani, Yoichiro, Takahashi, Atsushi, Hata, Jun, Furukawa, Ryohei, Shiwa, Yuh, Yamaji, Taiki, Hara, Megumi, Tanno, Kozo, Ohmomo, Hideki, Ono, Kanako, Takashima, Naoyuki, Matsuda, Koichi, Wakai, Kenji, Sawada, Norie, Iwasaki, Motoki, Yamagishi, Kazumasa, Ago, Tetsuro, Ninomiya, Toshiharu, Fukushima, Akimune, Hozawa, Atsushi, Minegishi, Naoko, Satoh, Mamoru, Endo, Ryujin, Sasaki, Makoto, Sakata, Kiyomi, Kobayashi, Seiichiro, Ogasawara, Kuniaki, Nakamura, Motoyuki, Hitomi, Jiro, Kita, Yoshikuni, Tanaka, Keitaro, Iso, Hiroyasu, Kitazono, Takanari, Kubo, Michiaki, Tanaka, Hideo, Tsugane, Shoichiro, Kiyohara, Yutaka, Yamamoto, Masayuki, Sobue, Kenji, and Shimizu, Atsushi

Abstract

Supplemental Digital Content is available in the text.

Published
2017
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15. Association between stroke-like episodes and neuronal hyperexcitability in MELAS with m.3243A>G: A case report

Author

Sakai, Shota, Osaki, Masato, Hidaka, Masaoki, Kimura, Shunsuke, Ohya, Yuichiro, Ago, Tetsuro, Kitazono, Takanari, and Arakawa, Shuji

Abstract

•The pathophysiology of the stroke-like episodes of MELAS has not completely been elucidated.•Here we report a case of stroke-like episodes, successfully treated with levetiracetam.•Neuronal hyperexcitability can be the underlying mechanism of stroke-like episodes in MELAS.

Published
2018
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16. Day-by-Day Blood Pressure Variability and Functional Outcome After Acute Ischemic Stroke

Author

Fukuda, Kenji, Kai, Hisashi, Kamouchi, Masahiro, Hata, Jun, Ago, Tetsuro, Nakane, Hiroshi, Imaizumi, Tsutomu, Kitazono, Takanari, Ishitsuka, Takao, Fujimoto, Shigeru, Ibayashi, Setsuro, Kusuda, Kenji, Arakawa, Shuji, Irie, Katsumi, Fujii, Kenichiro, Okada, Yasushi, Yasaka, Masahiro, Nagao, Tetsuhiko, Ooboshi, Hiroaki, Omae, Tsuyoshi, Toyoda, Kazunori, Sugimori, Hiroshi, Kuroda, Junya, Wakisaka, Yoshinobu, Matsuo, Ryu, and Fukushima, Yoshihisa

Abstract

The relationship between blood pressure (BP) variability and functional outcome in patients with acute ischemic stroke remains unclear. This study aimed to elucidate whether in-hospital day-by-day BP variability is associated with functional outcome after acute ischemic stroke.

Published
2015
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17. Sex Differences in Short-Term Outcomes After Acute Ischemic Stroke

Author

Irie, Fumi, Kamouchi, Masahiro, Hata, Jun, Matsuo, Ryu, Wakisaka, Yoshinobu, Kuroda, Junya, Ago, Tetsuro, Kitazono, Takanari, Ishitsuka, Takao, Fujimoto, Shigeru, Ibayashi, Setsuro, Kusuda, Kenji, Arakawa, Shuji, Tamaki, Kinya, Sadoshima, Seizo, Irie, Katsumi, Fujii, Kenichiro, Okada, Yasushi, Yasaka, Masahiro, Nagao, Tetsuhiko, Ooboshi, Hiroaki, Omae, Tsuyoshi, Toyoda, Kazunori, Nakane, Hiroshi, Sugimori, Hiroshi, Fukuda, Kenji, and Fukushima, Yoshihisa

Abstract

Variable sex differences in clinical outcomes after stroke have been reported worldwide. This study aimed to elucidate whether sex is an independent risk factor of poor functional outcome after acute ischemic stroke.

