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2. 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

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.

Published
2022

3. A functional genetic variation of SLC6A2 repressor hsa-miR-579-3p upregulates sympathetic noradrenergic processes of fear and anxiety

Author

Hommers, L. G., Richter, J., Yang, Y., Raab, A., Baumann, C., Lang, K., Schiele, M. A., Weber, H., Wittmann, A., Wolf, C., Alpers, G. W., Arolt, V., Domschke, K., Fehm, L., Fydrich, T., Gerlach, A., Gloster, A. T., Hamm, A. O., Helbig-Lang, S., Kircher, T., Lang, T., Pane-Farre, C. A., Pauli, P., Pfleiderer, B., Reif, A., Romanos, M., Straube, B., Stroehle, A., Wittchen, H. -U., Frantz, S., Ertl, G., Lohse, M. J., Lueken, U., Deckert, J., Hommers, L. G., Richter, J., Yang, Y., Raab, A., Baumann, C., Lang, K., Schiele, M. A., Weber, H., Wittmann, A., Wolf, C., Alpers, G. W., Arolt, V., Domschke, K., Fehm, L., Fydrich, T., Gerlach, A., Gloster, A. T., Hamm, A. O., Helbig-Lang, S., Kircher, T., Lang, T., Pane-Farre, C. A., Pauli, P., Pfleiderer, B., Reif, A., Romanos, M., Straube, B., Stroehle, A., Wittchen, H. -U., Frantz, S., Ertl, G., Lohse, M. J., Lueken, U., and Deckert, J.

Abstract

Increased sympathetic noradrenergic signaling is crucially involved in fear and anxiety as defensive states. MicroRNAs regulate dynamic gene expression during synaptic plasticity and genetic variation of microRNAs modulating noradrenaline transporter gene (SLC6A2) expression may thus lead to altered central and peripheral processing of fear and anxiety. In silico prediction of microRNA regulation of SLC6A2 was confirmed by luciferase reporter assays and identified hsa-miR-579-3p as a regulating microRNA. The minor (T)-allele of rs2910931 (MAF(cases) = 0.431, MAF(controls) = 0.368) upstream of MIR579 was associated with panic disorder in patients (p(allelic) = 0.004, n(cases) = 506, n(controls) = 506) and with higher trait anxiety in healthy individuals (p(ASI) = 0.029, p(ACQ) = 0.047, n = 3112). Compared to the major (A)allele, increased promoter activity was observed in luciferase reporter assays in vitro suggesting more effective MIR579 expression and SLC6A2 repression in vivo (p = 0.041). Healthy individuals carrying at least one (T)-allele showed a brain activation pattern suggesting increased defensive responding and sympathetic noradrenergic activation in midbrain and limbic areas during the extinction of conditioned fear. Panic disorder patients carrying two (T)-alleles showed elevated heart rates in an anxiety-provoking behavioral avoidance test (F(2, 270) = 5.47, p = 0.005). Fine-tuning of noradrenaline homeostasis by a MIR579 genetic variation modulated central and peripheral sympathetic noradrenergic activation during fear processing and anxiety. This study opens new perspectives on the role of microRNAs in the etiopathogenesis of anxiety disorders, particularly their cardiovascular symptoms and comorbidities.

Published
2018

4. A functional genetic variation of SLC6A2 repressor hsa-miR-579-3p upregulates sympathetic noradrenergic processes of fear and anxiety

Author

Hommers, L. G., Richter, J., Yang, Y., Raab, A., Baumann, C., Lang, K., Schiele, M. A., Weber, H., Wittmann, A., Wolf, C., Alpers, G. W., Arolt, V., Domschke, K., Fehm, L., Fydrich, T., Gerlach, Alexander L., Gloster, A. T., Hamm, A. O., Helbig-Lang, S., Kircher, T., Lang, T., Pané-Farré, C. A., Pauli, P., Pfleiderer, B., Reif, A., Romanos, M., Straube, B., Ströhle, A., Wittchen, H.-U., Frantz, S., Ertl, G., Lohse, M. J., Lueken, U., Deckert, J., Hommers, L. G., Richter, J., Yang, Y., Raab, A., Baumann, C., Lang, K., Schiele, M. A., Weber, H., Wittmann, A., Wolf, C., Alpers, G. W., Arolt, V., Domschke, K., Fehm, L., Fydrich, T., Gerlach, Alexander L., Gloster, A. T., Hamm, A. O., Helbig-Lang, S., Kircher, T., Lang, T., Pané-Farré, C. A., Pauli, P., Pfleiderer, B., Reif, A., Romanos, M., Straube, B., Ströhle, A., Wittchen, H.-U., Frantz, S., Ertl, G., Lohse, M. J., Lueken, U., and Deckert, J.

