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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
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-m...
| Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Formato: | Online Artículo Texto |
| Lenguaje: | English |
| Publicado: |
National Academy of Sciences
2023
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| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10483635/ https://www.ncbi.nlm.nih.gov/pubmed/37643212 http://dx.doi.org/10.1073/pnas.2302720120 |
| _version_ | 1785102425686802432 |
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| author | 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. Luís Royo, 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 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 |
| author_facet | 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. Luís Royo, 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 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 |
| author_sort | Le Guen, Yann |
| collection | PubMed |
| description | 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. |
| format | Online Article Text |
| id | pubmed-10483635 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2023 |
| publisher | National Academy of Sciences |
| record_format | MEDLINE/PubMed |
| spelling | pubmed-104836352023-09-08 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. Luís Royo, 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 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 Proc Natl Acad Sci U S A Biological Sciences 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. National Academy of Sciences 2023-08-29 2023-09-05 /pmc/articles/PMC10483635/ /pubmed/37643212 http://dx.doi.org/10.1073/pnas.2302720120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) . |
| spellingShingle | Biological Sciences 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. Luís Royo, 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 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 |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Biological Sciences |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10483635/ https://www.ncbi.nlm.nih.gov/pubmed/37643212 http://dx.doi.org/10.1073/pnas.2302720120 |
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