25 results on '"Vives-Bauza C"'
Search Results
2. Aproximación al conocimiento de las bases genéticas del ictus. Consorcio español de genética del ictus
- Author
-
Giralt-Steinhauer, E., Jiménez-Conde, J., Soriano Tárraga, C., Mola, M., Rodríguez-Campello, A., Cuadrado-Godia, E., Ois, A., Fernández-Cádenas, I., Carrera, C., Montaner, J., Díaz Navarro, R.M., Vives-Bauzá, C., and Roquer, J. more...
- Published
- 2014
- Full Text
- View/download PDF
Catalog
3. Stroke genetics informs drug discovery and risk prediction across ancestries
- Author
-
Mishra, A, Malik, R, Hachiya, T, Jurgenson, T, Namba, S, Posner, DC, Kamanu, FK, Koido, M, Le Grand, Q, Shi, M, He, Y, Georgakis, MK, Caro, I, Krebs, K, Liaw, Y-C, Vaura, FC, Lin, K, Winsvold, BS, Srinivasasainagendra, V, Parodi, L, Bae, H-J, Chauhan, G, Chong, MR, Tomppo, L, Akinyemi, R, Roshchupkin, GV, Habib, N, Jee, YH, Thomassen, JQ, Abedi, V, Carcel-Marquez, J, Nygaard, M, Leonard, HL, Yang, C, Yonova-Doing, E, Knol, MJ, Lewis, AJ, Judy, RL, Ago, T, Amouyel, P, Armstrong, ND, Bakker, MK, Bartz, TM, Bennett, DA, Bis, JC, Bordes, C, Borte, S, Cain, A, Ridker, PM, Cho, K, Chen, Z, Cruchaga, C, Cole, JW, de Jager, PL, de Cid, R, Endres, M, Ferreira, LE, Geerlings, MI, Gasca, NC, Gudnason, V, Hata, J, He, J, Heath, AK, Ho, Y-L, Havulinna, AS, Hopewell, JC, Hyacinth, HI, Inouye, M, Jacob, MA, Jeon, CE, Jern, C, Kamouchi, M, Keene, KL, Kitazono, T, Kittner, SJ, Konuma, T, Kumar, A, Lacaze, P, Launer, LJ, Lee, K-J, Lepik, K, Li, J, Li, L, Manichaikul, A, Markus, HS, Marston, NA, Meitinger, T, Mitchell, BD, Montellano, FA, Morisaki, T, Mosley, TH, Nalls, MA, Nordestgaard, BG, O'Donnell, MJ, Okada, Y, Onland-Moret, NC, Ovbiagele, B, Peters, A, Psaty, BM, Rich, SS, Rosand, J, Sabatine, MS, Sacco, RL, Saleheen, D, Sandset, EC, Salomaa, V, Sargurupremraj, M, Sasaki, M, Satizabal, CL, Schmidt, CO, Shimizu, A, Smith, NL, Sloane, KL, Sutoh, Y, Sun, YV, Tanno, K, Tiedt, S, Tatlisumak, T, Torres-Aguila, NP, Tiwari, HK, Tregouet, D-A, Trompet, S, Tuladhar, AM, Tybjaerg-Hansen, A, van Vugt, M, Vibo, R, Verma, SS, Wiggins, KL, Wennberg, P, Woo, D, Wilson, PWF, Xu, H, Yang, Q, Yoon, K, Millwood, IY, Gieger, C, Ninomiya, T, Grabe, HJ, Jukema, JW, Rissanen, IL, Strbian, D, Kim, YJ, Chen, P-H, Mayerhofer, E, Howson, JMM, Irvin, MR, Adams, H, Wassertheil-Smoller, S, Christensen, K, Ikram, MA, Rundek, T, Worrall, BB, Lathrop, GM, Riaz, M, Simonsick, EM, Korv, J, Franca, PHC, Zand, R, Prasad, K, Frikke-Schmidt, R, de Leeuw, F-E, Liman, T, Haeusler, KG, Ruigrok, YM, Heuschmann, PU, Longstreth, WT, Jung, KJ, Bastarache, L, Pare, G, Damrauer, SM, Chasman, DI, Rotter, JI, Anderson, CD, Zwart, J-A, Niiranen, TJ, Fornage, M, Liaw, Y-P, Seshadri, S, Fernandez-Cadenas, I, Walters, RG, Ruff, CT, Owolabi, MO, Huffman, JE, Milani, L, Kamatani, Y, Dichgans, M, Debette, S, Lee, J-M, Cheng, Y-C, Meschia, JF, Chen, WM, Sale, MM, Zonderman, AB, Evans, MK, Wilson, JG, Correa, A, Traylor, M, Lewis, CM, Reiner, A, Haessler, J, Langefeld, CD, Gottesman, RF, Yaffe, K, Liu, YM, Kooperberg, C, Lange, LA, Furie, KL, Arnett, DK, Benavente, OR, Grewal, RP, Peddareddygari, LR, Hveem, K, Lindstrom, S, Wang, L, Smith, EN, Gordon, W, Vlieg, AVH, de Andrade, M, Brody, JA, Pattee, JW, Brumpton, BM, Suchon, P, Chen, M-H, Frazer, KA, Turman, C, Germain, M, MacDonald, J, Braekkan, SK, Armasu, SM, Pankratz, N, Jackson, RD, Nielsen, JB, Giulianin, F, Puurunen, MK, Ibrahim, M, Heckbert, SR, Bammler, TK, McCauley, BM, Taylor, KD, Pankow, JS, Reiner, AP, Gabrielsen, ME, Deleuze, J-F, O'Donnell, CJ, Kim, J, McKnight, B, Kraft, P, Hansen, J-B, Rosendaal, FR, Heit, JA, Tang, W, Morange, P-E, Johnson, AD, Kabrhel, C, van Dijk, EJ, Koudstaal, PJ, Luijckx, G-J, Nederkoorn, PJ, van Oostenbrugge, RJ, Visser, MC, Wermer, MJH, Kappelle, LJ, Esko, T, Metspalu, A, Magi, R, Nelis, M, Levi, CR, Maguire, J, Jimenez-Conde, J, Sharma, P, Sudlow, CLM, Rannikmae, K, Schmidt, R, Slowik, A, Pera, J, Thijs, VNS, Lindgren, AG, Ilinca, A, Melander, O, Engstrom, G, Rexrode, KM, Rothwell, PM, Stanne, TM, Johnson, JA, Danesh, J, Butterworth, AS, Heitsch, L, Boncoraglio, GB, Kubo, M, Pezzini, A, Rolfs, A, Giese, A-K, Weir, D, Ross, OA, Lemmons, R, Soderholm, M, Cushman, M, Jood, K, McDonough, CW, Bell, S, Linkohr, B, Lee, T-H, Putaala, J, Lopez, OL, Carty, CL, Jian, X, Schminke, U, Cullell, N, Delgado, P, Ibanez, L, Krupinski, J, Lioutas, V, Matsuda, K, Montaner, J, Muino, E, Roquer, J, Sarnowski, C, Sattar, N, Sibolt, G, Teumer, A, Rutten-Jacobs, L, Kanai, M, Gretarsdottir, S, Rost, NS, Yusuf, S, Almgren, P, Ay, H, Bevan, S, Brown, RD, Carrera, C, Buring, JE, Chen, W-M, Cotlarciuc, I, de Bakker, PIW, DeStefano, AL, den Hoed, M, Duan, Q, Engelter, ST, Falcone, GJ, Gustafsson, S, Hassan, A, Holliday, EG, Howard, G, Hsu, F-C, Ingelsson, E, Harris, TB, Kissela, BM, Kleindorfer, DO, Langenberg, C, Leys, D, Lin, W-Y, Lorentzen, E, Magnusson, PK, McArdle, PF, Pulit, SL, Rice, K, Sakaue, S, Sapkota, BR, Tanislav, C, Thorleifsson, G, Thorsteinsdottir, U, Tzourio, C, van Duijn, CM, Walters, M, Wareham, NJ, Amin, N, Aparicio, HJ, Attia, J, Beiser, AS, Berr, C, Bustamante, M, Caso, V, Choi, SH, Chowhan, A, Dartigues, J-F, Delavaran, H, Dorr, M, Ford, I, Gurpreet, WS, Hamsten, A, Hozawa, A, Ingelsson, M, Iwasaki, M, Kaffashian, S, Kalra, L, Kjartansson, O, Kloss, M, Labovitz, DL, Laurie, CC, Lind, L, Lindgren, CM, Makoto, H, Minegishi, N, Morris, AP, Mueller-Nurasyid, M, Norrving, B, Ogishima, S, Parati, EA, Pedersen, NL, Perola, M, Jousilahti, P, Pileggi, S, Rabionet, R, Riba-Llena, I, Ribases, M, Romero, JR, Rudd, AG, Sarin, A-P, Sarju, R, Satoh, M, Sawada, N, Sigurdsson, A, Smith, A, Stine, OC, Stott, DJ, Strauch, K, Takai, T, Tanaka, H, Touze, E, Tsugane, S, Uitterlinden, AG, Valdimarsson, EM, van