Published
2015
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18. Thrombolytic therapy for stroke in patients with preexisting cognitive impairment

Author

Murao, Kei, Leys, Didier, Jacquin, Agnès, Kitazono, Takanari, Bordet, Régis, Béjot, Yannick, Kimura, Kazumi, Godefroy, Olivier, Wakisaka, Yoshinobu, Moulin, Solène, Ago, Tetsuro, Sibon, Igor, Bombois, Stéphanie, Mas, Jean-Louis, Hénon, Hilde, Pasquier, Florence, Giroud, Maurice, Cordonnier, Charlotte, and Okada, Yasushi

Abstract

We aimed to evaluate the influence of prestroke cognitive impairment (PSCI) on outcomes in stroke patients treated with IV recombinant tissue plasminogen activator (rtPA).

Published
2014
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19. ABCD3 and ABCD3-I Scores Are Superior to ABCD2 Score in the Prediction of Short- and Long-Term Risks of Stroke After Transient Ischemic Attack

Author

Kiyohara, Takuya, Kamouchi, Masahiro, Kumai, Yasuhiro, Ninomiya, Toshiharu, Hata, Jun, Yoshimura, Sohei, Ago, Tetsuro, Okada, Yasushi, Kitazono, Takanari, Ishitsuka, Takao, Fujimoto, Shigeru, Ibayashi, Setsuro, Kusuda, Kenji, Arakawa, Shuji, Tamaki, Kinya, Sadoshima, Seizo, Irie, Katsumi, Fujii, Kenichiro, Okada, Yasushi, Yasaka, Masahiro, Nagao, Tetsuhiko, Ooboshi, Hiroaki, Omae, Tsuyoshi, Toyoda, Kazunori, Nakane, Hiroshi, Sugimori, Hiroshi, Fukuda, Kenji, Matsuo, Ryu, Kuroda, Junya, and Fukushima, Yoshihisa

Abstract

Several risk scores have been developed to predict the stroke risk after transient ischemic attack (TIA). However, the validation of these scores in different cohorts is still limited. The objective of this study was to elucidate whether these scores were able to predict short-term and long-term risks of stroke in patients with TIA.

Published
2014
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20. Intensity of Anticoagulation and Clinical Outcomes in Acute Cardioembolic Stroke

Author

Nakamura, Asako, Ago, Tetsuro, Kamouchi, Masahiro, Hata, Jun, Matsuo, Ryu, Kuroda, Junya, Kuwashiro, Takahiro, Sugimori, Hiroshi, and Kitazono, Takanari

Abstract

The relationship between the intensity of anticoagulation at the onset of acute cardioembolic stroke and clinical outcome after stroke is unclear. Here, we elucidated the relationship between prothrombin time–international normalized ratio (PT-INR) values on admission and clinical outcomes in patients with acute cardioembolic stroke.

Published
2013
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21. PDGF Receptor Signaling in Pericytes Following Ischemic Brain Injury

Author

Arimura, Koichi, Ago, Tetsuro, Kamouchi, Masahiro, Nakamura, Kuniyuki, Ishitsuka, Koji, Kuroda, Junya, Sugimori, Hiroshi, Ooboshi, Hiroaki, Sasaki, Tomio, and Kitazono, Takanari

Abstract

Platelet derived growth factor (PDGF)-B plays a neuroprotective role in brain damages, including ischemic stroke. It has been suggested recently that PDGF receptor (PDGFR) expressed in brain pericytes as well as in neurons and astrocytes may mediate the neuroprotective role of PDGF-B. The aims of this study were to elucidate the roles of PDGFR signaling in brain pericytes after ischemic stroke. In a rat middle cerebral artery occlusion (MCAO) model, PDGFR expression was induced specifically in the pericytes in peri-infarct areas and its level was gradually increased. PDGF-B induced marked phosphorylation of Akt in cultured brain pericytes. Consistently, PDGF-B was upregulated in endothelial cells in per-infarct areas and Akt was strongly phosphorylated in the PDGFR-expressing pericytes in periinfarct areas after MCAO. In the cultured pericytes, PDGF-B induced cell growth and anti-apoptotic responses through Akt. Furthermore, PDGF-B significantly increased the expression of nerve growth factor (NGF) and neurotrophin-3 (NT- 3) through Akt in the pericytes. Thus, the PDGFR-Akt signaling in brain pericytes may play various important roles leading to neuroprotection after ischemic stroke.

