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Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

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اقرأ أكثر حفظ في قائمتي
  • معلومة اضافية
    • بيانات النشر:
      National Academy of Sciences
    • الموضوع:
      2023
    • Collection:
      Cardiff University: ORCA (Online Research @ Cardiff)
    • نبذة مختصرة :
      Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.
    • File Description:
      application/pdf
    • Relation:
      https://orca.cardiff.ac.uk/id/eprint/163289/1/le-guen-et-al-2023-multiancestry-analysis-of-the-hla-locus-in-alzheimer-s-and-parkinson-s-diseases-uncovers-a-shared.pdf; Le Guen, Yann, Luo, Guo, Ambati, Aditya, Damotte, Vincent, Jansen, Iris, Yu, Eric, Nicolas, Aude, de Rojas, Itziar, Peixoto Leal, Thiago, Miyashita, Akinori, Bellenguez, Céline, Lian, Michelle Mulan, Parveen, Kayenat, Morizono, Takashi, Park, Hyeonseul, Grenier-Boley, Benjamin, Naito, Tatsuhiko, Küçükali, Fahri, Talyansky, Seth D., Yogeshwar, Selina Maria, Sempere, Vicente, Satake, Wataru, Alvarez, Victoria, Arosio, Beatrice, Belloy, Michael E., Benussi, Luisa, Boland, Anne, Borroni, Barbara, Bullido, María J., Caffarra, Paolo, Clarimon, Jordi, Daniele, Antonio, Darling, Daniel, Debette, Stéphanie, Deleuze, Jean-François, Dichgans, Martin, Dufouil, Carole, During, Emmanuel, Düzel, Emrah, Galimberti, Daniela, Garcia-Ribas, Guillermo, García-Alberca, José María, García-González, Pablo, Giedraitis, Vilmantas, Goldhardt, Oliver, Graff, Caroline, Grünblatt, Edna, Hanon, Olivier, Hausner, Lucrezia, Heilmann-Heimbach, Stefanie, Holstege, Henne, Hort, Jakub, Jung, Yoo Jin, Jürgen, Deckert, Kern, Silke, Kuulasmaa, Teemu, Lee, Kun Ho, Lin, Ling, Masullo, Carlo, Mecocci, Patrizia, Mehrabian, Shima, de Mendonça, Alexandre, Boada, Mercè, Mir, Pablo, Moebus, Susanne, Moreno, Fermin, Nacmias, Benedetta, Nicolas, Gael, Niida, Shumpei, Nordestgaard, Børge G., Papenberg, Goran, Papma, Janne, Parnetti, Lucilla, Pasquier, Florence, Pastor, Pau, Peters, Oliver, Pijnenburg, Yolande A. 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Hardy, John, Rubinsztein, David C., Brayne, Carol, Gwilliam, Rhian, Deloukas, Panagiotis, Ben-Shlomo, Yoav, Mann, David, Hooper, Nigel M., Pickering-Brown, Stuart, Holmes, Clive, Sussams, Rebecca, Warner, Nick, Bayer, Anthony, Singleton, Andrew B., Hartmann, Annette M., Rujescu, Dan, Giegling, Ina, Hampel, Harald, Dichgans, Martin, Heuser, Isabella, Drichel, Dmitriy, Klopp, Norman, Nöthen, Markus M., Mayhaus, Manuel, Riemenschneider, Matthias, Pinchler, Sabrina, Feulner, Thomas, Gu, Wei, den Bussche, Hendrik, Scherer, Martin, Wiltfang, Jens, Kornhuber, Johannes, Hüll, Michael, Frölich, Lutz, Wichmann, H-Erich, Jöckel, Karl-Heinz, Moebus, Susanne, Riedel-Heller, Steffi, Kauwe, John, Morris, John, Mayo, Kevin, Tsolaki, Magda, O'Donovan, Michael, Jones, Lesley, Owen, Michael, Escott-Price, Valentina https://orca.cardiff.ac.uk/view/cardiffauthors/A015705M.html orcid:0000-0003-1784-5483 orcid:0000-0003-1784-5483, Ramirez, Alfredo, Holmans, Peter https://orca.cardiff.ac.uk/view/cardiffauthors/A0466487.html orcid:0000-0003-0870-9412 orcid:0000-0003-0870-9412, Williams, Julie, Foo, Jia Nee, Chew, Elaine Guo Yan, Chung, Sun Ju, Peng, Rong, Chao, Yinxia, Tan, Louis C.S., Tandiono, Moses, Lian, Michelle M., Ng, Ebonne Y., Prakash, Kumar-M., Au, Wing-Lok, Meah, Wee-Yang, Mok, Shi Qi, Annuar, Azlina Ahmad, Chan, Anne Y.Y., Chen, Ling, Chen, Yongping, Jeon, Beom S., Jiang, Lulu, Lim, Jia Lun, Lin, Juei-Jueng, Liu, Chunfeng, Mao, Chengjie, Mok, Vincent, Pei, Zhong, Shang, Hui-Fang, Shi, Chang-He, Song, Kyuyoung, Tan, Ai Huey, Wu, Yih-Ru, Xu, Yu-ming, Xu, Renshi, Yan, Yaping, Yang, Jing, Rong Zhang, Bao, Koh, Woon-Puay, Lim, Shen-Yang, Khor, Chiea Chuen, Liu, Jianjun and Tan, Eng-King 2023. Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes. Proceedings of the National Academy of Sciences 120 (36) , e2302720120. 10.1073/pnas.2302720120 https://doi.org/10.1073/pnas.2302720120 file https://orca.cardiff.ac.uk/id/eprint/163289/1/le-guen-et-al-2023-multiancestry-analysis-of-the-hla-locus-in-alzheimer-s-and-parkinson-s-diseases-uncovers-a-shared.pdf
    • الرقم المعرف:
      10.1073/pnas.2302720120
    • Rights:
      cc_by_4_0
    • الرقم المعرف:
      edsbas.9B1872A6