Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates A beta, tau, immunity and lipid processing
Autor: | KUNKLE, B. W., GRENIER-BOLEY, B., SIMS, R., BIS, J. C., DAMOTTE, V., NAJ, A. C., BOLAND, A., VRONSKAYA, M., VAN DER LEE, S. J., AMLIE-WOLF, A., BELLENGUEZ, C., FRIZATTI, A., CHOURAKI, V., MARTIN, E. R., SLEEGERS, K., BADARINARAYAN, N., JAKOBSDOTTIR, J., HAMILTON-NELSON, K. L., MORENO-GRAU, S., OLASO, R., RAYBOULD, R., CHEN, Y., KUZMA, A. B., HILTUNEN, M., MORGAN, T., AHMAD, S., VARDARAJAN, B. N., EPELBAUM, J., HOFFMANN, P., BOADA, M., BEECHAM, G. W., GARNIER, J. G., HAROLD, D., FITZPATRICK, A. L., VALLADARES, O., MOUTET, M. L., GERRISH, A., SMITH, A. V., QU, L., BACQ, D., DENNING, N., JIAN, X., ZHAO, Y., DEL ZOMPO, M., FOX, N. C., CHOI, S. H., MATEO, I., HUGHES, J. T., ADAMS, H. H., MALAMON, J., SANCHEZ-GARCIA, F., PATEL, Y., BRODY, J. A., DOMBROSKI, B. A., NARANJO, M. C. D., DANIILIDOU, M., EIRIKSDOTTIR, G., MUKHERJEE, S., WALLON, D., UPHILL, J., ASPELUND, T., CANTWELL, L. B., GARZIA, F., GALIMBERTI, D., HOFER, E., BUTKIEWICZ, M., FIN, B., SCARPINI, E., SARNOWSKI, C., BUSH, W. S., MESLAGE, S., KORNHUBER, J., WHITE, C. C., SONG, Y., BARBER, R. C., ENGELBORGHS, S., SORDON, S., VOIJNOVIC, D., ADAMS, P. M., VANDENBERGHE, R., MAYHAUS, M., CUPPLES, L. A., ALBERT, M. S., DE DEYN, P. P., GU, W., HIMALI, J. J., BEEKLY, D., SQUASSINA, A., HARTMANN, A. M., ORELLANA, A., BLACKER, D., RODRIGUEZ-RODRIGUEZ, E., LOVESTONE, S., GARCIA, M. E., DOODY, R. S., MUNOZ-FERNADEZ, C., SUSSAMS, R., LIN, H., FAIRCHILD, T. J., BENITO, Y. A., HOLMES, C., KARAMUJIC-COMIC, H., FROSCH, M. P., THONBERG, H., MAIER, W., ROSCHUPKIN, G., GHETTI, B., GIEDRAITIS, V., KAWALIA, A., LI, S., HUEBINGER, R. M., KILANDER, L., MOEBUS, S., HERNANDEZ, I., KAMBOH, M. I., BRUNDIN, R., TURTON, J., YANG, Q., KATZ, M. J., CONCARI, L., LORD, J., BEISER, A. S., KEENE, C. D., HELISALMI, S., KLOSZEWSKA, I., KUKULL, W. A., KOIVISTO, A. M., LYNCH, A., TARRAGA, L., LARSON, E. B., HAAPASALO, A., LAWLOR, B., MOSLEY, T. H., LIPTON, R. B., SOLFRIZZI, V., GILL, M., LONGSTRETH, W. T. Jr., MONTINE, T. J., FRISARDI, V., DIEZ-FAIREN, M., RIVADENEIRA, F., PETERSEN, R. C., DERAMECOURT, V., ALVAREZ, I., SALANI, F., CIARAMELLA, A., BOERWINKLE, E., REIMAN, E. M., FIEVET, N., ROTTER, J. I., REISCH, J. S., HANON, O., CUPIDI, C., ANDRE UITTERLINDEN, A. G., ROYALL, D. R., DUFOUIL, Carole, MALETTA, R. G., DE