Published
2012

22. Prestroke Glycemic Control Is Associated With the Functional Outcome in Acute Ischemic Stroke

Author

Kamouchi, Masahiro, Matsuki, Takayuki, Hata, Jun, Kuwashiro, Takahiro, Ago, Tetsuro, Sambongi, Yoshiki, Fukushima, Yoshihisa, Sugimori, Hiroshi, and Kitazono, Takanari

Abstract

Diabetes mellitus is an established risk factor for stroke. However, it is uncertain whether prestroke glycemic control (PSGC) status affects clinical outcomes of acute ischemic stroke. The aim of this study was to elucidate the association between PSGC status and neurological or functional outcomes in patients with acute ischemic stroke.

Published
2011
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24. Elucidation of Thioredoxin Target Protein Networks in Mouse

Author

Fu, Cexiong, Wu, Changgong, Liu, Tong, Ago, Tetsuro, Zhai, Peiyong, Sadoshima, Junichi, and Li, Hong

Abstract

Thioredoxin 1 (Trx1) is a key redox modulator that is functionally conserved across a wide range of species, including plants, bacteria, and mammals. Using a conserved CXXC motif, Trx1 catalyzes the reduction of cysteine disulfides and S-nitrosothiols. In contrast to small molecular reductants such as glutathione and cysteine that can reduce a wide range of oxidized proteins, Trx1 reduces only selected proteins via specific protein-protein interaction. Trx1 has been shown to regulate numerous signal transduction pathways, and its dysfunctions have been implicated in several diseases, including cancer, inflammation, and neurodegenerative and cardiovascular diseases. Identification of Trx1 target proteins may help to identify novel signaling mechanisms that are important for Trx1 antistress responses. In this study, we performed an ICAT proteomics study for the identification of Trx1 target proteins from the hearts of a cardiac specific Trx1-overexpressing transgenic mouse model (Tg-Trx1). Trx1-reduced proteins were distinguished from Trx1-induced proteins by comparison of the ICAT results with those obtained using a parallel iTRAQ (isobaric tags for relative and absolute quantitation) protein expression analysis. We were able to identify 78 putative Trx1 reductive sites in 55 proteins. Interestingly we identified a few protein functional networks that had not been shown previously to be regulated by Trx1, including the creatine-phosphocreatine shuttle, the mitochondrial permeability transition pore complex, and the cardiac contractile apparatus. The results presented here suggest that in addition to a general antioxidant function, Trx1 may be involved in the coordination of a wide array of cellular functions for maintaining proper cardiac energy dynamics and facilitating muscle contraction.

Published
2009

25. Elucidation of Thioredoxin Target Protein Networks in Mouse*

Author

Fu, Cexiong, Wu, Changgong, Liu, Tong, Ago, Tetsuro, Zhai, Peiyong, Sadoshima, Junichi, and Li, Hong

Abstract

Thioredoxin 1 (Trx1) is a key redox modulator that is functionally conserved across a wide range of species, including plants, bacteria, and mammals. Using a conserved CXXC motif, Trx1 catalyzes the reduction of cysteine disulfides and S-nitrosothiols. In contrast to small molecular reductants such as glutathione and cysteine that can reduce a wide range of oxidized proteins, Trx1 reduces only selected proteins via specific protein-protein interaction. Trx1 has been shown to regulate numerous signal transduction pathways, and its dysfunctions have been implicated in several diseases, including cancer, inflammation, and neurodegenerative and cardiovascular diseases. Identification of Trx1 target proteins may help to identify novel signaling mechanisms that are important for Trx1 antistress responses. In this study, we performed an ICAT proteomics study for the identification of Trx1 target proteins from the hearts of a cardiac specific Trx1-overexpressing transgenic mouse model (Tg-Trx1). Trx1-reduced proteins were distinguished from Trx1-induced proteins by comparison of the ICAT results with those obtained using a parallel iTRAQ (isobaric tags for relative and absolute quantitation) protein expression analysis. We were able to identify 78 putative Trx1 reductive sites in 55 proteins. Interestingly we identified a few protein functional networks that had not been shown previously to be regulated by Trx1, including the creatine-phosphocreatine shuttle, the mitochondrial permeability transition pore complex, and the cardiac contractile apparatus. The results presented here suggest that in addition to a general antioxidant function, Trx1 may be involved in the coordination of a wide array of cellular functions for maintaining proper cardiac energy dynamics and facilitating muscle contraction.

