Медицинская библиотека · Proceedings of the National Academy of Sciences of the United States of America · 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.
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 L, Piñol-Ripoll Gerard, Popp Julius, Porcel Laura Molina, Puerta Raquel, Pérez-Tur Jordi, Rainero Innocenzo, Ramakers Inez, Real Luis M, Riedel-Heller Steffi, Rodriguez-Rodriguez Eloy, Ross Owen A, Royo Luis Jose, Rujescu Dan, Scarmeas Nikolaos, Scheltens Philip, Scherbaum Norbert, Schneider Anja, Seripa Davide, Skoog Ingmar, Solfrizzi Vincenzo, Spalletta Gianfranco, Squassina Alessio, van Swieten John, Sánchez-Valle Raquel, Tan Eng-King, Tegos Thomas, Teunissen Charlotte, Thomassen Jesper Qvist, Tremolizzo Lucio, Vyhnalek Martin, Verhey Frans, Waern Margda, Wiltfang Jens, Zhang Jing, EADB, GR@ACE study group, DEGESCO consortium, DemGene, EADI, GERAD, Asian Parkinson’s Disease Genetics consortium, Zetterberg Henrik, Blennow Kaj, He Zihuai, Williams Julie, Amouyel Philippe, Jessen Frank, Kehoe Patrick G, Andreassen Ole A, Van Duin Cornelia, Tsolaki Magda, Sánchez-Juan Pascual, Frikke-Schmidt Ruth, Sleegers Kristel, Toda Tatsushi, Zettergren Anna, Ingelsson Martin, Okada Yukinori, Rossi Giacomina, Hiltunen Mikko, Gim Jungsoo, Ozaki Kouichi, Sims Rebecca, Foo Jia Nee, van der Flier Wiesje, Ikeuchi Takeshi, Ramirez Alfredo, Mata Ignacio, Ruiz Agustín, Gan-Or Ziv, Lambert Jean-Charles, Greicius Michael D, Mignot Emmanuel
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАПеревод пока не подготовлен
Аннотация
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.
Для цитирования: 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 L, Piñol-Ripoll Gerard, Popp Julius, Porcel Laura Molina, Puerta Raquel, Pérez-Tur Jordi, Rainero Innocenzo, Ramakers Inez, Real Luis M, Riedel-Heller Steffi, Rodriguez-Rodriguez Eloy, Ross Owen A, Royo Luis Jose, Rujescu Dan, Scarmeas Nikolaos, Scheltens Philip, Scherbaum Norbert, Schneider Anja, Seripa Davide, Skoog Ingmar, Solfrizzi Vincenzo, Spalletta Gianfranco, Squassina Alessio, van Swieten John, Sánchez-Valle Raquel, Tan Eng-King, Tegos Thomas, Teunissen Charlotte, Thomassen Jesper Qvist, Tremolizzo Lucio, Vyhnalek Martin, Verhey Frans, Waern Margda, Wiltfang Jens, Zhang Jing, EADB, GR@ACE study group, DEGESCO consortium, DemGene, EADI, GERAD, Asian Parkinson’s Disease Genetics consortium, Zetterberg Henrik, Blennow Kaj, He Zihuai, Williams Julie, Amouyel Philippe, Jessen Frank, Kehoe Patrick G, Andreassen Ole A, Van Duin Cornelia, Tsolaki Magda, Sánchez-Juan Pascual, Frikke-Schmidt Ruth, Sleegers Kristel, Toda Tatsushi, Zettergren Anna, Ingelsson Martin, Okada Yukinori, Rossi Giacomina, Hiltunen Mikko, Gim Jungsoo, Ozaki Kouichi, Sims Rebecca, Foo Jia Nee, van der Flier Wiesje, Ikeuchi Takeshi, Ramirez Alfredo, Mata Ignacio, Ruiz Agustín, Gan-Or Ziv, Lambert Jean-Charles, Greicius Michael D, Mignot Emmanuel. 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 of the United States of America. 2023. DOI: 10.1073/pnas.2302720120.
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