ROJAS, I., SANO, M., BRICE, A., CECCHETTI, R., GEORGE-HYSLOP, P. S., RITCHIE, K., TSOLAKI, M., TSUANG, D. W., DUBOIS, B., CRAIG, D., WU, C. K., SOININEN, H., AVRAMIDOU, D., ALBIN, R. L., FRATIGLIONI, L., GERMANOU, A., APOSTOLOVA, L. G., KELLER, L., KOUTROUMANI, M., ARNOLD, S. E., PANZA, F., GKATZIMA, O., ASTHANA, S., HANNEQUIN, D., WHITEHEAD, P., ATWOOD, C. S., CAFFARRA, P., HAMPEL, H., QUINTELA, I., CARRACEDO, A., LANNFELT, L., RUBINSZTEIN, D. C., BARNES, L. L., PASQUIER, F., FROLICH, L., BARRAL, S., MCGUINNESS, B., BEACH, T. G., JOHNSTON, J. A., BECKER, J. T., PASSMORE, P., BIGIO, E. H., SCHOTT, J. M., BIRD, T. D., WARREN, J. D., BOEVE, B. F., LUPTON, M. K., BOWEN, J. D., PROITSI, P., BOXER, A., POWELL, J. F., BURKE, J. R., KAUWE, J. S. K., BURNS, J. M., MANCUSO, M., BUXBAUM, J. D., BONUCCELLI, U., CAIRNS, N. J., MCQUILLIN, A., CAO, C., LIVINGSTON, G., CARLSON, C. S., BASS, N. J., CARLSSON, C. M., HARDY, J., CARNEY, R. M., BRAS, J., CARRASQUILLO, M. M., GUERREIRO, R., ALLEN, M., CHUI, H. C., FISHER, E., MASULLO, C., CROCCO, E. A., DECARLI, C., BISCEGLIO, G., DICK, M., MA, L., DUARA, R., GRAFF-RADFORD, N. R., EVANS, D. A., HODGES, A., FABER, K. M., SCHERER, M., FALLON, K. B., RIEMENSCHNEIDER, M., FARDO, D. W., HEUN, R., FARLOW, M. R., KOLSCH, H., FERRIS, S., LEBER, M., FOROUD, T. M., HEUSER, I., GALASKO, D. R., GIEGLING, I., GEARING, M., HULL, M., GESCHWIND, D. H., GILBERT, J. R., MORRIS, J., GREEN, R. C., MAYO, K., GROWDON, J. H., FEULNER, T., HAMILTON, R. L., HARRELL, L. E., DRICHEL, D., HONIG, L. S., CUSHION, T. D., HUENTELMAN, M. J., HOLLINGWORTH, P., HULETTE, C. M., HYMAN, B. T., MARSHALL, R., JARVIK, G. P., MEGGY, A., ABNER, E., MENZIES, G. E., JIN, L. W., LEONENKO, G., REAL, L. M., JUN, G. R., BALDWIN, C. T., GROZEVA, D., KARYDAS, A., RUSSO, G., KAYE, J. A., KIM, R., JESSEN, F., KOWALL, N. W., VELLAS, B., KRAMER, J. H., VARDY, E., LAFERLA, F. M., JOCKEL, K. H., LAH, J. J., DICHGANS, M., LEVERENZ, J. B., MANN, D., LEVEY, A. I., PICKERING-BROWN, S., LIEBERMAN, A. P., KLOPP, N., LUNETTA, K. L., WICHMANN, H. E., LYKETSOS, C. G., MORGAN, K., MARSON, D. C., BROWN, K., MARTINIUK, F., MEDWAY, C., MASH, D. C., NOTHEN, M. M., MASLIAH, E., HOOPER, N. M., MCCORMICK, W. C., DANIELE, A., MCCURRY, S. M., BAYER, A., MCDAVID, A. N., GALLACHER, J., MCKEE, A. C., VAN DEN BUSSCHE, H., MESULAM, M., BRAYNE, C., MILLER, B. L., RIEDEL-HELLER, S., MILLER, C. A., MILLER, J. W., AL-CHALABI, A., MORRIS, J. C., SHAW, C. E., MYERS, A. J., WILTFANG, J., O'BRYANT, S., OLICHNEY, J. M., ALVAREZ, V., PARISI, J. E., SINGLETON, A. B., PAULSON, H. L., COLLINGE, J., PERRY, W. R., MEAD, S., PESKIND, E., CRIBBS, D. H., ROSSOR, M., PIERCE, A., RYAN, N. S., POON, W. W., NACMIAS, B., POTTER, H., SORBI, S., QUINN, J. F., SACCHINELLI, E., RAJ, A., SPALLETTA, G., RASKIND, M., CALTAGIRONE, C., BOSSU, P., ORFEI, M. D., REISBERG, B., CLARKE, R., REITZ, C., SMITH, A. D., RINGMAN, J. M., WARDEN, D., ROBERSON, E. D., WILCOCK, G., ROGAEVA, E., BRUNI, A. C., ROSEN, H. J., GALLO, M., ROSENBERG, R. N., BEN-SHLOMO, Y., SAGER, M. A., MECOCCI, P., SAYKIN, A. J., PASTOR, P., CUCCARO, M. L., VANCE, J. M., SCHNEIDER, J. A., SCHNEIDER, L. S., SLIFER, S., SEELEY, W. W., SMITH, A. G., SONNEN, J. A., SPINA, S., STERN, R. A., SWERDLOW, R. H., TANG, M., TANZI, R. E., TROJANOWSKI, J. Q., TRONCOSO, J. C., VAN DEERLIN, V. M., VAN ELDIK, L. J., VINTERS, H. V., VONSATTEL, J. P., WEINTRAUB, S., WELSH-BOHMER, K. A., WILHELMSEN, K. C., WILLIAMSON, J., WINGO, T. S., WOLTJER, R. L., WRIGHT, C. B., YU, C. E., YU, L., SABA, Y., ALZHEIMER DISEASE GENETICS, Consortium, EUROPEAN ALZHEIMER'S DISEASE, Initiative, COHORTS FOR, Heart, AGING RESEARCH IN GENOMIC EPIDEMIOLOGY, Consortium, GENETIC ENVIRONMENTAL RISK IN AD/DEFINING GENETIC, Polygenic, ENVIRONMENTAL RISK FOR ALZHEIMER'S DISEASE, Consortium, PILOTTO, A., BULLIDO, M. J., PETERS, O., CRANE, P. K., BENNETT, D., BOSCO, P., COTO, E., BOCCARDI, V., DE JAGER, P. L., LLEO, A., WARNER, N., LOPEZ, O. L., INGELSSON, M., DELOUKAS, P., CRUCHAGA, C., GRAFF, C., GWILLIAM, R., FORNAGE, M., GOATE, A. M., SANCHEZ-JUAN, P., KEHOE, P. G., AMIN, N., ERTEKIN-TANER, N., BERR, C., DEBETTE, Stephanie, LOVE, S., LAUNER, L. J., YOUNKIN, S. G., DARTIGUES, Jean-Francois, CORCORAN, C., IKRAM, M. A., DICKSON, D. W., NICOLAS, G., CAMPION, D., TSCHANZ, J., SCHMIDT, H., HAKONARSON, H., CLARIMON, J., MUNGER, R., SCHMIDT, R., FARRER, L. A., VAN BROECKHOVEN, C., M, C. O' Donovan, DESTEFANO, A. L., JONES, L., HAINES, J. L., DELEUZE, J. F., OWEN, M. J., GUDNASON, V., MAYEUX, R., ESCOTT-PRICE, V., PSATY, B. M., RAMIREZ, A., WANG, L. S., RUIZ, A., VAN DUIJN, C. M., HOLMANS, P. A., SESHADRI, S., WILLIAMS, J., AMOUYEL, P., SCHELLENBERG, G. D., LAMBERT, J. C., PERICAK-VANCE, M. A. |
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Přispěvatelé: | Epidemiology, Internal Medicine, Neurology, Radiology & Nuclear Medicine, Amsterdam Reproduction & Development (AR&D), Clinical sciences, Pathologic Biochemistry and Physiology, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM) |
Rok vydání: | 2019 |
Předmět: |
Male
Medizin Gene Expression genetics [Alzheimer Disease] Genome-wide association study methods [Genome-Wide Association Study] SEPIA Genome-wide association studies genetic meta-analysis 0302 clinical medicine genetics [Immunity] genetics [Amyloid beta-Peptides] genetics tau genetics [Genetic Predisposition to Disease] new risk loci Aβ Genetics Medicine(all) 0303 health sciences medicine.diagnostic_test Alzheimer's disease Lipids 3. Good health Settore MED/26 - NEUROLOGIA VINTAGE Female