Published
2009
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26. Publisher Correction: Stroke genetics informs drug discovery and risk prediction across ancestries

Author

Mishra, Aniket, Malik, Rainer, Hachiya, Tsuyoshi, Jürgenson, Tuuli, Namba, Shinichi, Posner, Daniel C., Kamanu, Frederick K., Koido, Masaru, Le Grand, Quentin, Shi, Mingyang, He, Yunye, Georgakis, Marios K., Caro, Ilana, Krebs, Kristi, Liaw, Yi-Ching, Vaura, Felix C., Lin, Kuang, Winsvold, Bendik Slagsvold, Srinivasasainagendra, Vinodh, Parodi, Livia, Bae, Hee-Joon, Chauhan, Ganesh, Chong, Michael R., Tomppo, Liisa, Akinyemi, Rufus, Roshchupkin, Gennady V., Habib, Naomi, Jee, Yon Ho, Thomassen, Jesper Qvist, Abedi, Vida, Cárcel-Márquez, Jara, Nygaard, Marianne, Leonard, Hampton L., Yang, Chaojie, Yonova-Doing, Ekaterina, Knol, Maria J., Lewis, Adam J., Judy, Renae L., Ago, Tetsuro, Amouyel, Philippe, Armstrong, Nicole D., Bakker, Mark K., Bartz, Traci M., Bennett, David A., Bis, Joshua C., Bordes, Constance, Børte, Sigrid, Cain, Anael, Ridker, Paul M., Cho, Kelly, Chen, Zhengming, Cruchaga, Carlos, Cole, John W., de Jager, Phil L., de Cid, Rafael, Endres, Matthias, Ferreira, Leslie E., Geerlings, Mirjam I., Gasca, Natalie C., Gudnason, Vilmundur, Hata, Jun, He, Jing, Heath, Alicia K., Ho, Yuk-Lam, Havulinna, Aki S., Hopewell, Jemma C., Hyacinth, Hyacinth I., Inouye, Michael, Jacob, Mina A., Jeon, Christina E., Jern, Christina, Kamouchi, Masahiro, Keene, Keith L., Kitazono, Takanari, Kittner, Steven J., Konuma, Takahiro, Kumar, Amit, Lacaze, Paul, Launer, Lenore J., Lee, Keon-Joo, Lepik, Kaido, Li, Jiang, Li, Liming, Manichaikul, Ani, Markus, Hugh S., Marston, Nicholas A., Meitinger, Thomas, Mitchell, Braxton D., Montellano, Felipe A., Morisaki, Takayuki, Mosley, Thomas H., Nalls, Mike A., Nordestgaard, Børge G., O’Donnell, Martin J., Okada, Yukinori, Onland-Moret, N. Charlotte, Ovbiagele, Bruce, Peters, Annette, Psaty, Bruce M., Rich, Stephen S., Rosand, Jonathan, Sabatine, Marc S., Sacco, Ralph L., Saleheen, Danish, Sandset, Else Charlotte, Salomaa, Veikko, Sargurupremraj, Muralidharan, Sasaki, Makoto, Satizabal, Claudia L., Schmidt, Carsten O., Shimizu, Atsushi, Smith, Nicholas L., Sloane, Kelly L., Sutoh, Yoichi, Sun, Yan V., Tanno, Kozo, Tiedt, Steffen, Tatlisumak, Turgut, Torres-Aguila, Nuria P., Tiwari, Hemant K., Trégouët, David-Alexandre, Trompet, Stella, Tuladhar, Anil Man, Tybjærg-Hansen, Anne, van Vugt, Marion, Vibo, Riina, Verma, Shefali S., Wiggins, Kerri L., Wennberg, Patrik, Woo, Daniel, Wilson, Peter W. F., Xu, Huichun, Yang, Qiong, Yoon, Kyungheon, Millwood, Iona Y., Gieger, Christian, Ninomiya, Toshiharu, Grabe, Hans J., Jukema, J. Wouter, Rissanen, Ina L., Strbian, Daniel, Kim, Young Jin, Chen, Pei-Hsin, Mayerhofer, Ernst, Howson, Joanna M. M., Irvin, Marguerite R., Adams, Hieab, Wassertheil-Smoller, Sylvia, Christensen, Kaare, Ikram, Mohammad A., Rundek, Tatjana, Worrall, Bradford B., Lathrop, G. Mark, Riaz, Moeen, Simonsick, Eleanor M., Kõrv, Janika, França, Paulo H. C., Zand, Ramin, Prasad, Kameshwar, Frikke-Schmidt, Ruth, de Leeuw, Frank-Erik, Liman, Thomas, Haeusler, Karl Georg, Ruigrok, Ynte M., Heuschmann, Peter Ulrich, Longstreth, W. T., Jung, Keum Ji, Bastarache, Lisa, Paré, Guillaume, Damrauer, Scott M., Chasman, Daniel I., Rotter, Jerome I., Anderson, Christopher D., Zwart, John-Anker, Niiranen, Teemu J., Fornage, Myriam, Liaw, Yung-Po, Seshadri, Sudha, Fernández-Cadenas, Israel, Walters, Robin G., Ruff, Christian T., Owolabi, Mayowa O., Huffman, Jennifer E., Milani, Lili, Kamatani, Yoichiro, Dichgans, Martin, and Debette, Stephanie