der Lee, SJ, Wakai, K, Williams, SR, Wolfe, CDA, Wong, Q, Yamaji, T, Sanghera, DK, Stefansson, K, Martinez-Majander, N, Sobue, K, Soriano-Tarraga, C, Volzke, H, Akpa, O, Sarfo, FS, Akpalu, A, Obiako, R, Wahab, K, Osaigbovo, G, Owolabi, L, Komolafe, M, Jenkins, C, Arulogun, O, Ogbole, G, Adeoye, AM, Akinyemi, J, Agunloye, A, Fakunle, AG, Uvere, E, Olalere, A, Adebajo, OJ, Chen, J, Clarke, R, Collins, R, Guo, Y, Wang, C, Lv, J, Peto, R, Chen, Y, Fairhurst-Hunter, Z, Hill, M, Pozarickij, A, Schmidt, D, Stevens, B, Turnbull, I, Yu, C, Nagai, A, Murakami, Y, Shiroma, EJ, Sigurdsson, S, Ghanbari, M, Boerwinkle, E, Fongang, B, Wang, R, Ikram, MK, Volker, U, de Laat, KF, van Norden, AGW, de Kort, PL, Vermeer, SE, Brouwers, PJAM, Gons, RAR, den Heijer, T, van Dijk, GW, van Rooij, FGW, Aamodt, AH, Skogholt, AH, Willer, CJ, Heuch, I, Hagen, K, Fritsche, LG, Pedersen, LM, Ellekjaer, H, Zhou, W, Martinsen, AE, Kristoffersen, ES, Thomas, LF, Kleinschnitz, C, Frantz, S, Ungethum, K, Gallego-Fabrega, C, Lledos, M, Llucia-Carol, L, Sobrino, T, Campos, F, Castillo, J, Freijo, M, Arenillas, JF, Obach, V, Alvarez-Sabin, J, Molina, CA, Ribo, M, Munoz-Narbona, L, Lopez-Cancio, E, Millan, M, Diaz-Navarro, R, Vives-Bauza, C, Serrano-Heras, G, Segura, T, Dhar, R, Delgado-Mederos, R, Prats-Sanchez, L, Camps-Renom, P, Blay, N, Sumoy, L, Marti-Fabregas, J, Schnohr, P, Jensen, GB, Benn, M, Afzal, S, Kamstrup, PR, van Setten, J, van der Laan, SW, Vonk, JMJ, Kim, B-J, Curtze, S, Tiainen, M, Kinnunen, J, Menon, V, Sung, YJ, Saillour-Glenisson, F, Gravel, S, Mishra, A, Malik, R, Hachiya, T, Jurgenson, T, Namba, S, Posner, DC, Kamanu, FK, Koido, M, Le Grand, Q, Shi, M, He, Y, Georgakis, MK, Caro, I, Krebs, K, Liaw, Y-C, Vaura, FC, Lin, K, Winsvold, BS, Srinivasasainagendra, V, Parodi, L, Bae, H-J, Chauhan, G, Chong, MR, Tomppo, L, Akinyemi, R, Roshchupkin, GV, Habib, N, Jee, YH, Thomassen, JQ, Abedi, V, Carcel-Marquez, J, Nygaard, M, Leonard, HL, Yang, C, Yonova-Doing, E, Knol, MJ, Lewis, AJ, Judy, RL, Ago, T, Amouyel, P, Armstrong, ND, Bakker, MK, Bartz, TM, Bennett, DA, Bis, JC, Bordes, C, Borte, S, Cain, A, Ridker, PM, Cho, K, Chen, Z, Cruchaga, C, Cole, JW, de Jager, PL, de Cid, R, Endres, M, Ferreira, LE, Geerlings, MI, Gasca, NC, Gudnason, V, Hata, J, He, J, Heath, AK, Ho, Y-L, Havulinna, AS, Hopewell, JC, Hyacinth, HI, Inouye, M, Jacob, MA, Jeon, CE, Jern, C, Kamouchi, M, Keene, KL, Kitazono, T, Kittner, SJ, Konuma, T, Kumar, A, Lacaze, P, Launer, LJ, Lee, K-J, Lepik, K, Li, J, Li, L, Manichaikul, A, Markus, HS, Marston, NA, Meitinger, T, Mitchell, BD, Montellano, FA, Morisaki, T, Mosley, TH, Nalls, MA, Nordestgaard, BG, O'Donnell, MJ, Okada, Y, Onland-Moret, NC, Ovbiagele, B, Peters, A, Psaty, BM, Rich, SS, Rosand, J, Sabatine, MS, Sacco, RL, Saleheen, D, Sandset, EC, Salomaa, V, Sargurupremraj, M, Sasaki, M, Satizabal, CL, Schmidt, CO, Shimizu, A, Smith, NL, Sloane, KL, Sutoh, Y, Sun, YV, Tanno, K, Tiedt, S, Tatlisumak, T, Torres-Aguila, NP, Tiwari, HK, Tregouet, D-A, Trompet, S, Tuladhar, AM, Tybjaerg-Hansen, A, van Vugt, M, Vibo, R, Verma, SS, Wiggins, KL, Wennberg, P, Woo, D, Wilson, PWF, Xu, H, Yang, Q, Yoon, K, Millwood, IY, Gieger, C, Ninomiya, T, Grabe, HJ, Jukema, JW, Rissanen, IL, Strbian, D, Kim, YJ, Chen, P-H, Mayerhofer, E, Howson, JMM, Irvin, MR, Adams, H, Wassertheil-Smoller, S, Christensen, K, Ikram, MA, Rundek, T, Worrall, BB, Lathrop, GM, Riaz, M, Simonsick, EM, Korv, J, Franca, PHC, Zand, R, Prasad, K, Frikke-Schmidt, R, de Leeuw, F-E, Liman, T, Haeusler, KG, Ruigrok, YM, Heuschmann, PU, Longstreth, WT, Jung, KJ, Bastarache, L, Pare, G, Damrauer, SM, Chasman, DI, Rotter, JI, Anderson, CD, Zwart, J-A, Niiranen, TJ, Fornage, M, Liaw, Y-P, Seshadri, S, Fernandez-Cadenas, I, Walters, RG, Ruff, CT, Owolabi, MO, Huffman, JE, Milani, L, Kamatani, Y, Dichgans, M, Debette, S, Lee, J-M, Cheng, Y-C, Meschia, JF, Chen, WM, Sale, MM, Zonderman, AB, Evans, MK, Wilson, JG, Correa, A, Traylor, M, Lewis, CM, Reiner, A, Haessler, J, Langefeld, CD, Gottesman, RF, Yaffe, K, Liu, YM, Kooperberg, C, Lange, LA, Furie, KL, Arnett, DK, Benavente, OR, Grewal, RP, Peddareddygari, LR, Hveem, K, Lindstrom, S, Wang, L, Smith, EN, Gordon, W, Vlieg, AVH, de Andrade, M, Brody, JA, Pattee, JW, Brumpton, BM, Suchon, P, Chen, M-H, Frazer, KA, Turman, C, Germain, M, MacDonald, J, Braekkan, SK, Armasu, SM, Pankratz, N, Jackson, RD, Nielsen, JB, Giulianin, F, Puurunen, MK, Ibrahim, M, Heckbert, SR, Bammler, TK, McCauley, BM, Taylor, KD, Pankow, JS, Reiner, AP, Gabrielsen, ME, Deleuze, J-F, O'Donnell, CJ, Kim, J, McKnight, B, Kraft, P, Hansen, J-B, Rosendaal, FR, Heit, JA, Tang, W, Morange, P-E, Johnson, AD, Kabrhel, C, van Dijk, EJ, Koudstaal, PJ, Luijckx, G-J, Nederkoorn, PJ, van Oostenbrugge, RJ, Visser, MC, Wermer, MJH, Kappelle, LJ, Esko, T, Metspalu, A, Magi, R, Nelis, M, Levi, CR, Maguire, J, Jimenez-Conde, J, Sharma, P, Sudlow, CLM, Rannikmae, K, Schmidt, R, Slowik, A, Pera, J, Thijs, VNS, Lindgren, AG, Ilinca, A, Melander, O, Engstrom, G, Rexrode, KM, Rothwell, PM, Stanne, TM, Johnson, JA, Danesh, J, Butterworth, AS, Heitsch, L, Boncoraglio, GB, Kubo, M, Pezzini, A, Rolfs, A, Giese, A-K, Weir, D, Ross, OA, Lemmons, R, Soderholm, M, Cushman, M, Jood, K, McDonough, CW, Bell, S, Linkohr, B, Lee, T-H, Putaala, J, Lopez, OL, Carty, CL, Jian, X, Schminke, U, Cullell, N, Delgado, P, Ibanez, L, Krupinski, J, Lioutas, V, Matsuda, K, Montaner, J, Muino, E, Roquer, J, Sarnowski, C, Sattar, N, Sibolt, G, Teumer, A, Rutten-Jacobs, L, Kanai, M, Gretarsdottir, S, Rost, NS, Yusuf, S, Almgren, P, Ay, H, Bevan, S, Brown, RD, Carrera, C, Buring, JE, Chen, W-M, Cotlarciuc, I, de Bakker, PIW, DeStefano, AL, den