Amyloid beta methods [Genetic Testing] Tau protein lipid processing tau Proteins genetics [Genetic Loci] Biology Article FR 03 medical and health sciences Alzheimer Disease ddc:570 genetics [Haplotypes] medicine Genetic predisposition Humans Dementia Genetic Predisposition to Disease Genetic Testing LOAD genetics [Lipids] Risk factor immunity Aged 030304 developmental biology Genetic testing Amyloid beta-Peptides Lipid Metabolism medicine.disease Gene expression genetics [tau Proteins] Haplotypes Genetic Loci Case-Control Studies genetics [Lipid Metabolism] genome-wide association studies biology.protein [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie Human medicine 030217 neurology & neurosurgery Genome-Wide Association Study dementia |
Zdroj: | NATURE GENETICS r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau instname Nature Genetics, 51(3), 414-+. Nature Publishing Group 2019, ' Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing ', Nature Genetics, vol. 51, no. 3, pp. 414-430 . https://doi.org/10.1038/s41588-019-0358-2 Nature Genetics, 51(3), 414-430. Nature Publishing Group Kunkle, B W, Grenier-Boley, B, Sims, R, Bis, J C, Damotte, V, Naj, A C, Boland, A, Vronskaya, M, van der Lee, S J, Amlie-Wolf, A, Bellenguez, C, Frizatti, A, Chouraki, V, Martin, E R, Sleegers, K, Badarinarayan, N, Jakobsdottir, J, Hamilton-Nelson, K L, Moreno-Grau, S, Olaso, R, Raybould, R, Chen, Y, Kuzma, A B, Hiltunen, M, Morgan, T, Ahmad, S, Vardarajan, B N, Epelbaum, J, Hoffmann, P, Boada, M, Beecham, G W, Garnier, J G, Harold, D, Fitzpatrick, A L, Valladares, O, Moutet, M L, Gerrish, A, Smith, A V, Qu, L, Bacq, D, Denning, N, Jian, X, Zhao, Y, Del Zompo, M, Fox, N C, Choi, S H, Mateo, I, Hughes, J T, Adams, H H, Malamon, J, Sanchez-Garcia, F, Patel, Y, Brody, J A, Dombroski, B A, Naranjo, M C D, Daniilidou, M, Eiriksdottir, G, Mukherjee, S, Wallon, D, Uphill, J, Aspelund, T, Cantwell, L B, Garzia, F, Galimberti, D, Hofer, E, Butkiewicz, M, Fin, B, Scarpini, E, Sarnowski, C, Bush, W S, Meslage, S, Kornhuber, J, White, C C, Song, Y, Barber, R C, Engelborghs, S, Sordon, S, Voijnovic, D, Adams, P M, Vandenberghe, R, Mayhaus, M, Cupples, L A, Albert, M S, De Deyn, P P, Gu, W, Himali, J J, Beekly, D, Squassina, A, Hartmann, A M, Orellana, A, Blacker, D, Rodriguez-Rodriguez, E, Lovestone, S, Garcia, M E, Doody, R S, Munoz-Fernadez, C, Sussams, R, Lin, H, Fairchild, T J, Benito, Y A, Holmes, C, Karamujić-Čomić, H, Frosch, M P, Thonberg, H, Maier, W, Roschupkin, G, Ghetti, B, Giedraitis, V, Kawalia, A, Li, S, Huebinger, R M, Kilander, L, Moebus, S, Hernández, I, Kamboh, M I, Brundin, R M, Turton, J, Yang, Q, Katz, M