Published
2022
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27. Molecular mechanisms and physiological significance of autophagy during myocardial ischemia and reperfusion

Author

Matsui, Yutaka, Kyoi, Shiori, Takagi, Hiromitsu, Hsu, Chiao-Po, Hariharan, Nirmala, Ago, Tetsuro, Vatner, Stephen F., and Sadoshima, Junichi

Abstract

Autophagy is an intracellular bulk degradation process whereby cytoplasmic proteins and organelles are degraded and recycled through lysosomes. In the heart, autophagy plays a homeostatic role at basal levels, and the absence of autophagy causes cardiac dysfunction and the development of cardiomyopathy. Autophagy is induced during myocardial ischemia and further enhanced by reperfusion. Although induction of autophagy during the ischemic phase is protective, further enhancement of autophagy during the reperfusion phase may induce cell death and appears to be detrimental. In this review we discuss the functional significance of autophagy and the underlying signaling mechanism in the heart during ischemia/reperfusion.

Published
2008
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28. Thioredoxin1 Upregulates Mitochondrial Proteins Related to Oxidative Phosphorylation and TCA Cycle in the Heart

Author

Ago, Tetsuro, Yeh, Ijen, Yamamoto, Mitsutaka, Schinke-Braun, Martina, Brown, Jeffrey A., Tian, Bin, and Sadoshima, Junichi