Hoed, M, Duan, Q, Engelter, ST, Falcone, GJ, Gustafsson, S, Hassan, A, Holliday, EG, Howard, G, Hsu, F-C, Ingelsson, E, Harris, TB, Kissela, BM, Kleindorfer, DO, Langenberg, C, Leys, D, Lin, W-Y, Lorentzen, E, Magnusson, PK, McArdle, PF, Pulit, SL, Rice, K, Sakaue, S, Sapkota, BR, Tanislav, C, Thorleifsson, G, Thorsteinsdottir, U, Tzourio, C, van Duijn, CM, Walters, M, Wareham, NJ, Amin, N, Aparicio, HJ, Attia, J, Beiser, AS, Berr, C, Bustamante, M, Caso, V, Choi, SH, Chowhan, A, Dartigues, J-F, Delavaran, H, Dorr, M, Ford, I, Gurpreet, WS, Hamsten, A, Hozawa, A, Ingelsson, M, Iwasaki, M, Kaffashian, S, Kalra, L, Kjartansson, O, Kloss, M, Labovitz, DL, Laurie, CC, Lind, L, Lindgren, CM, Makoto, H, Minegishi, N, Morris, AP, Mueller-Nurasyid, M, Norrving, B, Ogishima, S, Parati, EA, Pedersen, NL, Perola, M, Jousilahti, P, Pileggi, S, Rabionet, R, Riba-Llena, I, Ribases, M, Romero, JR, Rudd, AG, Sarin, A-P, Sarju, R, Satoh, M, Sawada, N, Sigurdsson, A, Smith, A, Stine, OC, Stott, DJ, Strauch, K, Takai, T, Tanaka, H, Touze, E, Tsugane, S, Uitterlinden, AG, Valdimarsson, EM, van der Lee, SJ, Wakai, K, Williams, SR, Wolfe, CDA, Wong, Q, Yamaji, T, Sanghera, DK, Stefansson, K, Martinez-Majander, N, Sobue, K, Soriano-Tarraga, C, Volzke, H, Akpa, O, Sarfo, FS, Akpalu, A, Obiako, R, Wahab, K, Osaigbovo, G, Owolabi, L, Komolafe, M, Jenkins, C, Arulogun, O, Ogbole, G, Adeoye, AM, Akinyemi, J, Agunloye, A, Fakunle, AG, Uvere, E, Olalere, A, Adebajo, OJ, Chen, J, Clarke, R, Collins, R, Guo, Y, Wang, C, Lv, J, Peto, R, Chen, Y, Fairhurst-Hunter, Z, Hill, M, Pozarickij, A, Schmidt, D, Stevens, B, Turnbull, I, Yu, C, Nagai, A, Murakami, Y, Shiroma, EJ, Sigurdsson, S, Ghanbari, M, Boerwinkle, E, Fongang, B, Wang, R, Ikram, MK, Volker, U, de Laat, KF, van Norden, AGW, de Kort, PL, Vermeer, SE, Brouwers, PJAM, Gons, RAR, den Heijer, T, van Dijk, GW, van Rooij, FGW, Aamodt, AH, Skogholt, AH, Willer, CJ, Heuch, I, Hagen, K, Fritsche, LG, Pedersen, LM, Ellekjaer, H, Zhou, W, Martinsen, AE, Kristoffersen, ES, Thomas, LF, Kleinschnitz, C, Frantz, S, Ungethum, K, Gallego-Fabrega, C, Lledos, M, Llucia-Carol, L, Sobrino, T, Campos, F, Castillo, J, Freijo, M, Arenillas, JF, Obach, V, Alvarez-Sabin, J, Molina, CA, Ribo, M, Munoz-Narbona, L, Lopez-Cancio, E, Millan, M, Diaz-Navarro, R, Vives-Bauza, C, Serrano-Heras, G, Segura, T, Dhar, R, Delgado-Mederos, R, Prats-Sanchez, L, Camps-Renom, P, Blay, N, Sumoy, L, Marti-Fabregas, J, Schnohr, P, Jensen, GB, Benn, M, Afzal, S, Kamstrup, PR, van Setten, J, van der Laan, SW, Vonk, JMJ, Kim, B-J, Curtze, S, Tiainen, M, Kinnunen, J, Menon, V, Sung, YJ, Saillour-Glenisson, F, and Gravel, S more...
- 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 SH3PXD2A and FURIN) and variants (such as at GRK5 and 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. more...
- Published
- 2022
4. A polygenic risk score based on a cardioembolic stroke multitrait analysis improves a clinical prediction model for this stroke subtype
- Author
-
Cárcel-Márquez, J, Muiño, E, Gallego-Fabrega, C, Cullell, N, Lledós, M, Llucià-Carol, L, Sobrino, T, Campos, F, Castillo, J, Freijo, M, Arenillas, JF, Obach, V, Álvarez-Sabín, J, Molina, CA, Ribó, M, Jiménez-Conde, J, Roquer, J, Muñoz-Narbona, L, Lopez-Cancio, E, Millán, M, Diaz-Navarro, R, Vives-Bauza, C, Serrano-Heras, G, Segura, T, Ibañez, L, Heitsch, L, Delgado, P, Dhar, R, Krupinski, J, Delgado-Mederos, R, Prats-Sánchez, L, Camps-Renom, P, Blay, N, Sumoy, L, de Cid, R, Montaner, J, Cruchaga, C, Lee, JM, Martí-Fàbregas, J, Férnandez-Cadenas, I, Cárcel-Márquez, J, Muiño, E, Gallego-Fabrega, C, Cullell, N, Lledós, M, Llucià-Carol, L, Sobrino, T, Campos, F, Castillo, J, Freijo, M, Arenillas, JF, Obach, V, Álvarez-Sabín, J, Molina, CA, Ribó, M, Jiménez-Conde, J, Roquer, J, Muñoz-Narbona, L, Lopez-Cancio, E, Millán, M, Diaz-Navarro, R, Vives-Bauza, C, Serrano-Heras, G, Segura, T, Ibañez, L, Heitsch, L, Delgado, P, Dhar, R, Krupinski, J, Delgado-Mederos, R, Prats-Sánchez, L, Camps-Renom, P, Blay, N, Sumoy, L, de Cid, R, Montaner, J, Cruchaga, C, Lee, JM, Martí-Fàbregas, J, and Férnandez-Cadenas, I more...
- Abstract
Background: Occult atrial fibrillation (AF) is one of the major causes of embolic stroke of undetermined source (ESUS). Knowing the underlying etiology of an ESUS will reduce stroke recurrence and/or unnecessary use of anticoagulants. Understanding cardioembolic strokes (CES), whose main cause is AF, will provide tools to select patients who would benefit from anticoagulants among those with ESUS or AF. We aimed to discover novel loci associated with CES and create a polygenetic risk score (PRS) for a more efficient CES risk stratification. Methods: Multitrait analysis of GWAS (MTAG) was performed with MEGASTROKE-CES cohort (n = 362,661) and AF cohort (n = 1,030,836). We considered significant variants and replicated those variants with MTAG p-value < 5 × 10−8 influencing both traits (GWAS-pairwise) with a p-value < 0.05 in the original GWAS and in an independent cohort (n = 9,105). The PRS was created with PRSice-2 and evaluated in the independent cohort. Results: We found and replicated eleven loci associated with CES. Eight were novel loci. Seven of them had been previously associated with AF, namely, CAV1, ESR2, GORAB, IGF1R, NEURL1, WIPF1, and ZEB2. KIAA1755 locus had never been associated with CES/AF, leading its index variant to a missense change (R1045W). The PRS generated has been significantly associated with CES improving discrimination and patient reclassification of a model with age, sex, and hypertension. Conclusion: The loci found significantly associated with CES in the MTAG, together with the creation of a PRS that improves the predictive clinical models of CES, might help guide future clinical trials of anticoagulant therapy in patients with ESUS or AF. more...