Published
2018

5. A functional genetic variation of SLC6A2 repressor hsa-miR-579-3p upregulates sympathetic noradrenergic processes of fear and anxiety

Author

Hommers, L. G., Richter, J., Yang, Y., Raab, A., Baumann, C., Lang, K., Schiele, M. A., Weber, H., Wittmann, A., Wolf, C., Alpers, G. W., Arolt, V., Domschke, K., Fehm, L., Fydrich, T., Gerlach, A., Gloster, A. T., Hamm, A. O., Helbig-Lang, S., Kircher, T., Lang, T., Pane-Farre, C. A., Pauli, P., Pfleiderer, B., Reif, A., Romanos, M., Straube, B., Stroehle, A., Wittchen, H. -U., Frantz, S., Ertl, G., Lohse, M. J., Lueken, U., Deckert, J., Hommers, L. G., Richter, J., Yang, Y., Raab, A., Baumann, C., Lang, K., Schiele, M. A., Weber, H., Wittmann, A., Wolf, C., Alpers, G. W., Arolt, V., Domschke, K., Fehm, L., Fydrich, T., Gerlach, A., Gloster, A. T., Hamm, A. O., Helbig-Lang, S., Kircher, T., Lang, T., Pane-Farre, C. A., Pauli, P., Pfleiderer, B., Reif, A., Romanos, M., Straube, B., Stroehle, A., Wittchen, H. -U., Frantz, S., Ertl, G., Lohse, M. J., Lueken, U., and Deckert, J.

Abstract

Increased sympathetic noradrenergic signaling is crucially involved in fear and anxiety as defensive states. MicroRNAs regulate dynamic gene expression during synaptic plasticity and genetic variation of microRNAs modulating noradrenaline transporter gene (SLC6A2) expression may thus lead to altered central and peripheral processing of fear and anxiety. In silico prediction of microRNA regulation of SLC6A2 was confirmed by luciferase reporter assays and identified hsa-miR-579-3p as a regulating microRNA. The minor (T)-allele of rs2910931 (MAF(cases) = 0.431, MAF(controls) = 0.368) upstream of MIR579 was associated with panic disorder in patients (p(allelic) = 0.004, n(cases) = 506, n(controls) = 506) and with higher trait anxiety in healthy individuals (p(ASI) = 0.029, p(ACQ) = 0.047, n = 3112). Compared to the major (A)allele, increased promoter activity was observed in luciferase reporter assays in vitro suggesting more effective MIR579 expression and SLC6A2 repression in vivo (p = 0.041). Healthy individuals carrying at least one (T)-allele showed a brain activation pattern suggesting increased defensive responding and sympathetic noradrenergic activation in midbrain and limbic areas during the extinction of conditioned fear. Panic disorder patients carrying two (T)-alleles showed elevated heart rates in an anxiety-provoking behavioral avoidance test (F(2, 270) = 5.47, p = 0.005). Fine-tuning of noradrenaline homeostasis by a MIR579 genetic variation modulated central and peripheral sympathetic noradrenergic activation during fear processing and anxiety. This study opens new perspectives on the role of microRNAs in the etiopathogenesis of anxiety disorders, particularly their cardiovascular symptoms and comorbidities.

Published
2018

13. Immune cells as targets for cardioprotection: new players and novel therapeutic opportunities

Author

Andreadou I., Cabrera-Fuentes H., Devaux Y., Frangogiannis N., Frantz S., Guzik T., Liehn E., Gomes C., Schulz R., Hausenloy D., Andreadou I., Cabrera-Fuentes H., Devaux Y., Frangogiannis N., Frantz S., Guzik T., Liehn E., Gomes C., Schulz R., and Hausenloy D.

Abstract

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com. New therapies are required to reduce myocardial infarct (MI) size and prevent the onset of heart failure in patients presenting with acute myocardial infarction (AMI), one of the leading causes of death and disability globally. In this regard, the immune cell response to AMI, which comprises an initial pro-inflammatory reaction followed by an anti-inflammatory phase, contributes to final MI size and post-AMI remodelling [changes in left ventricular (LV) size and function]. The transition between these two phases is critical in this regard, with a persistent and severe pro-inflammatory reaction leading to adverse LV remodelling and increased propensity for developing heart failure. In this review article, we provide an overview of the immune cells involved in orchestrating the complex and dynamic inflammatory response to AMI-these include neutrophils, monocytes/macrophages, and emerging players such as dendritic cells, lymphocytes, pericardial lymphoid cells, endothelial cells, and cardiac fibroblasts. We discuss potential reasons for past failures of anti-inflammatory cardioprotective therapies, and highlight new treatment targets for modulating the immune cell response to AMI, as a potential therapeutic strategy to improve clinical outcomes in AMI patients. This article is part of a Cardiovascular Research Spotlight Issue entitled 'Cardioprotection Beyond the Cardiomyocyte', and emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225.

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