J, Concari, L, Lord, J, Beiser, A S, Keene, C D, Helisalmi, S, Kloszewska, I, Kukull, W A, Koivisto, A M, Lynch, A, Tarraga, L, Larson, E B, Haapasalo, A, Lawlor, B, Mosley, T H, Lipton, R B, Solfrizzi, V, Gill, M, Longstreth, W T, Montine, T J, Frisardi, V, Diez-Fairen, M, Rivadeneira, F, Petersen, R C, Deramecourt, V, Alvarez, I, Salani, F, Ciaramella, A, Boerwinkle, E, Reiman, E M, Fievet, N, Rotter, J I, Reisch, J S, Hanon, O, Cupidi, C, Andre Uitterlinden, A G, Royall, D R, Dufouil, C, Maletta, R G, de Rojas, I, Sano, M, Brice, A, Cecchetti, R, George-Hyslop, P S, Ritchie, K, Tsolaki, M, Tsuang, D W, Dubois, B, Craig, D, Wu, C K, Soininen, H, Avramidou, D, Albin, R L, Fratiglioni, L, Germanou, A, Apostolova, L G, Keller, L, Koutroumani, M, Arnold, S E, Panza, F, Gkatzima, O, Asthana, S, Hannequin, D, Whitehead, P, Atwood, C S, Caffarra, P, Hampel, H, Quintela, I, Carracedo, Á, Lannfelt, L, Rubinsztein, D C, Barnes, L L, Pasquier, F, Frölich, L, Barral, S, McGuinness, B, Beach, T G, Johnston, J A, Becker, J T, Passmore, P, Bigio, E H, Schott, J M, Bird, T D, Warren, J D, Boeve, B F, Lupton, M K, Bowen, J D, Proitsi, P, Boxer, A, Powell, J F, Burke, J R, Kauwe, J S K, Burns, J M, Mancuso, M, Buxbaum, J D, Bonuccelli, U, Cairns, N J, McQuillin, A, Cao, C, Livingston, G, Carlson, C S, Bass, N J, Carlsson, C M, Hardy, J, Carney, R M, Bras, J, Carrasquillo, M M, Guerreiro, R, Allen, M, Chui, H C, Fisher, E, Masullo, C, Crocco, E A, DeCarli, C, Bisceglio, G, Dick, M, Ma, L, Duara, R, Graff-Radford, N R, Evans, D A, Hodges, A, Faber, K M, Scherer, M, Fallon, K B, Riemenschneider, M, Fardo, D W, Heun, R, Farlow, M R, Kölsch, H, Ferris, S, Leber, M, Foroud, T M, Heuser, I, Galasko, D R, Giegling, I, Gearing, M, Hüll, M, Geschwind, D H, Gilbert, J R, Morris, J C, Green, R C, Mayo, K, Growdon, J H, Feulner, T, Hamilton, R L, Harrell, L E, Drichel, D, Honig, L S, Cushion, T D, Huentelman, M J, Hollingworth, P, Hulette, C M, Hyman, B T, Marshall, R, Jarvik, G P, Meggy, A, Abner, E, Menzies, G E, Jin, L W, Leonenko, G, Real, L M, Jun, G R, Baldwin, C T, Grozeva, D, Karydas, A, Russo, G, Kaye, J A, Kim, R, Jessen, F, Kowall, N W, Vellas, B, Kramer, J H, Vardy, E, LaFerla, F M, Jöckel, K H, Lah, J J, Dichgans, M, Leverenz, J B, Mann, D, Levey, A I, Pickering-Brown, S, Lieberman, A P, Klopp, N, Lunetta, K L, Wichmann, H E, Lyketsos, C G, Morgan, K, Marson, D C, Brown, K, Martiniuk, F, Medway, C, Mash, D C, Nöthen, M M, Masliah, E, Hooper, N M, McCormick, W C, Daniele, A, McCurry, S M, Bayer, A, McDavid, A N, Gallacher, J, McKee, A C, van den Bussche, H, Mesulam, M, Brayne, C, Miller, B