- Published
- 2022
5. Genetic influences on functional outcome after stroke
- Author
-
Alcaide, E, Martinez N, Escaramis, G, Lazcano, U, Mola-Caminal, M, Carrera, C, Vives-Bauza, C, Jimenez-Conde, J, Fernandez-Cadenas, I, and Raquel Rabionet Janssen
- Published
- 2022
6. Validation of a clinical-genetics score to predict hemorrhagic transformations after rtPA
- Author
-
Carrera, C, Cullell, N, Torres-Aguila, N, Muino, E, Bustamante, A, Davalos, A, Lopez-Cancio, E, Ribo, M, Molina, CA, Giralt-Steinhauer, E, Soriano-Tarraga, C, Mola-Caminal, M, Jimenez-Conde, J, Roquer, J, Vives-Bauza, C, Navarro, RD, Obach, V, Arenillas, JF, Segura, T, Serrano-Heras, G, Marti-Fabregas, J, Freijo, M, Cabezas, JA, Tatlisumak, T, Heitsch, L, Ibanez, L, Cruchaga, C, Lee, JM, Strbian, D, Montaner, J, Fernandez-Cadenas, I, Carcel-Marquez, J, Gonzalez, J, Munoz, L, Cortijo-Garcia, E, Bueno, RM, Havulinna, A, and Salomaa, V more...
- Abstract
Objective To validate the Genot-PA score, a clinical-genetic logistic regression score that stratifies the thrombolytic therapy safety, in a new cohort of patients with stroke. Methods We enrolled 1,482 recombinant tissue plasminogen activator (rtPA)-treated patients with stroke in Spain and Finland from 2003 to 2016. Cohorts were analyzed on the basis of ethnicity and therapy: Spanish patients treated with IV rtPA within 4.5 hours of onset (cohort A and B) or rtPA in combination with mechanical thrombectomy within 6 hours of onset (cohort C) and Finnish participants treated with IV rtPA within 4.5 hours of onset (cohort D). The Genot-PA score was calculated, and hemorrhagic transformation (HT) and parenchymal hematoma (PH) risks were determined for each score stratum. Results Genot-PA score was tested in 1,324 (cohort A, n = 726; B, n = 334; C, n = 54; and D, n = 210) patients who had enough information to complete the score. Of these, 213 (16.1%) participants developed HT and 85 (6.4%) developed PH. In cohorts A, B, and D, HT occurrence was predicted by the score (p = 2.02 x 10(-6), p = 0.023, p = 0.033); PH prediction was associated in cohorts A through C (p = 0.012, p = 0.034, p = 5.32 x 10(-4)). Increased frequency of PH events from the lowest to the highest risk group was found (cohort A 4%-15.7%, cohort B 1.5%-18.2%, cohort C 0%-100%). The best odds ratio for PH prediction in the highest-risk group was obtained in cohort A (odds ratio 5.16, 95% confidence interval 1.46-18.08, p = 0.009). Conclusion The Genot-PA score predicts HT in patients with stroke treated with IV rtPA. Moreover, in an exploratory study, the score was associated with PH risk in mechanical thrombectomy-treated patients. more...
- Published
- 2019
7. A mitochondrial DNA duplication as a marker of skeletal muscle specific mutations in the mitochondrial genome
- Author
-
Mancuso, M, Vives-Bauza, C, Filosto, M, Marti, R, Solano, A, Montoya, J, Gamez, J, DiMauro, S, and Andreu, A L
- Published
- 2004
8. Familial expansile osteolysis in a large Spanish kindred resulting from an insertion mutation in the TNFRSF11A gene
- Author
-
Palenzuela, L, Vives-Bauza, C, Fernández-Cadenas, I, Meseguer, A, Font, N, Sarret, E, Schwartz, S, and Andreu, A L
- Published
- 2002
9. Anti-NMDAR antibodies in new-onset psychosis. Positive results in an HIV-infected patient
- Author
-
Arboleya S, Clemente A, Deng S, Bedmar M, Salvador I, Herbera P, Cunill V, Vives-Bauza C, Haro JM, Canellas F, and Julià MR
- Published
- 2016
10. Effects of iron salts and haemosiderin from a thalassaemia patient on oxygen radical damage as measured in the comet assay
- Author
-
Anderson, D., Yardley-Jones, A., Hambly, R.J., Vives-Bauza, C., Smykatz-Kloss, V., Chua-anusorn, W., Webb, J., Anderson, D., Yardley-Jones, A., Hambly, R.J., Vives-Bauza, C., Smykatz-Kloss, V., Chua-anusorn, W., and Webb, J. more...
- Abstract
Thalassaemia is a group of genetic diseases where haemoglobin synthesis is impaired. This chronic anaemia leads to increased dietary iron absorption, which develops into iron overload pathology. Treatment through regular transfusions increases oxygen capacity but also provides iron through the red cells' haemoglobin. An essential treatment, in parallel with transfusions, is the use of chelating agents to remove the excess iron deposited in tissues. These deposits are found in the liver, spleen, heart, and pancreas and are associated with cardiac failure and diabetes. The deposits in these tissues of patients have been isolated as haemosiderin. Thalassaemia patients are particularly at risk of free radical induced damage. Thus, the present study has investigated, as a model system, human cells in vitro in the Comet assay in the presence of free radicals. This assay measures DNA damage, particularly DNA strand breakage. The effects of iron overload on cells oxidatively stressed with hydrogen peroxide (H 2O 2) have been determined as well as the effect of the chelating agent, deferoxamine. Iron overload was simulated with ferric (FeCl 3) and ferrous chloride (FeCl 2), ferrous sulphate (FeSO 4) and haemosiderins. Both human lymphocytes from a male and a female donor and human adenocarcinoma colonic cells showed an increase in DNA damage in the Comet assay after treatment with H 2O 2. Ferric chloride produced an increase in DNA damage in human colonic cells, but little or no damage in human lymphocytes. Ferrous chloride also produced weak DNA damage in human lymphocytes, but ferrous sulphate produced a dose-related response. Deferoxamine produced no DNA damage. When H 2O 2 was combined with FeCl 3, FeCl 2, or FeSO 4, the DNA damage produced was as least as great as or slightly greater than with H 2O 2 alone. When deferoxamine was combined with H 2O 2 and FeSO 4 there was a consistent decrease in response. There was little or no decrease in response when deferoxamine was more...
- Published
- 2000
11. Effect of iron salts, haemosiderins, and chelating agents on the lymphocytes of a thalassaemia patient without chelation therapy as measured in the comet assay
- Author
-
Anderson, D., Yardley-Jones, A., Vives-Bauza, C., Chua-anusorn, W., Cole, C., Webb, J., Anderson, D., Yardley-Jones, A., Vives-Bauza, C., Chua-anusorn, W., Cole, C., and Webb, J.
- Abstract
Impairment of haemoglobin synthesis occurs in the genetic diseases known as thalassaemia. The consequent chronic anaemia leads to increased dietary iron absorption which results in iron overload. Treatment through regular blood transfusions increases oxygen capacity, but also adds iron from haemoglobin. An essential treatment, in parallel with transfusions, is the use of chelating agents to remove the excess iron. Thalassaemia patients are particularly at risk of free radical damage. Human lymphocytes from normal individuals can be investigated in vitro as a model system in the presence of free radicals in the Comet assay. This assay measures DNA damage, particularly DNA strand breakage. We examined cells from an Australian thalassaemic patient (sickle/beta thal double heterozygote-sickle phenotype) who had not yet received chelation therapy to determine if the cells were more sensitive to simulated iron overload and to haemosiderins. Lymphocytes from the patient were received as frozen samples after 28 h on dry ice and then placed in liquid nitrogen. Normal lymphocytes frozen under the same conditions and normal nonfrozen lymphocytes were compared. The lymphocytes from a normal female did not respond in vitro to ferric chloride (FeCl 3) or haemosiderin but did to ferrous chloride (FeCl 2) and ferrous sulphate (FeSO 4). Deferoxamine appeared to reduce the response to FeCl 2 and FeSO 4 but deferiprone did not. When the lymphocytes from the nonchelated patient were treated with FeSO 4 and hydrogen peroxide, deferoxamine and deferiprone both reduced the response. Over the same dose range of iron salt (FeSO 4), the lymphocytes from the thalassaemic patient were more sensitive, with much higher background levels of damage and induced damage. When deferiprone and deferoxamine were compared over a nontoxic range, deferiprone appeared to produce a greater reduction of damage in lymphocytes of the thalassaemia patient. Ferritin iron appears to be more available than haemosid more...