Abstract

Thioredoxin1 (Trx1) inhibits hypertrophy and exhibits protective functions in the heart. To elucidate further the cardiac functions of Trx1, we used a DNA microarray analysis, with hearts from transgenic mice with cardiac- specific overexpression of Trx1 (Tg-Trx1, n= 4) and nontransgenic controls (n= 4). Expression of a large number of genes is regulated in Tg-Trx1, with a greater number of genes downregulated, versus upregulated, at high-fold changes. The peroxisome proliferator–activated receptor γγcoactivator-1αα (PGC-1αα) gene was among the top 50 significantly upregulated genes. By pathway analyses, we found that genes involved in both mitochondrial oxidative phosphorylation and the TCA cycle were upregulated in Tg-Trx1. We confirmed upregulation of cytochrome coxidase (COX) components and mitochondrial transcription factor A in Tg-Trx1. The activity of citrate synthase and COX and the cardiac ATP content were significantly higher in Tg-Trx1. A transcription factor binding-site analysis showed that upregulated genes frequently contained binding sites for nuclear respiratory factor 1 (NRF1). Expression of NRF1 and PGC-1αα was upregulated in Tg-Trx1, and Trx1 stimulated the transcriptional activity of NRF1 and NRF2 in cardiac myocytes. These results suggest that, in cardiac myocytes, Trx1 upregulates mitochondrial proteins and enhances mitochondrial functions, possibly through PGC-1αα and NRFs.

Published
2006
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29. Chronic administration of a tyrosine kinase inhibitor restores functional and morphological changes of the basilar artery during chronic hypertension

Author

Kitayama, Jiro, Kitazono, Takanari, Ooboshi, Hiroaki, Ago, Tetsuro, Ohgami, Tetsuya, Fujishima, Masatoshi, and Ibayashi, Setsuro

Abstract

Activation of tyrosine kinase appears to play an important role in pathogenesis of cardiovascular disease during chronic hypertension. In the present study, we tested the hypothesis that long-term treatment with an inhibitor of tyrosine kinase would have beneficial effects on hypertension-induced morphological and functional changes of the cerebral artery.

Published
2002

30. Increased activity of calcium channels and Rho-associated kinase in the basilar artery during chronic hypertension in vivo

Author

Kitazono, Takanari, Ago, Tetsuro, Kamouchi, Masahiro, Santa, Naohiko, Ooboshi, Hiroaki, Fujishima, Masatoshi, and Ibayashi, Setsuro

Abstract

Several factors mediating vascular responses appear to play an important role in the increased resistance of cerebral blood vessels during hypertension. The objective of this study was to elucidate the mechanisms by which hypertension increases the basal tone of the basilar artery in vivo.

Published
2002

31. The PX Domain as a Novel Phosphoinositide- Binding Module

Author

Ago, Tetsuro, Takeya, Ryu, Hiroaki, Hidekazu, Kuribayashi, Futoshi, Ito, Takashi, Kohda, Daisuke, and Sumimoto, Hideki

Abstract

The phox (phagocyte oxidase) homology (PX) domain occurs in the mammalian phox proteins p40phox and p47phox, the polarity establishment protein Bem1p in budding yeast, and a variety of proteins involved in membrane trafficking. Here we show that the PX domains of p40phox and p47phox directly bind to phosphoinositides: p40phox prefers Ptdlns(3)P, while p47phox does Ptdlns(4)P and Ptdlns(3,4)P2. In addition, the Bem1p PX domain also interacts with Ptdlns(4)P. When the p40phox PX domain is expressed as a fusion to green fluorescent protein in HeLa cells, it exists at early endosomes where Ptdlns(3)P is enriched. Furthermore, a mutant p40phox PX carrying the substitution of Lys for Arg105 only weakly binds to phosphoinositides in vitro, and fails to locate to early endosomes. Thus the PX domain functions as a novel phosphoinositide-binding module and likely participates in targeting of proteins to membranes.

Published
2001
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32. Solution structure of the PX domain, a target of the SH3 domain

Author

Hiroaki, Hidekazu, Ago, Tetsuro, Ito, Takashi, Sumimoto, Hideki, and Kohda, Daisuke

Abstract

The phox homology (PX) domain is a novel protein module containing a conserved proline-rich motif. We have shown that the PX domain isolated from the human p47phoxprotein, a soluble subunit of phagocyte NADPH oxidase, binds specifically to the C-terminal SH3 domain derived from the same protein. The solution structure of p47 PX has an α + β structure with a novel folding motif topology and reveals that the proline-rich motif is presented on the molecular surface for easy recognition by the SH3 domain. The proline-rich motif of p47 PX in the free state adopts a distorted left-handed polyproline type II helix conformation.