L, Riedel-Heller, S, Miller, C A, Miller, J W, Al-Chalabi, A, Morris, J C, Shaw, C E, Myers, A J, Wiltfang, J, O’Bryant, S, Olichney, J M, Alvarez, V, Parisi, J E, Singleton, A B, Paulson, H L, Collinge, J, Perry, W R, Mead, S, Peskind, E, Cribbs, D H, Rossor, M, Pierce, A, Ryan, N S, Poon, W W, Nacmias, B, Potter, H, Sorbi, S, Quinn, J G, Sacchinelli, E, Raj, A, Spalletta, G, Raskind, M, Caltagirone, C, Bossù, P, Orfei, M D, Reisberg, B, Clarke, R, Reitz, C, Smith, A D, Ringman, J M, Warden, D, Roberson, E D, Wilcock, G, Rogaeva, E, Bruni, A C, Rosen, H J, Gallo, M, Rosenberg, R N, Ben-Shlomo, Y, Sager, M A, Mecocci, P, Saykin, A J, Pastor, P, Cuccaro, M L, Vance, J M, Schneider, J A, Schneider, L S, Slifer, S, Seeley, W W, Smith, A G, Sonnen, J A, Spina, S, Stern, R A, Swerdlow, R H, Tang, M, Tanzi, R E, Trojanowski, J Q, Troncoso, J C, Van Deerlin, V M, Van Eldik, L J, Vinters, H V, Vonsattel, J P, Weintraub, S, Welsh-Bohmer, K A, Wilhelmsen, K C, Williamson, J, Wingo, T S, Woltjer, R L, Wright, C B, Yu, C E, Yu, L, Saba, Y, Pilotto, A, Bullido, M J, Peters, O, Crane, P K, Bennett, D, Bosco, P, Coto, E, Boccardi, V, De Jager, P L, Lleo, A, Warner, N, Lopez, O L, Ingelsson, M, Deloukas, P, Cruchaga, C, Graff, C, Gwilliam, R, Fornage, M, Goate, A M, Sanchez-Juan, P, Kehoe, P G, Amin, N, Ertekin-Taner, N, Berr, C, Debette, S, Love, S, Launer, L J, Younkin, S G, Dartigues, J F, Corcoran, C, Ikram, M A, Dickson, D W, Nicolas, G, Campion, D, Tschanz, J A, Schmidt, H, Hakonarson, H, Clarimon, J, Munger, R, Schmidt, R, Farrer, L A, Van Broeckhoven, C, C. O’Donovan, M, DeStefano, A L, Jones, L, Haines, J L, Deleuze, J F, Owen, M J, Gudnason, V, Mayeux, R, Escott-Price, V, Psaty, B M, Ramirez, A, Wang, L S, Ruiz, A, van Duijn, C M, Holmans, P A, Seshadri, S, Williams, J, Amouyel, P, Schellenberg, G D, Lambert, J C & Pericak-Vance, M A 2019, ' Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing ', Nature Genetics, vol. 51, no. 3, pp. 414-430 . https://doi.org/10.1038/s41588-019-0358-2 Nature Genetics Nature Genetics, Nature Publishing Group, 2019, 51 (3), pp.414-430. ⟨10.1038/s41588-019-0358-2⟩ Nature genetics 51(3), 414-430 (2019). doi:10.1038/s41588-019-0358-2 Nature genetics |
ISSN: | 1061-4036 1546-1718 |
DOI: | 10.1038/s41588-019-0358-2 |
Popis: | Risk for late-onset Alzheimers disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimers or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimers disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 2009»10−7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education. |
Databáze: | OpenAIRE |
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