- Published
- 2000
12. Multi-ancestry GWAS reveals excitotoxicity associated with outcome after ischaemic stroke.
- Author
-
Ibanez L, Heitsch L, Carrera C, Farias FHG, Del Aguila JL, Dhar R, Budde J, Bergmann K, Bradley J, Harari O, Phuah CL, Lemmens R, Viana Oliveira Souza AA, Moniche F, Cabezas-Juan A, Arenillas JF, Krupinksi J, Cullell N, Torres-Aguila N, Muiño E, Cárcel-Márquez J, Marti-Fabregas J, Delgado-Mederos R, Marin-Bueno R, Hornick A, Vives-Bauza C, Navarro RD, Tur S, Jimenez C, Obach V, Segura T, Serrano-Heras G, Chung JW, Roquer J, Soriano-Tarraga C, Giralt-Steinhauer E, Mola-Caminal M, Pera J, Lapicka-Bodzioch K, Derbisz J, Davalos A, Lopez-Cancio E, Muñoz L, Tatlisumak T, Molina C, Ribo M, Bustamante A, Sobrino T, Castillo-Sanchez J, Campos F, Rodriguez-Castro E, Arias-Rivas S, Rodríguez-Yáñez M, Herbosa C, Ford AL, Gutierrez-Romero A, Uribe-Pacheco R, Arauz A, Lopes-Cendes I, Lowenkopf T, Barboza MA, Amini H, Stamova B, Ander BP, Sharp FR, Kim GM, Bang OY, Jimenez-Conde J, Slowik A, Stribian D, Tsai EA, Burkly LC, Montaner J, Fernandez-Cadenas I, Lee JM, and Cruchaga C more...
- Subjects
- Bayes Theorem, Genome-Wide Association Study, Humans, United States, Brain Ischemia complications, Brain Ischemia genetics, Ischemic Stroke, Stroke complications, Stroke genetics
- Abstract
During the first hours after stroke onset, neurological deficits can be highly unstable: some patients rapidly improve, while others deteriorate. This early neurological instability has a major impact on long-term outcome. Here, we aimed to determine the genetic architecture of early neurological instability measured by the difference between the National Institutes of Health Stroke Scale (NIHSS) within 6 h of stroke onset and NIHSS at 24 h. A total of 5876 individuals from seven countries (Spain, Finland, Poland, USA, Costa Rica, Mexico and Korea) were studied using a multi-ancestry meta-analyses. We found that 8.7% of NIHSS at 24 h of variance was explained by common genetic variations, and also that early neurological instability has a different genetic architecture from that of stroke risk. Eight loci (1p21.1, 1q42.2, 2p25.1, 2q31.2, 2q33.3, 5q33.2, 7p21.2 and 13q31.1) were genome-wide significant and explained 1.8% of the variability suggesting that additional variants influence early change in neurological deficits. We used functional genomics and bioinformatic annotation to identify the genes driving the association from each locus. Expression quantitative trait loci mapping and summary data-based Mendelian randomization indicate that ADAM23 (log Bayes factor = 5.41) was driving the association for 2q33.3. Gene-based analyses suggested that GRIA1 (log Bayes factor = 5.19), which is predominantly expressed in the brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated GNPAT (log Bayes factor = 7.64) ABCB5 (log Bayes factor = 5.97) for the 1p21.1 and 7p21.1 loci. Human brain single-nuclei RNA-sequencing indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23, a presynaptic protein and GRIA1, a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability. These data provide the first genetic evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischaemic stroke., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.) more...
- Published
- 2022
- Full Text
- View/download PDF
13. A Polygenic Risk Score Based on a Cardioembolic Stroke Multitrait Analysis Improves a Clinical Prediction Model for This Stroke Subtype.
- Author
-
Cárcel-Márquez J, Muiño E, Gallego-Fabrega C, Cullell N, Lledós M, Llucià-Carol L, Sobrino T, Campos F, Castillo J, Freijo M, Arenillas JF, Obach V, Álvarez-Sabín J, Molina CA, Ribó M, Jiménez-Conde J, Roquer J, Muñoz-Narbona L, Lopez-Cancio E, Millán M, Diaz-Navarro R, Vives-Bauza C, Serrano-Heras G, Segura T, Ibañez L, Heitsch L, Delgado P, Dhar R, Krupinski J, Delgado-Mederos R, Prats-Sánchez L, Camps-Renom P, Blay N, Sumoy L, de Cid R, Montaner J, Cruchaga C, Lee JM, Martí-Fàbregas J, and Férnandez-Cadenas I more...
- Abstract
Background: Occult atrial fibrillation (AF) is one of the major causes of embolic stroke of undetermined source (ESUS). Knowing the underlying etiology of an ESUS will reduce stroke recurrence and/or unnecessary use of anticoagulants. Understanding cardioembolic strokes (CES), whose main cause is AF, will provide tools to select patients who would benefit from anticoagulants among those with ESUS or AF. We aimed to discover novel loci associated with CES and create a polygenetic risk score (PRS) for a more efficient CES risk stratification., Methods: Multitrait analysis of GWAS (MTAG) was performed with MEGASTROKE-CES cohort ( n = 362,661) and AF cohort ( n = 1,030,836). We considered significant variants and replicated those variants with MTAG p -value < 5 × 10
-8 influencing both traits (GWAS-pairwise) with a p -value < 0.05 in the original GWAS and in an independent cohort ( n = 9,105). The PRS was created with PRSice-2 and evaluated in the independent cohort., Results: We found and replicated eleven loci associated with CES. Eight were novel loci. Seven of them had been previously associated with AF, namely, CAV1, ESR2, GORAB, IGF1R, NEURL1, WIPF1 , and ZEB2 . KIAA1755 locus had never been associated with CES/AF, leading its index variant to a missense change (R1045W). The PRS generated has been significantly associated with CES improving discrimination and patient reclassification of a model with age, sex, and hypertension., Conclusion: The loci found significantly associated with CES in the MTAG, together with the creation of a PRS that improves the predictive clinical models of CES, might help guide future clinical trials of anticoagulant therapy in patients with ESUS or AF., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cárcel-Márquez, Muiño, Gallego-Fabrega, Cullell, Lledós, Llucià-Carol, Sobrino, Campos, Castillo, Freijo, Arenillas, Obach, Álvarez-Sabín, Molina, Ribó, Jiménez-Conde, Roquer, Muñoz-Narbona, Lopez-Cancio, Millán, Diaz-Navarro, Vives-Bauza, Serrano-Heras, Segura, Ibañez, Heitsch, Delgado, Dhar, Krupinski, Delgado-Mederos, Prats-Sánchez, Camps-Renom, Blay, Sumoy, de Cid, Montaner, Cruchaga, Lee, Martí-Fàbregas and Férnandez-Cadenas.) more...- Published
- 2022
- Full Text
- View/download PDF
14. Single nucleotide variations in ZBTB46 are associated with post-thrombolytic parenchymal haematoma.
- Author
-
Carrera C, Cárcel-Márquez J, Cullell N, Torres-Águila N, Muiño E, Castillo J, Sobrino T, Campos F, Rodríguez-Castro E, Llucià-Carol L, Millán M, Muñoz-Narbona L, López-Cancio E, Bustamante A, Ribó M, Álvarez-Sabín J, Jiménez-Conde J, Roquer J, Giralt-Steinhauer E, Soriano-Tárraga C, Mola-Caminal M, Vives-Bauza C, Navarro RD, Tur S, Obach V, Arenillas JF, Segura T, Serrano-Heras G, Martí-Fàbregas J, Delgado-Mederos R, Freijo-Guerrero MM, Moniche F, Cabezas JA, Castellanos M, Gallego-Fabrega C, González-Sanchez J, Krupinsky J, Strbian D, Tatlisumak T, Thijs V, Lemmens R, Slowik A, Pera J, Kittner S, Cole J, Heitsch L, Ibañez L, Cruchaga C, Lee JM, Montaner J, and Fernández-Cadenas I more...