Published
2001
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33. Mechanism for Phosphorylation-induced Activation of the Phagocyte NADPH Oxidase Protein p47 phox

Author

Ago, Tetsuro, Nunoi, Hiroyuki, Ito, Takashi, and Sumimoto, Hideki

Abstract

Activation of the superoxide-producing phagocyte NADPH oxidase requires interaction between p47 phoxand p22 phox, which is mediated via the SH3 domains of the former protein. This interaction is considered to be induced by exposure of the domains that are normally masked by an intramolecular interaction with the C-terminal region of p47 phox. Here we locate the intramolecular SH3-binding site at the region of amino acid residues 286–340, where Ser-303, Ser-304, and Ser-328 that are among several serines known to become phosphorylated upon cell stimulation exist. Simultaneous replacement of the three serines in p47 phoxwith aspartates or glutamates, each mimicking phosphorylated residues, is sufficient for disruption of the intramolecular interaction and resultant access to p22 phox. The triply mutated proteins are also capable of activating the NADPH oxidase without in vitroactivators such as arachidonate under cell-free conditions. In a whole-cell system where expression of the wild-type p47 phoxreconstitutes the stimulus-dependent oxidase activity, substitution of the kinase-insensitive residue alanine for Ser-328 as well as for Ser-303/Ser-304 leads to a defective production of superoxide. These findings suggest that phosphorylation of the three serines in p47 phoxinduces a conformational change to a state accessible to p22 phox, thereby activating the NADPH oxidase.

Published
1999
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34. Publisher Correction: Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

Author

Malik, Rainer, Chauhan, Ganesh, Traylor, Matthew, Sargurupremraj, Muralidharan, Okada, Yukinori, Mishra, Aniket, Rutten-Jacobs, Loes, Giese, Anne-Katrin, Laan, Sander, Gretarsdottir, Solveig, Anderson, Christopher, Chong, Michael, Adams, Hieab, Ago, Tetsuro, Almgren, Peter, Amouyel, Philippe, Ay, Hakan, Bartz, Traci, Benavente, Oscar, Bevan, Steve, Boncoraglio, Giorgio, Brown, Robert, Butterworth, Adam, Carrera, Caty, Carty, Cara, Chasman, Daniel, Chen, Wei-Min, Cole, John, Correa, Adolfo, Cotlarciuc, Ioana, Cruchaga, Carlos, Danesh, John, Bakker, Paul, DeStefano, Anita, Hoed, Marcel, Duan, Qing, Engelter, Stefan, Falcone, Guido, Gottesman, Rebecca, Grewal, Raji, Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeffrey, Harris, Tamara, Hassan, Ahamad, Havulinna, Aki, Heckbert, Susan, Holliday, Elizabeth, Howard, George, Hsu, Fang-Chi, Hyacinth, Hyacinth, Ikram, M., Ingelsson, Erik, Irvin, Marguerite, Jian, Xueqiu, Jiménez-Conde, Jordi, Johnson, Julie, Jukema, J., Kanai, Masahiro, Keene, Keith, Kissela, Brett, Kleindorfer, Dawn, Kooperberg, Charles, Kubo, Michiaki, Lange, Leslie, Langefeld, Carl, Langenberg, Claudia, Launer, Lenore, Lee, Jin-Moo, Lemmens, Robin, Leys, Didier, Lewis, Cathryn, Lin, Wei-Yu, Lindgren, Arne, Lorentzen, Erik, Magnusson, Patrik, Maguire, Jane, Manichaikul, Ani, McArdle, Patrick, Meschia, James, Mitchell, Braxton, Mosley, Thomas, Nalls, Michael, Ninomiya, Toshiharu, O’Donnell, Martin, Psaty, Bruce, Pulit, Sara, Rannikmäe, Kristiina, Reiner, Alexander, Rexrode, Kathryn, Rice, Kenneth, Rich, Stephen, Ridker, Paul, Rost, Natalia, Rothwell, Peter, Rotter, Jerome, Rundek, Tatjana, Sacco, Ralph, Sakaue, Saori, Sale, Michele, Salomaa, Veikko, Sapkota, Bishwa, Schmidt, Reinhold, Schmidt, Carsten, Schminke, Ulf, Sharma, Pankaj, Slowik, Agnieszka, Sudlow, Cathie, Tanislav, Christian, Tatlisumak, Turgut, Taylor, Kent, Thijs, Vincent, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tiedt, Steffen, Trompet, Stella, Tzourio, Christophe, Duijn, Cornelia, Walters, Matthew, Wareham, Nicholas, Wassertheil-Smoller, Sylvia, Wilson, James, Wiggins, Kerri, Yang, Qiong, Yusuf, Salim, Bis, Joshua, Pastinen, Tomi, Ruusalepp, Arno, Schadt, Eric, Koplev, Simon, Björkegren, Johan, Codoni, Veronica, Civelek, Mete, Smith, Nicholas, Trégouët, David, Christophersen, Ingrid, Roselli, Carolina, Lubitz, Steven, Ellinor, Patrick, Tai, E., Kooner, Jaspal, Kato, Norihiro, He, Jiang, Harst, Pim, Elliott, Paul, Chambers, John, Takeuchi, Fumihiko, Johnson, Andrew, Sanghera, Dharambir, Melander, Olle, Jern, Christina, Strbian, Daniel, Fernandez-Cadenas, Israel, Longstreth, W., Rolfs, Arndt, Hata, Jun, Woo, Daniel, Rosand, Jonathan, Pare, Guillaume, Hopewell, Jemma, Saleheen, Danish, Stefansson, Kari, Worrall, Bradford, Kittner, Steven, Seshadri, Sudha, Fornage, Myriam, Markus, Hugh, Howson, Joanna, Kamatani, Yoichiro, Debette, Stephanie, and Dichgans, Martin

Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2019
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35. Carotid artery stenting for carotid web resistant to medical treatment

Author

Ono, Kotaro, Arimura, Koichi, Nishimura, Ataru, Iwaki, Katsuma, Okuda, Tomohiro, Ago, Tetsuro, and Iihara, Koji

Abstract

•Carotid web, a risk factor for ischemic stroke, is a nonatherosclerotic abnormality located in the posterior wall of the proximal internal carotid artery.•The optimal treatment strategy is still controversial for Carotid web.•In our presented case, cerebral infarction recurred despite medical treatment, but carotid artery stenting was successful.•Carotid revascularization with stenting might be a potential treatment option for the patient with carotid web resistant to medical treatment.

Published
2021
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36. Relationship Between Asian Dust and Ischemic Stroke

Author

Kamouchi, Masahiro, Ueda, Kayo, Ago, Tetsuro, Nitta, Hiroshi, and Kitazono, Takanari

Abstract

Particulate matter is increasingly recognized as a cause of human diseases, including cardiovascular diseases. However, the association between Asian dust (AD), a windblown sand dust originating from mineral soil in the deserts of China and Mongolia, and the incidence of cardiovascular diseases is unclear. The aim of the present study was to elucidate whether AD is associated with the incidence of ischemic stroke.

Published
2012
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37. A CADASIL-Like Case with a Novel Noncysteine Mutation of the NOTCH3 Gene and Granular Deposits in the Renal Arterioles

Author

Nakamura, Kuniyuki, Ago, Tetsuro, Tsuchimoto, Akihiro, Noda, Nozomi, Nakamura, Asako, Ninomiya, Toshiharu, Uchiumi, Takeshi, Tsuruya, Kazuhiko, Kamouchi, Masahiro, Ooboshi, Hiroaki, and Kitazono, Takanari

Abstract

We herein report the finding of a 62-year-old male, who developed dysarthria and dysphagia, with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy- (CADASIL-) like cerebral lesions. He also suffered from slowly progressive renal failure with the findings of granular deposits similar to electron-dense granular osmiophilic material in the renal arterioles. We found a novel heterozygous missense mutation of the NOTCH3 gene, c.4039G>C in exon 24, resulting in a p.Gly1347Arg substitution in its extracellular domain. The noncysteine substitution may underlie the pathogenesis of white matter lesions in the brain and of the chronic renal failure in the present case.

Published
2015
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