- Subjects
- Aged, Aged, 80 and over, Female, Fibrinolytic Agents adverse effects, Genome-Wide Association Study, Humans, Ischemic Stroke genetics, Male, Middle Aged, Treatment Outcome, Cerebral Hemorrhage chemically induced, Cerebral Hemorrhage genetics, Ischemic Stroke drug therapy, Polymorphism, Single Nucleotide, Thrombolytic Therapy adverse effects, Tissue Plasminogen Activator adverse effects, Transcription Factors genetics
- Abstract
Haemorrhagic transformation is a complication of recombinant tissue-plasminogen activator treatment. The most severe form, parenchymal haematoma, can result in neurological deterioration, disability, and death. Our objective was to identify single nucleotide variations associated with a risk of parenchymal haematoma following thrombolytic therapy in patients with acute ischaemic stroke. A fixed-effect genome-wide meta-analysis was performed combining two-stage genome-wide association studies (n = 1904). The discovery stage (three cohorts) comprised 1324 ischaemic stroke individuals, 5.4% of whom had a parenchymal haematoma. Genetic variants yielding a P-value < 0.05 1 × 10-5 were analysed in the validation stage (six cohorts), formed by 580 ischaemic stroke patients with 12.1% haemorrhagic events. All participants received recombinant tissue-plasminogen activator; cases were parenchymal haematoma type 1 or 2 as defined by the European Cooperative Acute Stroke Study (ECASS) criteria. Genome-wide significant findings (P < 5 × 10-8) were characterized by in silico functional annotation, gene expression, and DNA regulatory elements. We analysed 7 989 272 single nucleotide polymorphisms and identified a genome-wide association locus on chromosome 20 in the discovery cohort; functional annotation indicated that the ZBTB46 gene was driving the association for chromosome 20. The top single nucleotide polymorphism was rs76484331 in the ZBTB46 gene [P = 2.49 × 10-8; odds ratio (OR): 11.21; 95% confidence interval (CI): 4.82-26.55]. In the replication cohort (n = 580), the rs76484331 polymorphism was associated with parenchymal haematoma (P = 0.01), and the overall association after meta-analysis increased (P = 1.61 × 10-8; OR: 5.84; 95% CI: 3.16-10.76). ZBTB46 codes the zinc finger and BTB domain-containing protein 46 that acts as a transcription factor. In silico studies indicated that ZBTB46 is expressed in brain tissue by neurons and endothelial cells. Moreover, rs76484331 interacts with the promoter sites located at 20q13. In conclusion, we identified single nucleotide variants in the ZBTB46 gene associated with a higher risk of parenchymal haematoma following recombinant tissue-plasminogen activator treatment., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.) more...
- Published
- 2021
- Full Text
- View/download PDF
15. RP11-362K2.2:RP11-767I20.1 Genetic Variation Is Associated with Post-Reperfusion Therapy Parenchymal Hematoma. A GWAS Meta-Analysis.
- Author
-
Muiño E, Cárcel-Márquez J, Carrera C, Llucià-Carol L, Gallego-Fabrega C, Cullell N, Lledós M, Castillo J, Sobrino T, Campos F, Rodríguez-Castro E, Millán M, Muñoz-Narbona L, Bustamante A, López-Cancio E, Ribó M, Álvarez-Sabín J, Jiménez-Conde J, Roquer J, Giralt-Steinhauer E, Soriano-Tárraga C, Vives-Bauza C, Díaz-Navarro R, Tur S, Obach V, Arenillas JF, Segura T, Serrano-Heras G, Martí-Fàbregas J, Delgado-Mederos R, Camps-Renom P, Prats-Sánchez L, Guisado D, Guasch M, Marin R, Martínez-Domeño A, Freijo-Guerrero MDM, Moniche F, Cabezas JA, Castellanos M, Krupinsky J, Strbian D, Tatlisumak T, Thijs V, Lemmens R, Slowik A, Pera J, Heitsch L, Ibañez L, Cruchaga C, Dhar R, Lee JM, Montaner J, Fernández-Cadenas I, Consortium OBOISG, and Consortium TSSG more...
- Abstract
Stroke is one of the most common causes of death and disability. Reperfusion therapies are the only treatment available during the acute phase of stroke. Due to recent clinical trials, these therapies may increase their frequency of use by extending the time-window administration, which may lead to an increase in complications such as hemorrhagic transformation, with parenchymal hematoma (PH) being the more severe subtype, associated with higher mortality and disability rates. Our aim was to find genetic risk factors associated with PH, as that could provide molecular targets/pathways for their prevention/treatment and study its genetic correlations to find traits sharing genetic background. We performed a GWAS and meta-analysis, following standard quality controls and association analysis (fastGWAS), adjusting age, NIHSS, and principal components. FUMA was used to annotate, prioritize, visualize, and interpret the meta-analysis results. The total number of patients in the meta-analysis was 2034 (216 cases and 1818 controls). We found rs79770152 having a genome-wide significant association (beta 0.09, p -value 3.90 × 10
-8 ) located in the RP11-362K2.2:RP11-767I20.1 gene and a suggestive variant (rs13297983: beta 0.07, p -value 6.10 × 10-8 ) located in PCSK5 associated with PH occurrence. The genetic correlation showed a shared genetic background of PH with Alzheimer's disease and white matter hyperintensities. In addition, genes containing the ten most significant associations have been related to aggregated amyloid-β, tau protein, white matter microstructure, inflammation, and matrix metalloproteinases. more...- Published
- 2021
- Full Text
- View/download PDF
16. Early Neurological Change After Ischemic Stroke Is Associated With 90-Day Outcome.
- Author
-
Heitsch L, Ibanez L, Carrera C, Binkley MM, Strbian D, Tatlisumak T, Bustamante A, Ribó M, Molina C, Dávalos A, López-Cancio E, Muñoz-Narbona L, Soriano-Tárraga C, Giralt-Steinhauer E, Obach V, Slowik A, Pera J, Lapicka-Bodzioch K, Derbisz J, Sobrino T, Castillo J, Campos F, Rodríguez-Castro E, Arias-Rivas S, Segura T, Serrano-Heras G, Vives-Bauza C, Díaz-Navarro R, Tur S, Jimenez C, Martí-Fàbregas J, Delgado-Mederos R, Arenillas J, Krupinski J, Cullell N, Torres-Aguila NP, Muiño E, Cárcel-Márquez J, Moniche F, Cabezas JA, Ford AL, Dhar R, Roquer J, Khatri P, Jiménez-Conde J, Fernandez-Cadenas I, Montaner J, Rosand J, Cruchaga C, and Lee JM more...
- Subjects
- Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Ischemic Stroke, Recovery of Function, Severity of Illness Index
- Abstract
Background and Purpose: Large-scale observational studies of acute ischemic stroke (AIS) promise to reveal mechanisms underlying cerebral ischemia. However, meaningful quantitative phenotypes attainable in large patient populations are needed. We characterize a dynamic metric of AIS instability, defined by change in National Institutes of Health Stroke Scale score (NIHSS) from baseline to 24 hours baseline to 24 hours (NIHSS
baseline - NIHSS24hours = ΔNIHSS6-24h ), to examine its relevance to AIS mechanisms and long-term outcomes., Methods: Patients with NIHSS prospectively recorded within 6 hours after onset and then 24 hours later were enrolled in the GENISIS study (Genetics of Early Neurological Instability After Ischemic Stroke). Stepwise linear regression determined variables that independently influenced ΔNIHSS6 -24h . In a subcohort of tPA (alteplase)-treated patients with large vessel occlusion, the influence of early sustained recanalization and hemorrhagic transformation on ΔNIHSS6-24h was examined. Finally, the association of ΔNIHSS6 -24h with 90-day favorable outcomes (modified Rankin Scale score 0-2) was assessed. Independent analysis was performed using data from the 2 NINDS-tPA stroke trials (National Institute of Neurological Disorders and Stroke rt-PA)., Results: For 2555 patients with AIS, median baseline NIHSS was 9 (interquartile range, 4-16), and median ΔNIHSS6 -24h was 2 (interquartile range, 0-5). In a multivariable model, baseline NIHSS, tPA-treatment, age, glucose, site, and systolic blood pressure independently predicted ΔNIHSS6 -24h (R2 =0.15). In the large vessel occlusion subcohort, early sustained recanalization and hemorrhagic transformation increased the explained variance (R2 =0.27), but much of the variance remained unexplained. ΔNIHSS6 -24h had a significant and independent association with 90-day favorable outcome. For the subjects in the 2 NINDS-tPA trials, ΔNIHSS3 -24h was similarly associated with 90-day outcomes., Conclusions: The dynamic phenotype, ΔNIHSS6-24h , captures both explained and unexplained mechanisms involved in AIS and is significantly and independently associated with long-term outcomes. Thus, ΔNIHSS6 -24h promises to be an easily obtainable and meaningful quantitative phenotype for large-scale genomic studies of AIS. more...- Published
- 2021
- Full Text
- View/download PDF
17. Genome-Wide Association Study of White Blood Cell Counts in Patients With Ischemic Stroke.
- Author
-
Torres-Aguila NP, Carrera C, Giese AK, Cullell N, Muiño E, Cárcel-Márquez J, Gallego-Fabrega C, González-Sánchez J, Del Mar Freijo M, Álvarez-Sabín J, Molina C, Ribó M, Jimenez-Conde J, Roquer J, Sobrino T, Campos F, Castillo J, Muñoz-Narbona L, Lopez-Cancio E, Dàvalos A, Diaz-Navarro R, Tur S, Vives-Bauza C, Serrano-Heras G, Segura T, Krupinski J, Delgado-Mederos R, Martí-Fàbregas J, Heitsch L, Ibañez L, Cruchaga C, Rost NS, Montaner J, Lee JM, and Fernandez-Cadenas I more...
- Subjects
- Aged, Aged, 80 and over, Brain Ischemia genetics, Chromosomes, Human, Pair 14 genetics, Female, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Prognosis, Stroke genetics, Brain Ischemia immunology, Leukocyte Count, Leukocytes immunology, Stroke immunology
- Abstract
Background and Purpose- Immune cells play a key role in the first 24h poststroke (acute phase), being associated with stroke outcome. We aimed to find genetic risk factors associated with leukocyte counts during the acute phase of stroke. Methods- Ischemic stroke patients with leukocyte counts data during the first 24h were included. Genome-wide association study and gene expression studies were performed. Results- Our genome-wide association study, which included 2064 (Discovery) and 407 (Replication) patients, revealed a new locus (14q24.3) associated with leukocyte counts. After Joint analysis (n=2471) 5 more polymorphisms reached genome-wide significance ( P <5×10
-8 ). The 14q24.3 locus was associated with acute stroke outcome (rs112809786, P =0.036) and with ACOT1 and PTGR2 gene expression. Previous polymorphisms associated with leukocyte counts in general-population did not show any significance in our study. Conclusions- We have found the first locus associated with leukocyte counts in ischemic stroke, also associated with acute outcome. Genetic analysis of acute endophenotypes could be useful to find the genetic factors associated with stroke outcome. Our findings suggested a different modulation of immune cells in stroke compared with healthy conditions. more...- Published
- 2019
- Full Text
- View/download PDF
18. CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis.
- Author
-
Genin EC, Plutino M, Bannwarth S, Villa E, Cisneros-Barroso E, Roy M, Ortega-Vila B, Fragaki K, Lespinasse F, Pinero-Martos E, Augé G, Moore D, Burté F, Lacas-Gervais S, Kageyama Y, Itoh K, Yu-Wai-Man P, Sesaki H, Ricci JE, Vives-Bauza C, and Paquis-Flucklinger V more...
- Subjects
- Alleles, Cell Line, Cytochromes c metabolism, DNA Repair drug effects, DNA, Mitochondrial analysis, DNA, Mitochondrial metabolism, HeLa Cells, Humans, Hydrogen Peroxide toxicity, Lysosomes metabolism, Membrane Potential, Mitochondrial, Mitochondria metabolism, Mitochondrial Diseases genetics, Mitochondrial Diseases pathology, Mitochondrial Proteins metabolism, Mutation, Oxidative Stress drug effects, Real-Time Polymerase Chain Reaction, Apoptosis genetics, Genome, Mitochondrial, Mitochondria genetics, Mitochondrial Proteins genetics
- Abstract
CHCHD10-related diseases include mitochondrial DNA instability disorder, frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) clinical spectrum, late-onset spinal motor neuropathy (SMAJ), and Charcot-Marie-Tooth disease type 2 (CMT2). Here, we show that CHCHD10 resides with mitofilin, CHCHD3 and CHCHD6 within the "mitochondrial contact site and cristae organizing system" (MICOS) complex. CHCHD10 mutations lead to MICOS complex disassembly and loss of mitochondrial cristae with a decrease in nucleoid number and nucleoid disorganization. Repair of the mitochondrial genome after oxidative stress is impaired in CHCHD10 mutant fibroblasts and this likely explains the accumulation of deleted mtDNA molecules in patient muscle. CHCHD10 mutant fibroblasts are not defective in the delivery of mitochondria to lysosomes suggesting that impaired mitophagy does not contribute to mtDNA instability. Interestingly, the expression of CHCHD10 mutant alleles inhibits apoptosis by preventing cytochrome c release., (© 2015 The Authors. Published under the terms of the CC BY 4.0 license.) more...
- Published
- 2016
- Full Text
- View/download PDF
19. Dual cases of type 1 narcolepsy with schizophrenia and other psychotic disorders.
- Author
-
Canellas F, Lin L, Julià MR, Clemente A, Vives-Bauza C, Ollila HM, Hong SC, Arboleya SM, Einen MA, Faraco J, Fernandez-Vina M, and Mignot E
- Subjects
- Adolescent, Adult, Aged, Antibodies, Antinuclear analysis, Antipsychotic Agents therapeutic use, Child, Diagnosis, Differential, Enzyme-Linked Immunosorbent Assay, Female, Hallucinations complications, Histocompatibility Testing methods, Humans, Male, Narcolepsy diagnosis, Polysomnography, Psychotic Disorders diagnosis, Psychotic Disorders drug therapy, Schizophrenia diagnosis, Schizophrenia drug therapy, Surveys and Questionnaires, Narcolepsy complications, Psychotic Disorders complications, Schizophrenia complications
- Abstract
Objective: Cases of narcolepsy in association with psychotic features have been reported but never fully characterized. These patients present diagnostic and treatment challenges and may shed new light on immune associations in schizophrenia., Method: Our case series was gathered at two narcolepsy specialty centers over a 9-year period. A questionnaire was created to improve diagnosis of schizophrenia or another psychotic disorder in patients with narcolepsy. Pathophysiological investigations included full HLA Class I and II typing, testing for known systemic and intracellular/synaptic neuronal antibodies, recently described neuronal surface antibodies, and immunocytochemistry on brain sections to detect new antigens., Results: Ten cases were identified, one with schizoaffective disorder, one with delusional disorder, two with schizophreniform disorder, and 6 with schizophrenia. In all cases, narcolepsy manifested first in childhood or adolescence, followed by psychotic symptoms after a variable interval. These patients had auditory hallucinations, which was the most differentiating clinical feature in comparison to narcolepsy patients without psychosis. Narcolepsy therapy may have played a role in triggering psychotic symptoms but these did not reverse with changes in narcolepsy medications. Response to antipsychotic treatment was variable. Pathophysiological studies did not reveal any known autoantibodies or unusual brain immunostaining pattern. No strong HLA association outside of HLA DQB1*06:02 was found, although increased DRB3*03 and DPA1*02:01 was notable., Conclusion: Narcolepsy can occur in association with schizophrenia, with significant diagnostic and therapeutic challenges. Dual cases maybe under diagnosed, as onset is unusually early, often in childhood. Narcolepsy and psychosis may share an autoimmune pathology; thus, further investigations in larger samples are warranted., (© 2014 American Academy of Sleep Medicine.) more...
- Published
- 2014
- Full Text
- View/download PDF
20. PINK1 points Parkin to mitochondria.
- Author
-
Vives-Bauza C and Przedborski S
- Subjects
- Animals, Autophagy, Humans, Parkinson Disease enzymology, Parkinson Disease pathology, Signal Transduction, Ubiquitination, Voltage-Dependent Anion Channel 1 metabolism, Mitochondria metabolism, Protein Kinases metabolism, Ubiquitin-Protein Ligases metabolism
- Abstract
For decades, it has been presumed that mitochondrial dysfunction, in the form of impaired complex I activity, may contribute to the cause of Parkinson disease (PD). ( 1) The discovery that several gene mutations cause familial forms of PD ( 1) has led to a renewed enthusiasm for the mitochondrial hypothesis of PD, but this time from a quite distinct and, perhaps, more realistic angle. Among these genes, those that code for PTEN-induced kinase-1 (PINK1) ( 2) and for the E3-ubiquitin ligase Parkin ( 3) did attract major interest from mitochondriologists, in part, because both proteins interact with each other and apparently function, genetically, within the same molecular pathway to modulate mitochondrial dynamics in Drosophila. ( 4-6). more...
- Published
- 2010
- Full Text
- View/download PDF
21. PINK1/Parkin direct mitochondria to autophagy.
- Author
-
Vives-Bauza C, de Vries RL, Tocilescu M, and Przedborski S
- Subjects
- HeLa Cells, Humans, Membrane Potential, Mitochondrial physiology, Parkinson Disease metabolism, Protein Kinases genetics, Ubiquitin-Protein Ligases genetics, Autophagy physiology, Mitochondria metabolism, Protein Kinases metabolism, Ubiquitin-Protein Ligases metabolism
- Published
- 2010
- Full Text
- View/download PDF
22. PINK1-dependent recruitment of Parkin to mitochondria in mitophagy.
- Author
-
Vives-Bauza C, Zhou C, Huang Y, Cui M, de Vries RL, Kim J, May J, Tocilescu MA, Liu W, Ko HS, Magrané J, Moore DJ, Dawson VL, Grailhe R, Dawson TM, Li C, Tieu K, and Przedborski S
- Subjects
- Carbonyl Cyanide m-Chlorophenyl Hydrazone metabolism, Cell Line, Humans, Ionophores metabolism, Microtubules metabolism, Microtubules ultrastructure, Mitochondria ultrastructure, Parkinson Disease genetics, Parkinson Disease metabolism, Protein Binding, Protein Kinases genetics, Protein Transport physiology, Ubiquitin-Protein Ligases genetics, Autophagy physiology, Membrane Potential, Mitochondrial physiology, Mitochondria metabolism, Protein Kinases metabolism, Ubiquitin-Protein Ligases metabolism
- Abstract
Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) and PARK2/Parkin mutations cause autosomal recessive forms of Parkinson's disease. Upon a loss of mitochondrial membrane potential (DeltaPsi(m)) in human cells, cytosolic Parkin has been reported to be recruited to mitochondria, which is followed by a stimulation of mitochondrial autophagy. Here, we show that the relocation of Parkin to mitochondria induced by a collapse of DeltaPsi(m) relies on PINK1 expression and that overexpression of WT but not of mutated PINK1 causes Parkin translocation to mitochondria, even in cells with normal DeltaPsi(m). We also show that once at the mitochondria, Parkin is in close proximity to PINK1, but we find no evidence that Parkin catalyzes PINK1 ubiquitination or that PINK1 phosphorylates Parkin. However, co-overexpression of Parkin and PINK1 collapses the normal tubular mitochondrial network into mitochondrial aggregates and/or large perinuclear clusters, many of which are surrounded by autophagic vacuoles. Our results suggest that Parkin, together with PINK1, modulates mitochondrial trafficking, especially to the perinuclear region, a subcellular area associated with autophagy. Thus by impairing this process, mutations in either Parkin or PINK1 may alter mitochondrial turnover which, in turn, may cause the accumulation of defective mitochondria and, ultimately, neurodegeneration in Parkinson's disease. more...
- Published
- 2010
- Full Text
- View/download PDF
23. Novel role of ATPase subunit C targeting peptides beyond mitochondrial protein import.
- Author
-
Vives-Bauza C, Magrané J, Andreu AL, and Manfredi G
- Subjects
- Adenosine Triphosphate biosynthesis, Animals, Down-Regulation, Electron Transport Complex IV metabolism, Gene Expression Regulation, Enzymologic, Gene Silencing, Genetic Complementation Test, HeLa Cells, Humans, Isoenzymes genetics, Isoenzymes metabolism, Mice, Mitochondria genetics, Mitochondrial Proton-Translocating ATPases genetics, Oxidative Phosphorylation, Protein Subunits genetics, Protein Transport, RNA, Messenger genetics, RNA, Messenger metabolism, Recombinant Proteins metabolism, Mitochondria enzymology, Mitochondrial Proton-Translocating ATPases metabolism, Peptides metabolism, Protein Sorting Signals, Protein Subunits metabolism
- Abstract
In mammals, subunit c of the F(1)F(0)-ATP synthase has three isoforms (P1, P2, and P3). These isoforms differ by their cleavable mitochondrial targeting peptides, whereas the mature peptides are identical. To investigate this apparent genetic redundancy, we knocked down each of the three subunit c isoform by RNA interference in HeLa cells. Silencing any of the subunit c isoforms individually resulted in an ATP synthesis defect, indicating that these isoforms are not functionally redundant. We found that subunit c knockdown impaired the structure and function of the mitochondrial respiratory chain. In particular, P2 silencing caused defective cytochrome oxidase assembly and function. Because the expression of exogenous P1 or P2 was able to rescue the respective silencing phenotypes, but the two isoforms were unable to cross-complement, we hypothesized that their functional specificity resided in their targeting peptides. In fact, the expression of P1 and P2 targeting peptides fused to GFP variants rescued the ATP synthesis and respiratory chain defects in the silenced cells. Our results demonstrate that the subunit c isoforms are nonredundant, because they differ functionally by their targeting peptides, which, in addition to mediating mitochondrial protein import, play a yet undiscovered role in respiratory chain maintenance. more...
- Published
- 2010
- Full Text
- View/download PDF
24. PINK1 defect causes mitochondrial dysfunction, proteasomal deficit and alpha-synuclein aggregation in cell culture models of Parkinson's disease.
- Author
-
Liu W, Vives-Bauza C, Acín-Peréz- R, Yamamoto A, Tan Y, Li Y, Magrané J, Stavarache MA, Shaffer S, Chang S, Kaplitt MG, Huang XY, Beal MF, Manfredi G, and Li C
- Subjects
- Humans, Mitochondrial Proteins metabolism, Models, Biological, Mutation, Oxidative Phosphorylation, Parkinson Disease, Mitochondria pathology, Proteasome Endopeptidase Complex deficiency, Protein Kinases genetics, alpha-Synuclein metabolism
- Abstract
Mutations in PTEN induced kinase 1 (PINK1), a mitochondrial Ser/Thr kinase, cause an autosomal recessive form of Parkinson's disease (PD), PARK6. Here, we report that PINK1 exists as a dimer in mitochondrial protein complexes that co-migrate with respiratory chain complexes in sucrose gradients. PARK6 related mutations do not affect this dimerization and its associated complexes. Using in vitro cell culture systems, we found that mutant PINK1 or PINK1 knock-down caused deficits in mitochondrial respiration and ATP synthesis. Furthermore, proteasome function is impaired with a loss of PINK1. Importantly, these deficits are accompanied by increased alpha-synclein aggregation. Our results indicate that it will be important to delineate the relationship between mitochondrial functional deficits, proteasome dysfunction and alpha-synclein aggregation. more...
- Published
- 2009
- Full Text
- View/download PDF
25. The age lipid A2E and mitochondrial dysfunction synergistically impair phagocytosis by retinal pigment epithelial cells.
- Author
-
Vives-Bauza C, Anand M, Shiraz AK, Magrane J, Gao J, Vollmer-Snarr HR, Manfredi G, and Finnemann SC
- Subjects
- Adenosine Triphosphate genetics, Adenosine Triphosphate metabolism, Aging genetics, Aging pathology, Animals, Antioxidants metabolism, Antioxidants pharmacology, Cell Death drug effects, Cell Death genetics, Cell Line, DNA, Mitochondrial genetics, DNA, Mitochondrial metabolism, Epithelial Cells metabolism, Epithelial Cells pathology, Glucose metabolism, Humans, Lipofuscin pharmacology, Lysosomes genetics, Lysosomes metabolism, Lysosomes pathology, Macular Degeneration genetics, Macular Degeneration metabolism, Macular Degeneration pathology, Membrane Potential, Mitochondrial drug effects, Membrane Potential, Mitochondrial genetics, Mitochondria genetics, Mitochondria pathology, Mitosis drug effects, Mitosis genetics, Oxidative Phosphorylation drug effects, Pigment Epithelium of Eye pathology, Point Mutation, Pyridinium Compounds pharmacology, Pyruvic Acid metabolism, Rats, Rats, Long-Evans, Retinoids pharmacology, Aging metabolism, Lipofuscin metabolism, Mitochondria metabolism, Phagocytosis drug effects, Phagocytosis genetics, Pigment Epithelium of Eye metabolism, Pyridinium Compounds metabolism, Retinoids metabolism
- Abstract
Accumulation of indigestible lipofuscin and decreased mitochondrial energy production are characteristic age-related changes of post-mitotic retinal pigment epithelial (RPE) cells in the human eye. To test whether these two forms of age-related impairment have interdependent effects, we quantified the ATP-dependent phagocytic function of RPE cells loaded or not with the lipofuscin component A2E and inhibiting or not mitochondrial ATP synthesis either pharmacologically or genetically. We found that physiological levels of lysosomal A2E reduced mitochondrial membrane potential and inhibited oxidative phosphorylation (OXPHOS) of RPE cells. Furthermore, in media with physiological concentrations of glucose or pyruvate, A2E significantly inhibited phagocytosis. Antioxidants reversed these effects of A2E, suggesting that A2E damage is mediated by oxidative processes. Because mitochondrial mutations accumulate with aging, we generated novel genetic cellular models of RPE carrying mitochondrial DNA point mutations causing either moderate or severe mitochondrial dysfunction. Exploring these mutant RPE cells we found that, by itself, only the severe but not the moderate OXPHOS defect reduces phagocytosis. However, sub-toxic levels of lysosomal A2E are sufficient to reduce phagocytic activity of RPE with moderate OXPHOS defect and cause cell death of RPE with severe OXPHOS defect. Taken together, RPE cells rely on OXPHOS for phagocytosis when the carbon energy source is limited. Our results demonstrate that A2E accumulation exacerbates the effects of moderate mitochondrial dysfunction. They suggest that synergy of sub-toxic lysosomal and mitochondrial changes in RPE cells with age may cause RPE dysfunction that is known to contribute to human retinal diseases like age-related macular degeneration. more...
- Published
- 2008
- Full Text
- View/download PDF
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.